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Drs. Hope Rugo, Sheri Brenner, and Mikolaj Slawkowski-Rode discuss the struggle that health care professionals experience when terminally ill patients are suffering and approaches to help clinicians understand and respond to suffering in a more patient-centered and therapeutic way. TRANSCRIPT Dr. Hope Rugo: Hello, and welcome to By the Book, a monthly podcast series from ASCO that features engaging conversations between editors and authors of the ASCO Educational Book.  I'm your host, Dr. Hope Rugo. I'm director of the Women's Cancers Program and division chief of breast medical oncology at the City of Hope Cancer Center, and I'm also the editor-in-chief of the Educational Book. On today's episode, we'll be exploring the complexities of grief and oncology and the struggle we experience as healthcare professionals when terminally ill patients are suffering. Our guests will discuss approaches to help clinicians understand and respond to suffering in a more patient-centered and therapeutic way, as outlined in their recently published article titled, “Oncology and Suffering: Strategies on Coping With Grief for Healthcare Professionals.” I'm delighted today to welcome Dr. Keri Brenner, a clinical associate professor of medicine, palliative care attending, and psychiatrist at Stanford University, and Dr. Mikołaj Sławkowski-Rode, a senior research fellow in philosophy in the Humanities Research Institute at the University of Buckingham, where he also serves as director of graduate research in p hilosophy. He is also a research fellow in philosophy at Blackfriars Hall at the University of Oxford and associate professor at the University of Warsaw.  Our full disclosures are available in the transcript of this episode. Dr. Brenner and Dr. Sławkowski-Rode, thanks for being on the podcast today. Dr. Keri Brenner: Great to be here, Dr. Rugo. Thank you so much for that kind introduction. Dr. Mikołaj Sławkowski-Rode: Thank you very much, Dr. Rugo. It's a pleasure and an honor. Dr. Hope Rugo: So I'm going to start with some questions for both of you. I'll start with Dr. Brenner. You've spoken and written about the concept of suffering when there is no cure. For oncologists, what does it mean to attune to suffering, not just disease? And how might this impact the way they show up in difficult conversations with patients? Dr. Keri Brenner: Suffering is something that's so omnipresent in the work of clinical oncology, and I like to begin by just thinking about what is suffering, because it's a word that we use so commonly, and yet, it's important to know what we're talking about. I think about the definition of Eric Cassell, who was a beloved mentor of mine for decades, and he defined suffering as the state of severe distress that's associated with events that threaten the intactness of a person. And my colleague here at Stanford, Tyler Tate, has been working on a definition of suffering that encompasses the experience of a gap between how things are versus how things ought to be. Both of these definitions really touch upon suffering in a person-centered way that's relational about one's identity, meaning, autonomy, and connectedness with others. So these definitions alone remind us that suffering calls for a person-centered response, not the patient as a pathology, but the panoramic view of who the patient is as a person and their lived reality of illness. And in this light, the therapeutic alliance becomes one of our most active ingredients in care. The therapeutic alliance is that collaborative, trusting bond as persons that we have between clinician and patient, and it's actually one of the most powerful predictors of meaningful outcomes in our care, especially in oncologic care.  You know, I'll never forget my first day of internship at Massachusetts General Hospital. A faculty lecturer shared this really sage insight with us that left this indelible mark. She shared, “As physicians and healers, your very self is the primary instrument of healing. Our being is the median of the medicine.” So, our very selves as embodied, relationally grounded people, that's the median of the medicine and the first most enduring medicine that we offer. That has really borne fruit in the evidence that we see around the therapeutic alliance. And we see this in oncologic care, that in advanced cancer, a strong alliance with one's oncologist truly improves a patient's quality of life, treatment adherence, emotional well-being, and even surpasses structured interventions like psychotherapeutic interventions. Dr. Hope Rugo: That's just incredibly helpful information and actually terminology as well, and I think the concept of suffering differs so much. Suffering comes in many shapes and forms, and I think you really have highlighted that. But many oncologists struggle with knowing what to do when patients are suffering but can't be fixed, and I think a lot of times that has to do with oncologists when patients have pain or shortness of breath or issues like that. There are obviously many ways people suffer. But I think what's really challenging is how clinicians understand suffering and what the best approaches to respond to suffering are in the best patient-centered and therapeutic way. Dr. Keri Brenner: I get that question a lot from my trainees in palliative care, not knowing what to do. And my first response is, this is about how to be, not about knowing what to do, but how to be. In our medical training, we're trained often how to think and treat, but rarely how to be, how to accompany others. And I often have this image that I tell my trainees of, instead of this hierarchical approach of a fix-it mentality of all we're going to do, when it comes to elements of unavoidable loss, mortality, unavoidable sufferings, I imagine something more like accompaniment, a patient walking through some dark caverns, and I am accompanying them, trying to walk beside them, shining a light as a guide throughout that darkness. So it's a spirit of being and walking with. And it's so tempting in medicine to either avoid the suffering altogether or potentially overidentify with it, where the suffering just becomes so all-consuming like it's our own. And we're taught to instead strike a balance of authentic accompaniment through it. I often teach this key concept in my palli-psych work with my team about formulation. Formulation is a working hypothesis. It's taking a step back and asking, “Why? Why is this patient behaving in this manner? What might the patient's core inner struggle be?” Because asking that “why” and understanding the nuanced dimensions of a patient's core inner struggle will really help guide our therapeutic interactions and guide the way that we accompany them and where we choose to shine that light as we're walking with them. And oftentimes people think, “Well Keri, that sounds so sappy or oversentimental,” and it's not. You know, I'm just thinking about a case that I had a couple months ago, and it was a 28-year-old man with gastric cancer, metastatic disease, and that 28-year-old man, he was actually a college Division I athlete, and his dad was an acclaimed Division I coach. And our typical open-ended palliative care questions, that approach, infuriated them. They needed to know that I was showing up confident, competent, and that I was ready, on my A-game, with a real plan for them to follow through. And so my formulation about them was they needed somebody to show up with that confidence and competence, like the Division I athletes that they were, to really meet them and accompany them where they were on how they were going to walk through that experience of illness. Dr. Hope Rugo: These kinds of insights are so helpful to think about how we manage something that we face every day in oncology care. And I think that there are many ways to manage this.  Maybe I'll ask Dr. Sławkowski-Rode one question just that I think sequences nicely with what you're talking about.  A lot of our patients are trying to think about sort of the bigger picture and how that might help clinicians understand and support patients. So, the whole concept of spirituality, you know, how can we really use that as oncology clinicians to better understand and support patients with advanced illness, and how can that help patients themselves? And we'll talk about that in two different ways, but we'll just start with this broader question. Dr. Mikołaj Sławkowski-Rode: I think spirituality, and here, I usually refer to spirituality in terms of religious belief. Most people in the world are religious believers, and it is very intuitive and natural that religious beliefs would be a resource that people who help patients with a terminal diagnosis and healthcare professionals who work with those patients appeal to when they try to help them deal with the trauma and the stress of these situations.  Now, I think that the interesting thing there is that very often the benefit of appealing to a religious belief is misunderstood in terms of what it delivers. And there are many, many studies on how religious belief can be used to support therapy and to support patients in getting through the experience of suffering and defeating cancer or facing a terminal diagnosis. There's a wealth of literature on this. But most of the literature focuses on this idea that by appealing to religious belief, we help patients and healthcare practitioners who are working with them get over the fact and that there's a terminal diagnosis determining the course of someone's life and get on with our lives and engaging with whatever other pursuits we might have, with our job if we're healthcare practitioners, and with the other things that we might be passionate about in our lives. And the idea here is that this is what religion allows us to do because we sort of defer the need to worry about what's going to happen to us until the afterlife or some perspective beyond the horizon of our life here.  However, my view is – I have worked beyond philosophy also with theologians from many traditions, and my view here is that religion is something that does allow us to get on with our life but not because we're able to move on or move past the concerns that are being threatened by illness or death, but by forming stronger bonds with these things that we value in our life in a way and to have a sense of hope that these will be things that we will be able to keep an attachment to despite the threat to our life. So, in a sense, I think very many approaches in the field have the benefit of religion upside down, as it were, when it comes to helping patients and healthcare professionals who are engaged with their illness and treating it. Dr. Hope Rugo: You know, it's really interesting the points that you make, and I think really important, but, you know, sometimes the oncologists are really struggling with their own emotional reactions, how they are reacting to patients, and dealing with sort of taking on the burden, which, Dr. Brenner, you were mentioning earlier. How can oncologists be aware of their own emotional reactions? You know, they're struggling with this patient who they're very attached to who's dying or whatever the situation is, but you want to avoid burnout as an oncologist but also understand the patient's inner world and support them. Dr. Keri Brenner: I believe that these affective, emotional states, they're contagious. As we accompany patients through these tragic losses, it's very normal and expected that we ourselves will experience that full range of the human experience as we accompany the patients. And so the more that we can recognize that this is a normative dimension of our work, to have a nonjudgmental stance about the whole panoramic set of emotions that we'll experience as we accompany patients with curiosity and openness about that, the more sustainable the work will become. And I often think about the concept of countertransference given to us by Sigmund Freud over 100 years ago. Countertransference is the clinician's response to the patient, the thoughts, feelings, associations that come up within us, shaped by our own history, our own life events, those unconscious processes that come to the foreground as we are accompanying patients with illness. And that is a natural part of the human experience. Historically, countertransference was viewed as something negative, and now it's actually seen as a key that can unlock and enlighten the formulation about what might be going on within the patient themselves even. You know, I was with a patient a couple weeks ago, and I found myself feeling pretty helpless and hopeless in the encounter as I was trying to care for them. And I recognized that countertransference within myself that I was feeling demoralized. It was a prompt for me to take a step back, get on the balcony, and be curious about that because I normally don't feel helpless and hopeless caring for my patients. Well, ultimately, I discovered through processing it with my interdisciplinary team that the patient likely had demoralization as a clinical syndrome, and so it's natural many of us were feeling helpless and hopeless also accompanying them with their care. And it allowed us to have a greater interdisciplinary approach and a more therapeutic response and deeper empathy for the patient's plight. And we can really be curious about our countertransferences. You know, a few months ago, I was feeling bored and distracted in a family meeting, which is quite atypical for me when I'm sharing serious illness news. And it was actually a key that allowed me to recognize that the patient was trying to distract all of us talking about inconsequential facts and details rather than the gravitas of her illness.  Being curious about these affective states really allows us to have greater sustainability within our own practice because it normalizes that human spectrum of emotions and also allows us to reduce unconscious bias and have greater inclusivity with our practice because what Freud also said is that what we can't recognize and say within our own selves, if we don't have that self-reflective capacity, it will come out in what we do. So really recognizing and having the self-awareness and naming some of these emotions with trusted colleagues or even within our own selves allows us to ensure that it doesn't come out in aberrant behaviors like avoiding the patient, staving off that patient till the end of the day, or overtreating, offering more chemotherapy or not having the goals of care, doing everything possible when we know that that might result in medically ineffective care. Dr. Hope Rugo: Yeah, I love the comments that you made, sort of weaving in Freud, but also, I think the importance of talking to colleagues and to sharing some of these issues because I do think that oncologists suffer from the fact that no one else in your life wants to hear about dying people. They don't really want to hear about the tragic cases either. So, I think that using your community, your oncology community and greater community within medicine, is an important part of being able to sort of process. Dr. Keri Brenner: Yes, and Dr. Rugo, this came up in our ASCO [Education] Session. I'd love to double click into some of those ways that we can do this that aren't too time consuming in our everyday practice. You know, within palliative care, we have interdisciplinary rounds where we process complex cases. Some of us do case supervision with a trusted mentor or colleague where we bring complex cases to them. My team and I offer process rounds virtually where we go through countertransference, formulation, and therapeutic responses on some tough cases.  You know, on a personal note, just last week when I left a family meeting feeling really depleted and stuck, I called one of my trusted colleagues and just for 3 minutes constructively, sort of cathartically vented what was coming up within me after that family meeting, which allowed me to have more of an enlightened stance on what to do next and how to be therapeutically helpful for the case. One of my colleagues calls this "friend-tors." They coined the phrase, and they actually wrote a paper about it. Who within your peer group of trusted colleagues can you utilize and phone in real time or have process opportunities with to get a pulse check on where what's coming up within us as we're doing this work? Dr. Hope Rugo: Yeah, and it's an interesting question about how one does that and, you know, maintaining that as you move institutions or change places or become more senior, it's really important.  One of the, I think, the challenges sometimes is that we come from different places from our patients, and that can be an issue, I think when our patients are very religious and the provider is not, or the reverse, patients who don't have religious beliefs and you're trying to sort of focus on the spirituality, but it doesn't really ring true. So, Dr. Sławkowski-Rode, what resources can patients and practitioners draw on when they're facing death and loss in the absence of, or just different religious beliefs that don't fit into the standard model? Dr. Mikołaj Sławkowski-Rode: You're absolutely right that this can be an extremely problematic situation to be in when there is that disconnect of religious belief or more generally spiritual engagement with the situation that we're in. But I just wanted to tie into what Dr. Brenner was saying just before. I couldn't agree more, and I think that a lot of healthcare practitioners, oncologists in particular who I've had the pleasure to talk to at ASCO and at other events as well, are very often quite skeptical about emotional engagement in their profession. They feel as though this is something to be managed, as it were, and something that gets in the way. And they can often be very critical of methods that help them understand the emotions and extend them towards patients because they feel that this will be an obstacle to doing their job and potentially an obstacle also to helping patients to their full ability if they focus on their own emotions or the burden that emotionally, spiritually, and in other ways the illness is for the patient. They feel that they should be focusing on the cancer rather than on the patient's emotions. And I think that a useful comparison, although, you know, perhaps slightly drastic, is that of combat experience of soldiers. They also need to be up and running and can't be too emotionally invested in the situation that they're in. But there's a crucial difference, which is that soldiers are usually engaged in very short bursts of activity with the time to go back and rethink, and they often have a lot of support for this in between. Whereas doctors are in a profession where their exposure to the emotions of patients and their own emotions, the emotions of families of patients is constant. And I think that there's a great danger in thinking that this is something to be avoided and something to compartmentalize in order to avoid burnout. I think, in a way, burnout is more sure to happen if your emotions and your attachment to your patients goes ignored for too long. So that's just following up on Keri's absolutely excellent points. As far as the disconnect is concerned, that's, in fact, an area in which I'm particularly interested in. That's where my research comes in. I'm interested in the kinds of connections that we have with other people, especially in terms of maintaining bonds when there is no spiritual belief, no spiritual backdrop to support this connection. In most religious traditions, we have the framework of the religious belief that tells us that the person who we've lost or the values that have become undermined in our life are something that hasn't been destroyed permanently but something that we can still believe we have a deep connection to despite its absence from our life. And how do you rebuild that sense of the existence of the things that you have perceivably lost without the appeal to some sort of transcendent realm which is defined by a given religion? And that is a hard question. That's a question, I think, that can be answered partly by psychology but also partly by philosophy in terms of looking at who we are as human beings and our nature as people who are essentially, or as entities that are essentially connected to one another. That connection, I believe, is more direct than the mediation of religion might at first suggest. I think that we essentially share the world not only physically, it's not just the case that we're all here, but more importantly, the world that we live in is not just the physical world but the world of meanings and values that helps us orient ourselves in society and amongst one another as friends and foes. And it is that shared sense of the world that we can appeal to when we're thinking about retaining the value or retaining the connection with the people who we have lost or the people who are helping through, go through an experience of facing death. And just to finish, there's a very interesting question, I think, something that we possibly don't have time to explore, about the degree of connection that we have with other people. So, what I've just been saying is something that rings more true or is more intuitive when we think about the connections that we have to our closest ones. We share a similar outlook onto the world, and our preferences and our moods and our emotions and our values are shaped by life with the other person. And so, appealing to these values can give us a sense of a continued presence. But what in those relationships where the connection isn't that close? For example, given the topic of this podcast, the connection that a patient has with their doctor and vice versa. In what sense can we talk about a shared world of experience? Well, I think, obviously, we should admit degrees to the kind of relationship that can sustain our connection with another person. But at the same time, I don't think there's a clear cutoff point. And I think part of emotional engagement in medical practice is finding yourself somewhere on that spectrum rather than thinking you're completely off of it. That's what I would say. Dr. Hope Rugo: That's very helpful and I think a very helpful way of thinking about how to manage this challenging situation for all of us.  One of the things that really, I think, is a big question for all of us throughout our careers, is when to address the dying process and how to do that. Dr. Brenner, you know, I still struggle with this – what to do when patients refuse to discuss end-of-life but they're very close to end of life? They don't want to talk about it. It's very stressful for all of us, even where you're going to be, how you're going to manage this. They're just absolutely opposed to that discussion. How should we approach those kinds of discussions? How do we manage that? How do you address the code discussion, which is so important? You know, these patients are not able to stay at home at end-of-life in general, so you really do need to have a code discussion before you're admitting them. It actually ends up being kind of a challenge and a mess all around. You know, I would love your advice about how to manage those situations. Dr. Keri Brenner: I think that's one of the most piercing and relevant inquiries we have within our clinical work and challenges. I often think of denial not as an all-or-nothing concept but rather as parts of self. There's a part of everyone's being where the unconscious believes it's immortal and will live on forever, and yet we all know intellectually that we all have mortality and finitude and transience, and that time will end. We often think of this work as more iterative and gradual and exposure based. There's potency to words. Saying, “You are dying within days,” is a lot higher potency of a phrase to share than, “This is serious illness. This illness is incurable. Time might be shorter than we hoped.” And so the earlier and more upstream we begin to have these conversations, even in small, subtle ways, it starts to begin to expose the patient to the concept so they can go from the head to the heart, not only knowing their prognosis intellectually but also affectively, to integrate it into who they are as a person because all patients are trying to live well while also we're gradually exposing them to this awareness of mortality within their own lived experience of illness. And that, ideally, happens gradually over time. Now, there are moments where the medical frame is very limited, and we might have short days, and we have to uptitrate those words and really accompany them more radically through those high-affective moments. And that's when we have to take a lot of more nuanced approaches, but I would say the more earlier and upstream the better. And then the second piece to that question as well is coping with our own mortality. The more we can be comfortable with our own transience and finitude and limitations, the more we will be able to accompany others through that. And even within my own life, I've had to integrate losses in a way where before I go in to talk to one of my own palliative care patients, one mantra I often say to myself is, “I'm just a few steps behind you. I don't know if it's going to be 30 days or 30 years, but I'm just a few steps behind you on this finite, transient road of life that is the human experience.” And that creates a stance of accompaniment that patients really can experience as they're traversing these tragedies. Dr. Hope Rugo: That's great. And I think those are really important points and actually some pearls, which I think we can take into the clinic. I think being really concrete when really the expected life expectancy is a few days to a couple of weeks can be very, very helpful. And making sure the patients hear you, but also continuing to let them know that, as oncologists, we're here for them. We're not abandoning them. I think that's a big worry for many, certainly of my patients, is that somehow when they would go to hospice or be a ‘no code', that we're not going to support them anymore or treat them anymore. That is a really important process of that as well. And of course, engaging the team makes a big difference because the whole oncology team can help to manage situations that are particularly challenging like that. And just as we close, I wanted to ask one last question of you, Dr. Brenner, that suffering, grief, and burnout, you've really made the point that these are not problems to fix but dimensions that we want to attend to and acknowledge as part of our lives, the dying process is part of all of our lives. It's just dealing with this in the unexpected and the, I think, unpredictability of life, you know, that people take on a lot of guilt and all sorts of things about, all sorts of emotions. And the question is now, people have listened to this podcast, what can they take back to their oncology teams to build a culture that supports clinicians and their team at large to engage with these realities in a meaningful and sustainable way? I really feel like if we could build the whole team approach where we're supporting each other and supporting the patients together, that that will help this process immeasurably. Dr. Keri Brenner: Yes, and I'm thinking about Dr. Sławkowski-Rode's observation about the combat analogy, and it made me recognize this distinction between suppression and repression. Repression is this unconscious process, and this is what we're taught to do in medical training all the time, to just involuntarily shove that tragedy under the rug, just forget about it and see the next patient and move on. And we know that if we keep unconsciously shoving things under the rug, that it will lead to burnout and lack of sustainability for our clinical teams. Suppression is a more conscious process. That deliberate effort to say, “This was a tragedy that I bore witness to. I know I need to put that in a box on the shelf for now because I have 10 other patients I have to see.” And yet, do I work in a culture where I can take that off the shelf during particular moments and process it with my interdisciplinary team, phone a friend, talk to a trusted colleague, have some trusted case supervision around it, or process rounds around it, talk to my social worker? And I think the more that we model this type of self-reflective capacity as attendings, folks who have been in the field for decades, the more we create that ethos and culture that is sustainable because clinician self-reflection is never a weakness, rather it's a silent strength. Clinician self-reflection is this portal for wisdom, connectedness, sustainability, and ultimately transformative growth within ourselves. Dr. Hope Rugo: That's such a great point, and I think this whole discussion has been so helpful for me and I hope for our audience that we really can take these points and bring them to our practice. I think, “Wow, this is such a great conversation. I'd like to have the team as a whole listen to this as ways to sort of strategize talking about the process, our patients, and being supportive as a team, understanding how we manage spirituality when it connects and when it doesn't.” All of these points, they're bringing in how we process these issues and the whole idea of suppressing versus sort of deciding that it never happened at all is, I think, very important because that's just a tool for managing our daily lives, our busy clinics, and everything we manage. Dr. Keri Brenner: And Dr. Rugo, it's reminding me at Stanford, you know, we have this weekly practice that's just a ritual where every Friday morning for 30 minutes, our social worker leads a process rounds with us as a team, where we talk about how the work that we're doing clinically is affecting us in our lives in ways that have joy and greater meaning and connectedness and other ways that might be depleting. And that kind of authentic vulnerability with one another allows us to show up more authentically for our patients. So those rituals, that small 30 minutes once a week, goes a long way. And it reminds me that sometimes slowing things down with those rituals can really get us to more meaningful, transformative places ultimately. Dr. Hope Rugo: It's a great idea, and I think, you know, making time for that in everybody's busy days where they just don't have any time anymore is important. And you don't have to do it weekly, you could even do something monthly. I think there's a lot of options, and that's a great suggestion. I want to thank you both for taking your time out for this enriching and incredibly helpful conversation. Our listeners will find a link to the Ed Book article we discussed today, which is excellent, in the transcript of this episode. I want to thank you again, Dr. Brenner and Dr. Sławkowski-Rode, for your time and for your excellent thoughts and advice and direction. Dr. Mikołaj Sławkowski-Rode: Thank you very much, Dr. Rugo. Dr. Keri Brenner: Thank you. Dr. Hope Rugo: And thanks to our listeners for joining us today. Please join us again next month on By the Book for more insightful views on topics you'll be hearing at the education sessions from ASCO meetings and our deep dives on new approaches that are shaping modern oncology. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers:      Dr. Hope Rugo @hope.rugo Dr. Keri Brenner @keri_brenner Dr. Mikolaj Slawkowski-Rode @MikolajRode Follow ASCO on social media:      @ASCO on X (formerly Twitter)      ASCO on Bluesky     ASCO on Facebook      ASCO on LinkedIn      Disclosures:     Dr. Hope Rugo: Honoraria: Mylan/Viatris, Chugai Pharma Consulting/Advisory Role: Napo Pharmaceuticals, Sanofi, Bristol Myer Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Merck, Daiichi Sankyo, AstraZeneca, Gilead Sciences, Hoffman La-Roche AG/Genentech, In., Stemline Therapeutics, Ambryx Dr. Keri Brenner: No relationships to disclose Dr. Mikolaj Slawkowski-Rode: No relationships to disclose    

Dr. Paul Hanona and Dr. Arturo Loaiza-Bonilla discuss how to safely and smartly integrate AI into the clinical workflow and tap its potential to improve patient-centered care, drug development, and access to clinical trials. TRANSCRIPT Dr. Paul Hanona: Hello, I'm Dr. Paul Hanona, your guest host of the ASCO Daily News Podcast today. I am a medical oncologist as well as a content creator @DoctorDiscover, and I'm delighted to be joined today by Dr. Arturo Loaiza-Bonilla, the chief of hematology and oncology at St. Luke's University Health Network. Dr. Bonilla is also the co-founder and chief medical officer at Massive Bio, an AI-driven platform that matches patients with clinical trials and novel therapies. Dr. Loaiza-Bonilla will share his unique perspective on the potential of artificial intelligence to advance precision oncology, especially through clinical trials and research, and other key advancements in AI that are transforming the oncology field. Our full disclosures are available in the transcript of the episode. Dr. Bonilla, it's great to be speaking with you today. Thanks for being here. Dr. Arturo Loaiza-Bonilla: Oh, thank you so much, Dr. Hanona. Paul, it's always great to have a conversation. Looking forward to a great one today. Dr. Paul Hanona: Absolutely. Let's just jump right into it. Let's talk about the way that we see AI being embedded in our clinical workflow as oncologists. What are some practical ways to use AI? Dr. Arturo Loaiza-Bonilla: To me, responsible AI integration in oncology is one of those that's focused on one principle to me, which is clinical purpose is first, instead of the algorithm or whatever technology we're going to be using. If we look at the best models in the world, they're really irrelevant unless we really solve a real day-to-day challenge, either when we're talking to patients in the clinic or in the infusion chair or making decision support. Currently, what I'm doing the most is focusing on solutions that are saving us time to be more productive and spend more time with our patients. So, for example, we're using ambient AI for appropriate documentation in real time with our patients. We're leveraging certain tools to assess for potential admission or readmission of patients who have certain conditions as well. And it's all about combining the listening of physicians like ourselves who are end users, those who create those algorithms, data scientists, and patient advocates, and even regulators, before they even write any single line of code. I felt that on my own, you know, entrepreneurial aspects, but I think it's an ethos that we should all follow. And I think that AI shouldn't be just bolted on later. We always have to look at workflows and try to look, for example, at clinical trial matching, which is something I'm very passionate about. We need to make sure that first, it's easier to access for patients, that oncologists like myself can go into the interface and be able to pull the data in real time when you really need it, and you don't get all this fatigue alerts. To me, that's the responsible way of doing so. Those are like the opportunities, right? So, the challenge is how we can make this happen in a meaningful way – we're just not reacting to like a black box suggestion or something that we have no idea why it came up to be. So, in terms of success – and I can tell you probably two stories of things that we know we're seeing successful – we all work closely with radiation oncologists, right? So, there are now these tools, for example, of automated contouring in radiation oncology, and some of these solutions were brought up in different meetings, including the last ASCO meeting. But overall, we know that transformer-based segmentation tools; transformer is just the specific architecture of the machine learning algorithm that has been able to dramatically reduce the time for colleagues to spend allotting targets for radiation oncology. So, comparing the target versus the normal tissue, which sometimes it takes many hours, now we can optimize things over 60%, sometimes even in minutes. So, this is not just responsible, but it's also an efficiency win, it's a precision win, and we're using it to adapt even mid-course in response to tumor shrinkage. Another success that I think is relevant is, for example, on the clinical trial matching side. We've been working on that and, you know, I don't want to preach to the choir here, but having the ability for us to structure data in real time using these tools, being able to extract information on biomarkers, and then show that multi-agentic AI is superior to what we call zero-shot or just throwing it into ChatGPT or any other algorithm, but using the same tools but just fine-tuned to the point that we can be very efficient and actually reliable to the level of almost like a research coordinator, is not just theory. Now, it can change lives because we can get patients enrolled in clinical trials and be activated in different places wherever the patient may be. I know it's like a long answer on that, but, you know, as we talk about responsible AI, that's important. And in terms of what keeps me up at night on this: data drift and biases, right? So, imaging protocols, all these things change, the lab switch between different vendors, or a patient has issues with new emerging data points. And health systems serve vastly different populations. So, if our models are trained in one context and deployed in another, then the output can be really inaccurate. So, the idea is to become a collaborative approach where we can use federated learning and patient-centricity so we can be much more efficient in developing those models that account for all the populations, and any retraining that is used based on data can be diverse enough that it represents all of us and we can be treated in a very good, appropriate way. So, if a clinician doesn't understand why a recommendation is made, as you probably know, you probably don't trust it, and we shouldn't expect them to. So, I think this is the next wave of the future. We need to make sure that we account for all those things. Dr. Paul Hanona: Absolutely. And even the part about the clinical trials, I want to dive a little bit more into in a few questions. I just kind of wanted to make a quick comment. Like you said, some of the prevalent things that I see are the ambient scribes. It seems like that's really taken off in the last year, and it seems like it's improving at a pretty dramatic speed as well. I wonder how quickly that'll get adopted by the majority of physicians or practitioners in general throughout the country. And you also mentioned things with AI tools regarding helping regulators move things quicker, even the radiation oncologist, helping them in their workflow with contouring and what else they might have to do. And again, the clinical trials thing will be quite interesting to get into. The first question I had subsequent to that is just more so when you have large datasets. And this pertains to two things: the paper that you published recently regarding different ways to use AI in the space of oncology referred to drug development, the way that we look at how we design drugs, specifically anticancer drugs, is pretty cumbersome. The steps that you have to take to design something, to make sure that one chemical will fit into the right chemical or the structure of the molecule, that takes a lot of time to tinker with. What are your thoughts on AI tools to help accelerate drug development? Dr. Arturo Loaiza-Bonilla: Yes, that's the Holy Grail and something that I feel we should dedicate as much time and effort as possible because it relies on multimodality. It cannot be solved by just looking at patient histories. It cannot be solved by just looking at the tissue alone. It's combining all these different datasets and being able to understand the microenvironment, the patient condition and prior treatments, and how dynamic changes that we do through interventions and also exposome – the things that happen outside of the patient's own control – can be leveraged to determine like what's the best next step in terms of drugs. So, the ones that we heard the news the most is, for example, the Nobel Prize-winning [for Chemistry awarded to Demis Hassabis and John Jumper for] AlphaFold, an AI system that predicts protein structures right? So, we solved this very interesting concept of protein folding where, in the past, it would take the history of the known universe, basically – what's called the Levinthal's paradox – to be able to just predict on amino acid structure alone or the sequence alone, the way that three-dimensionally the proteins will fold. So, with that problem being solved and the Nobel Prize being won, the next step is, “Okay, now we know how this protein is there and just by sequence, how can we really understand any new drug that can be used as a candidate and leverage all the data that has been done for many years of testing against a specific protein or a specific gene or knockouts and what not?” So, this is the future of oncology and where we're probably seeing a lot of investments on that. The key challenge here is mostly working on the side of not just looking at pathology, but leveraging this digital pathology with whole slide imaging and identifying the microenvironment of that specific tissue. There's a number of efforts currently being done. One isn't just H&E, like hematoxylin and eosin, slides alone, but with whole imaging, now we can use expression profiles, spatial transcriptomics, and gene whole exome sequencing in the same space and use this transformer technology in a multimodality approach that we know already the slide or the pathology, but can we use that to understand, like, if I knock out this gene, how is the microenvironment going to change to see if an immunotherapy may work better, right? If we can make a microenvironment more reactive towards a cytotoxic T cell profile, for example. So, that is the way where we're really seeing the field moving forward, using multimodality for drug discovery. So, the FDA now seems to be very eager to support those initiatives, so that's of course welcome. And now the key thing is the investment to do this in a meaningful way so we can see those candidates that we're seeing from different companies now being leveraged for rare disease, for things that are going to be almost impossible to collect enough data, and make it efficient by using these algorithms that sometimes, just with multiple masking – basically, what they do is they mask all the features and force the algorithm to find solutions based on the specific inputs or prompts we're doing. So, I'm very excited about that, and I think we're going to be seeing that in the future. Dr. Paul Hanona: So, essentially, in a nutshell, we're saying we have the cancer, which is maybe a dandelion in a field of grass, and we want to see the grass that's surrounding the dandelion, which is the pathology slides. The problem is, to the human eye, it's almost impossible to look at every single piece of grass that's surrounding the dandelion. And so, with tools like AI, we can greatly accelerate our study of the microenvironment or the grass that's surrounding the dandelion and better tailor therapy, come up with therapy. Otherwise, like you said, to truly generate a drug, this would take years and years. We just don't have the throughput to get to answers like that unless we have something like AI to help us. Dr. Arturo Loaiza-Bonilla: Correct. Dr. Paul Hanona: And then, clinical trials. Now, this is an interesting conversation because if you ever look up our national guidelines as oncologists, there's always a mention of, if treatment fails, consider clinical trials. Or in the really aggressive cancers, sometimes you might just start out with clinical trials. You don't even give the standard first-line therapy because of how ineffective it is. There are a few issues with clinical trials that people might not be aware of, but the fact that the majority of patients who should be on clinical trials are never given the chance to be on clinical trials, whether that's because of proximity, right, they might live somewhere that's far from the institution, or for whatever reason, they don't qualify for the clinical trial, they don't meet the strict inclusion criteria.  But a reason you mentioned early on is that it's simply impossible for someone to be aware of every single clinical trial that's out there. And then even if you are aware of those clinical trials, to actually find the sites and put in the time could take hours. And so, how is AI going to revolutionize that? Because in my mind, it's not that we're inventing a new tool. Clinical trials have always been available. We just can't access them. So, if we have a tool that helps with access, wouldn't that be huge? Dr. Arturo Loaiza-Bonilla: Correct. And that has been one of my passions. And for those who know me and follow me and we've spoke about it in different settings, that's something that I think we can solve. This other paradox, which is the clinical trial enrollment paradox, right? We have tens of thousands of clinical trials available with millions of patients eager to learn about trials, but we don't enroll enough and many trials close to accrual because of lack of enrollment. It is completely paradoxical and it's because of that misalignment because patients don't know where to go for trials and sites don't know what patients they can help because they haven't reached their doors yet. So, the solution has to be patient-centric, right? We have to put the patient at the center of the equation. And that was precisely what we had been discussing during the ASCO meeting. There was an ASCO Education Session where we talked about digital prescreening hubs, where we, in a patient-centric manner, the same way we look for Uber, Instacart, any solution that you may think of that you want something that can be leveraged in real time, we can use these real-world data streams from the patient directly, from hospitals, from pathology labs, from genomics companies, to continuously screen patients who can match to the inclusion/exclusion criteria of unique trials. So, when the patient walks into the clinic, the system already knows if there's a trial and alerts the site proactively. The patient can actually also do decentralization. So, there's a number of decentralized clinical trial solutions that are using what I call the “click and mortar” approach, which is basically the patient is checking digitally and then goes to the site to activate. We can also have the click and mortar in the bidirectional way where the patient is engaged in person and then you give the solution like the ones that are being offered on things that we're doing at Massive Bio and beyond, which is having the patient to access all that information and then they make decisions and enroll when the time is right.  As I mentioned earlier, there is this concept drift where clinical trials open and close, the patient line of therapy changes, new approvals come in and out, and sites may not be available at a given time but may be later. So, having that real-time alerts using tools that are able already to extract data from summarization that we already have in different settings and doing this natural language ingestion, we can not only solve this issue with manual chart review, which is extremely cumbersome and takes forever and takes to a lot of one-time assessments with very high screen failures, to a real-time dynamic approach where the patient, as they get closer to that eligibility criteria, they get engaged. And those tools can be built to activate trials, audit trials, and make them better and accessible to patients. And something that we know is, for example, 91%-plus of Americans live close to either a pharmacy or an imaging center. So, imagine that we can potentially activate certain of those trials in those locations. So, there's a number of pharmacies, special pharmacies, Walgreens, and sometimes CVS trying to do some of those efforts. So, I think the sky's the limit in terms of us working together. And we've been talking with corporate groups, they're all interested in those efforts as well, to getting patients digitally enabled and then activate the same way we activate the NCTN network of the corporate groups, that are almost just-in-time. You can activate a trial the patient is eligible for and we get all these breakthroughs from the NIH and NCI, just activate it in my site within a week or so, as long as we have the understanding of the protocol. So, using clinical trial matching in a digitally enabled way and then activate in that same fashion, but not only for NCTN studies, but all the studies that we have available will be the key of the future through those prescreening hubs. So, I think now we're at this very important time where collaboration is the important part and having this silo-breaking approach with interoperability where we can leverage data from any data source and from any electronic medical records and whatnot is going to be essential for us to move forward because now we have the tools to do so with our phones, with our interests, and with the multiple clinical trials that are coming into the pipelines. Dr. Paul Hanona: I just want to point out that the way you described the process involves several variables that practitioners often don't think about. We don't realize the 15 steps that are happening in the background. But just as a clarifier, how much time is it taking now to get one patient enrolled on a clinical trial? Is it on the order of maybe 5 to 10 hours for one patient by the time the manual chart review happens, by the time the matching happens, the calls go out, the sign-up, all this? And how much time do you think a tool that could match those trials quicker and get you enrolled quicker could save? Would it be maybe an hour instead of 15 hours? What's your thought process on that? Dr. Arturo Loaiza-Bonilla: Yeah, exactly. So one is the matching, the other one is the enrollment, which, as you mentioned, is very important. So, it can take, from, as you said, probably between 4 days to sometimes 30 days. Sometimes that's how long it takes for all the things to be parsed out in terms of logistics and things that could be done now agentically. So, we can use agents to solve those different steps that may take multiple individuals. We can just do it as a supply chain approach where all those different steps can be done by a single agent in a simultaneous fashion and then we can get things much faster. With an AI-based solution using these frontier models and multi-agentic AI – and we presented some of this data in ASCO as well – you can do 5,000 patients in an hour, right? So, just enrolling is going to be between an hour and maximum enrollment, it could be 7 days for those 5,000 patients if it was done at scale in a multi-level approach where we have all the trials available. Dr. Paul Hanona: No, definitely a very exciting aspect of our future as oncologists. It's one thing to have really neat, novel mechanisms of treatment, but what good is it if we can't actually get it to people who need it? I'm very much looking for the future of that.  One of the last questions I want to ask you is another prevalent way that people use AI is just simply looking up questions, right? So, traditionally, the workflow for oncologists is maybe going on national guidelines and looking up the stage of the cancer and seeing what treatments are available and then referencing the papers and looking at who was included, who wasn't included, the side effects to be aware of, and sort of coming up with a decision as to how to treat a cancer patient. But now, just in the last few years, we've had several tools become available that make getting questions easier, make getting answers easier, whether that's something like OpenAI's tools or Perplexity or Doximity or OpenEvidence or even ASCO has a Guidelines Assistant as well that is drawing from their own guidelines as to how to treat different cancers. Do you see these replacing traditional sources? Do you see them saving us a lot more time so that we can be more productive in clinic? What do you think is the role that they're going to play with patient care? Dr. Arturo Loaiza-Bonilla: Such a relevant question, particularly at this time, because these AI-enabled query tools, they're coming left and right and becoming increasingly common in our daily workflows and things that we're doing. So, traditionally, when we go and we look for national guidelines, we try to understand the context ourselves and then we make treatment decisions accordingly. But that is a lot of a process that now AI is helping us to solve. So, at face value, it seems like an efficiency win, but in many cases, I personally evaluate platforms as the chief of hem/onc at St. Luke's and also having led the digital engagement things through Massive Bio and trying to put things together, I can tell you this: not all tools are created equal. In cancer care, each data point can mean the difference between cure and progression, so we cannot really take a lot of shortcuts in this case or have unverified output. So, the tools are helpful, but it has to be grounded in truth, in trusted data sources, and they need to be continuously updated with, like, ASCO and NCCN and others. So, the reason why the ASCO Guidelines Assistant, for instance, works is because it builds on all these recommendations, is assessed by end users like ourselves. So, that kind of verification is critical, right? We're entering a phase where even the source material may be AI-generated. So, the role of human expert validation is really actually more important, not less important. You know, generalist LLMs, even when fine-tuned, they may not be enough. You can pull a few API calls from PubMed, etc., but what we need now is specialized, context-aware, agentic tools that can interpret multimodal and real-time clinical inputs. So, something that we are continuing to check on and very relevant to have entities and bodies like ASCO looking into this so they can help us to be really efficient and really help our patients. Dr. Paul Hanona: Dr. Bonilla, what do you want to leave the listener with in terms of the future direction of AI, things that we should be cautious about, and things that we should be optimistic about? Dr. Arturo Loaiza-Bonilla: Looking 5 years ahead, I think there's enormous promise. As you know, I'm an AI enthusiast, but always, there's a few priorities that I think – 3 of them, I think – we need to tackle head-on. First is algorithmic equity. So, most AI tools today are trained on data from academic medical centers but not necessarily from community practices or underrepresented populations, particularly when you're looking at radiology, pathology, and what not. So, those blind spots, they need to be filled, and we can eliminate a lot of disparities in cancer care. So, those frameworks to incentivize while keeping the data sharing using federated models and things that we can optimize is key. The second one is the governance on the lifecycle. So, you know, AI is not really static. So, unlike a drug that is approved and it just, you know, works always, AI changes. So, we need to make sure that we have tools that are able to retrain and recall when things degrade or models drift. So, we need to use up-to-date AI for clinical practice, so we are going to be in constant revalidation and make it really easy to do. And lastly, the human-AI interface. You know, clinicians don't need more noise or we don't need more black boxes. We need decision support that is clear, that we can interpret, and that is actionable. “Why are you using this? Why did we choose this drug? Why this dose? Why now?” So, all these things are going to help us and that allows us to trace evidence with a single click. So, I always call it back to the Moravec's paradox where we say, you know, evolution gave us so much energy to discern in the sensory-neural and dexterity. That's what we're going to be taking care of patients. We can use AI to really be a force to help us to be better clinicians and not to really replace us. So, if we get this right and we decide for transparency with trust, inclusion, etc., it will never replace any of our work, which is so important, as much as we want, we can actually take care of patients and be personalized, timely, and equitable. So, all those things are what get me excited every single day about these conversations on AI. Dr. Paul Hanona: All great thoughts, Dr. Bonilla. I'm very excited to see how this field evolves. I'm excited to see how oncologists really come to this field. I think with technology, there's always a bit of a lag in adopting it, but I think if we jump on board and grow with it, we can do amazing things for the field of oncology in general. Thank you for the advancements that you've made in your own career in the field of AI and oncology and just ultimately with the hopeful outcomes of improving patient care, especially cancer patients. Dr. Arturo Loaiza-Bonilla: Thank you so much, Dr. Hanona. Dr. Paul Hanona: Thanks to our listeners for your time today. If you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today's speakers:    Dr. Arturo Loaiza-Bonilla @DrBonillaOnc Dr. Paul Hanona @DoctorDiscover on YouTube Follow ASCO on social media:      @ASCO on Twitter      ASCO on Facebook      ASCO on LinkedIn    ASCO on BlueSky Disclosures: Paul Hanona: No relationships to disclose. Dr. Arturo-Loaiza-Bonilla: Leadership: Massive Bio Stock & Other Ownership Interests: Massive Bio Consulting or Advisory Role: Massive Bio, Bayer, PSI, BrightInsight, CardinalHealth, Pfizer, AstraZeneca, Medscape Speakers' Bureau: Guardant Health, Ipsen, AstraZeneca/Daiichi Sankyo, Natera

Dr. Diwakar Davar and Dr. Jason Luke discuss novel agents in melanoma and other promising new data in the field of immunotherapy that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Diwakar Davar: Hello. My name is Diwakar Davar, and I am welcoming you to the ASCO Daily News Podcast. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. Today, I'm joined by my colleague and good friend, Dr. Jason Luke. Dr. Luke is a professor of medicine. He is also the associate director of clinical research and the director of the Phase 1 IDDC Program at the University of Pittsburgh's Hillman Cancer Center. He and I are going to be discussing some key advancements in melanoma and skin cancers that were presented at the 2025 ASCO Annual Meeting. Our full disclosures are available in the transcript of this episode.  Jason, it is great to have you back on the podcast. Dr. Jason Luke: Thanks again so much for the opportunity, and I'm really looking forward to it. Dr. Diwakar Davar: Perfect. So we will go ahead and start talking a little bit about a couple of key abstracts in both the drug development immunotherapy space and the melanoma space. The first couple of abstracts, the first two, will cover melanoma. So, the first is LBA9500, which was essentially the primary results of RELATIVITY-098. RELATIVITY-098 was a phase 3 trial that compared nivolumab plus relatlimab in a fixed-dose combination against nivolumab alone for the adjuvant treatment of resected high-risk disease. Jason, do you want to maybe give us a brief context of what this is? Dr. Jason Luke: Yeah, it's great, thanks. So as almost all listeners, of course, will be aware, the use of anti–PD-1 immunotherapies really revolutionized melanoma oncology over the last 10 to 15 years. And it has become a standard of care in the adjuvant setting as well. But to review, in patients with stage III melanoma, treatment can be targeted towards BRAF with BRAF and MEK combination therapy, where that's relevant, or anti–PD-1 with nivolumab or pembrolizumab are a standard of care. And more recently, we've had the development of neoadjuvant approaches for palpable stage III disease. And in that space, if patients present, based on two different studies, either pembrolizumab or nivolumab plus ipilimumab can be given prior to surgery for somewhere in the 6- to 9-week range. And so all of these therapies have improved time-to-event endpoints, such as relapse-free or event-free survival. It's worth noting, however, that despite those advances, we've had a couple different trials now that have actually failed in this adjuvant setting, most high profile being the CheckMate-915 study, which looked at nivolumab plus ipilimumab and unfortunately was a negative study. So, with RELATIVITY-047, which was the trial of nivolumab plus relatlimab that showed an improvement in progression-free survival for metastatic disease, there's a lot of interest, and we've been awaiting these data for a long time for RELATIVITY-098, which, of course, is this adjuvant trial of LAG-3 blockade with relatlimab plus nivolumab. Dr. Diwakar Davar: Great. So with that, let's briefly discuss the trial design and the results. So this was a randomized, phase 3, blinded study, so double-blinded, so neither the investigators knew what the patients were getting, nor did the patients know what they were getting. The treatment investigational arm was nivolumab plus relatlimab in the fixed-dose combination. So that's the nivolumab standard fixed dose with relatlimab that was FDA approved in RELATIVITY-047. And the control arm was nivolumab by itself. The duration of treatment was 1 year. The patient population consisted of resected high-risk stage III or IV patients. The primary endpoint was investigator-assessed RFS. Stage and geography were the standard stratifying factors, and they were included, and most of the criteria were balanced across both arms. What we know at this point is that the 2-year RFS rate was 64% and 62% in the nivolumab and nivolumab-combination arms, respectively. The 2-year DMFS rate was similarly equivalent: 76% with nivolumab monotherapy, 73% with the combination. And similar to what you had talked about with CheckMate 915, unfortunately, the addition of LAG-3 did not appear to improve the RFS or DMFS compared to control in this patient population. So, tell us a little bit about your take on this and what do you think might be the reasons why this trial was negative? Dr. Jason Luke: It's really unfortunate that we have this negative phase 3 trial. There had been a lot of hope that the combination of nivolumab with relatlimab would be a better tolerated combination that increased the efficacy. So in the metastatic setting, we do have 047, the study that demonstrated nivolumab plus relatlimab, but now we have this negative trial in the adjuvant setting. And so as to why exactly, I think is a complicated scenario. You know, when we look at the hazard ratios for relapse-free survival, the primary endpoint, as well as the secondary endpoints for distant metastasis-free survival, we see that the hazard ratio is approximately 1. So there's basically no difference. And that really suggests that relatlimab in this setting had no impact whatsoever on therapeutic outcomes in terms of efficacy. Now, it's worth noting that there was a biomarker subanalysis that was presented in conjunction with these data that looked at some immunophenotyping, both from circulating T cells, CD8 T cells, as well as from the tumor microenvironment from patients who were treated, both in the previous metastatic trial, the RELATIVITY-047 study, and now in this adjuvant study in the RELATIVITY-098 study. And to briefly summarize those, what was identified was that T cells in advanced melanoma seemed to have higher expression levels of LAG-3 relative to T cells that are circulating in patients that are in the adjuvant setting. In addition to that, there was a suggestion that the magnitude of increase is greater in the advanced setting versus adjuvant. And the overall summary of this is that the suggested rationale for why this was a negative trial may have been that the target of LAG-3 is not expressed as highly in the adjuvant setting as it is in the metastatic setting. And so while the data that were presented, I think, support this kind of an idea, I am a little bit cautious that this is actually the reason for why the trial was negative, however. I would say we're not really sure yet as to why the trial was negative, but the fact that the hazard ratios for the major endpoints were essentially 1 suggests that there was no impact whatsoever from relatlimab. And this really makes one wonder whether or not building on anti–PD-1 in the adjuvant setting is feasible because anti–PD-1 works so well. You would think that even if the levels of LAG-3 expression were slightly different, you would have seen a trend in one direction or another by adding a second drug, relatlimab, in this scenario. So overall, I think it's an unfortunate circumstance that the trial is negative. Clearly there's going to be no role for relatlimab in the adjuvant setting. I think this really makes one wonder about the utility of LAG-3 blockade and how powerful it really can be. I think it's probably worth pointing out there's another adjuvant trial ongoing now of a different PD-1 and LAG-3 combination, and that's cemiplimab plus fianlimab, a LAG-3 antibody that's being dosed from another trial sponsor at a much higher dose, and perhaps that may make some level of difference. But certainly, these are unfortunate results that will not advance the field beyond where we were at already. Dr. Diwakar Davar: And to your point about third-generation checkpoint factors that were negative, I guess it's probably worth noting that a trial that you were involved with, KeyVibe-010, that evaluated the PD-1 TIGIT co-formulation of vibostolimab, MK-4280A, was also, unfortunately, similarly negative. So, to your point, it's not clear that all these third-generation receptors are necessarily going to have the same impact in the adjuvant setting, even if they, you know, for example, like TIGIT, and they sometimes may not even have an effect at all in the advanced cancer setting. So, we'll see what the HARMONY phase 3 trial, that's the Regeneron cemiplimab/fianlimab versus pembrolizumab control with cemiplimab with fianlimab at two different doses, we'll see how that reads out. But certainly, as you've said, LAG-3 does not, unfortunately, appear to have an impact in the adjuvant setting. So let's move on to LBA9501. This is the primary analysis of EORTC-2139-MG or the Columbus-AD trial. This was a randomized trial of encorafenib and binimetinib, which we will abbreviate as enco-bini going forward, compared to placebo in high-risk stage II setting in melanoma in patients with BRAF V600E or K mutant disease. So Jason, you know, you happen to know one or two things about the resected stage II setting, so maybe contextualize the stage II setting for us based on the trials that you've led, KEYNOTE-716, as well as CheckMate-76K, set us up to talk about Columbus-AD. Dr. Jason Luke: Thanks for that introduction, and certainly stage II disease has been something I've worked a lot on. The rationale for that has been that building off of the activity of anti–PD-1 in metastatic melanoma and then seeing the activity in stage III, like we just talked about, it was a curious circumstance that dating back about 7 to 8 years ago, there was no availability to use anti–PD-1 for high-risk stage II patients, even though the risk of recurrence and death from melanoma in the context of stage IIB and IIC melanoma is in fact similar or actually higher than in stage IIIA or IIIB, where anti–PD-1 was approved. And in that context, a couple of different trials that you alluded to, the Keynote-716 study that I led, as well as the CheckMate 76K trial, evaluated pembrolizumab and nivolumab, respectively, showing an improvement in relapse-free and distant metastasis-free survival, and both of those agents have subsequently been approved for use in the adjuvant setting by the US FDA as well as the European Medicines Agency.  So bringing then to this abstract, throughout melanoma oncology, we've seen that the impact of anti–PD-1 immunotherapy versus BRAF and MEK-targeted therapy have had very similar outcomes on a sort of comparison basis, both in frontline metastatic and then in adjuvant setting. So it was a totally reasonable question to ask: Could we use adjuvant BRAF and MEK inhibitor therapy? And I think all of us expected the answer would be yes. As we get into the discussion of the trial, I think the unfortunate circumstance was that the timing of this clinical trial being delayed somewhat, unfortunately, made it very difficult to accrue the trial, and so we're going to have to try to read through the tea leaves sort of, based on only a partially complete data set. Dr. Diwakar Davar: So, in terms of the results, they wanted to enroll 815 patients, they only enrolled 110. The RFS and DMFS were marginally improved in the treatment arm but certainly not significantly, which is not surprising because the trial had only accrued 16% to 18% of its complete accrual. As such, we really can't abstract from the stage III COMBI-AD data to stage II patients. And certainly in this setting, one would argue that the primary treatment options certainly remain either anti–PD-1 monotherapy, either with pembrolizumab or nivolumab, based on 716 or 76K, or potentially active surveillance for the patients who are not inclined to get treated.  Can you tell us a little bit about how you foresee drug development going forward in this space because, you know, for example, with HARMONY, certainly IIC disease is a part of HARMONY. We will know at least a little bit about that in this space. So what do you think about the stage IIB/C patient population? Is this a patient population in which future combinations are going to be helpful, and how would you think about where we can go forward from here? Dr. Jason Luke: It is an unfortunate circumstance that this trial could not be accrued at the pace that was necessary. I think all of us believe that the results would have been positive if they'd been able to accrue the trial. In the preliminary data set that they did disclose of that 110 patients, you know, it's clear there is a difference at a, you know, a landmark at a year. They showed a 16% difference, and that would be in line with what has been seen in stage III. And so, you know, I think it's really kind of too bad. There's really going to be no regulatory approach for this consideration. So using BRAF and MEK inhibition in stage II is not going to be part of standard practice moving into the future. To your point, though, about where will the field go? I think what we're already realizing is that in the adjuvant setting, we're really overtreating the total population. And so beyond merely staging by AJCC criteria, we need to move to biomarker selection to help inform which patients truly need the treatment. And in that regard, I don't think we've crystallized together as a field as yet, but the kinds of things that people are thinking about are the integration of molecular biomarkers like ctDNA. When it's positive, it can be very helpful, but in melanoma, we found that, unfortunately, the rates are quite low, you know, in the 10% to 15% range in the adjuvant setting. So then another consideration would be factors in the primary tumor, such as gene expression profiling or other considerations.  And so I think the future of adjuvant clinical trials will be an integration of both the standard AJCC staging system as well as some kind of overlaid molecular biomarker that helps to enrich for a higher-risk population of patients because on a high level, when you abstract out, it's just clearly the case that we're rather substantially overtreating the totality of the population, especially given that in all of our adjuvant studies to date for anti–PD-1, we have not yet shown that there's an overall survival advantage. And so some are even arguing perhaps we should even reserve treatment until patients progress. I think that's a complicated subject, and standard of care at this point is to offer adjuvant therapy, but certainly a lot more to do because many patients, you know, unfortunately, still do progress and move on to metastatic disease. Dr. Diwakar Davar: Let's transition to Abstract 2508. So we're moving on from the melanoma to the novel immunotherapy abstracts. And this is a very, very, very fascinating drug. It's IMA203. So Abstract 2508 is a phase 1 clinical update of IMA203. IMA203 is an autologous TCR-T construct targeting PRAME in patients with heavily pretreated PD-1-refractory metastatic melanoma. So Jason, in the PD-1 and CTLA-4-refractory settings, treatment options are either autologous TIL, response rate, you know, ballpark 29% to 31%, oncolytic viral therapy, RP1 with nivolumab, ORR about 30-ish percent. So new options are needed. Can you tell us a little bit about IMA203? Perhaps tell us for the audience, what is the difference between a TCR-T and traditional autologous TIL? And a little bit about this drug, IMA203, and how it distinguishes itself from the competing TIL products in the landscape. Dr. Jason Luke: I'm extremely enthusiastic about IMA203. I think that it really has transformative potential based on these results and hopefully from the phase 3 trial that's open to accrual now. So, what is IMA203? We said it's a TCR-T cell product. So what that means is that T cells are removed from a patient, and then they can be transduced through various technologies, but inserted into those T cells, we can then add a T-cell receptor that's very specific to a single antigen, and in this case, it's PRAME. So that then is contrasted quite a bit from the TIL process, which includes a surgical resection of a tumor where T cells are removed, but they're not specific necessarily to the cancer, and they're grown up in the lab and then given to the patient. They're both adoptive cell transfer products, but they're very different. One is genetically modified, and the other one is not. And so the process for generating a TCR-T cell is that patients are required to have a new biomarker that some may not be familiar with, which is HLA profiling. So the T-cell receptor requires matching to the concomitant HLA for which the peptide is bound in. And so the classic one that is used in most oncology practices is A*02:01 because approximately 48% of Caucasians have A*02:01, and the frequency of HLA in other ethnicities starts to become highly variable. But in patients who are identified to have A*02:01 genotype, we can then remove blood via leukapheresis or an apheresis product, and then insert via lentiviral transduction this T-cell receptor targeting PRAME. Patients are then brought back to the hospital where they can receive lymphodepleting chemotherapy and then receive the reinfusion of the TCR-T cells. Again, in contrast with the TIL process, however, these T cells are extremely potent, and we do not need to give high-dose interleukin-2, which is administered in the context of TIL. Given that process, we have this clinical trial in front of us now, and at ASCO, the update was from the phase 1 study, which was looking at IMA203 in an efficacy population of melanoma patients who were refractory at checkpoint blockade and actually multiple lines of therapy. So here, there were 33 patients and a response rate of approximately 50% was observed in this population of patients, notably with a duration of response approximately a year in that treatment group. And I realize that these were heavily pretreated patients who had a range of very high-risk features. And approximately half the population had uveal melanoma, which people may be aware is a generally speaking more difficult-to-treat subtype of melanoma that metastasizes to the liver, which again has been a site of resistance to cancer immunotherapy. So these results are extremely promising. To summarize them from what I said, it's easier to make TCR-T cells because we can remove blood from the patient to transduce the T cells, and we don't have to put them through surgery. We can then infuse them, and based on these results, it looks like the response rate to IMA203 is a little bit more than double what we expect from lifileucel. And then, whereas with lifileucel or TILs, we have to give high-dose IL-2, here we do not have to give high-dose IL-2. And so that's pretty promising. And a clinical trial is ongoing now called the SUPREME phase 3 clinical trial, which is hoping to validate these results in a randomized global study. Dr. Diwakar Davar: Now, one thing that I wanted to go over with you, because you know this trial particularly well, is what you think of the likelihood of success, and then we'll talk a little bit about the trial design. But in your mind, do you think that this is a trial that has got a reasonable likelihood of success, maybe even a high likelihood of success? And maybe let's contextualize that to say an alternative trial, such as, for example, the TebeAM trial, which is essentially a T-cell bispecific targeting GP100. It's being compared against SOC, investigator's choice control, also in a similarly heavily pretreated patient population. Dr. Jason Luke: So both trials, I think, have a strong chance of success. They are very different kinds of agents. And so the CD3 bispecific that you referred to, tebentafusp, likely has an effect of delaying progression, which in patients with advanced disease could have a value that might manifest as overall survival. With TCR-T cells, by contrast, we see a very high response rate with some of the patients going into very durable long-term benefit. And so I do think that the SUPREME clinical trial has a very high chance of success. It will be the first clinical trial in solid tumor oncology randomizing patients to receive a cell therapy as compared with a standard of care. And within that standard of care control arm, TILs are allowed as a treatment. And so it will also be the first study that will compare TCR-T cells against TILs in a randomized phase 3. But going back to the data that we've seen in the phase 1 trial, what we observe is that the duration of response is really connected to the quality of the response, meaning if you have more than a 50% tumor shrinkage, those patients do very, very well. But even in patients who have less than 50% tumor shrinkage, the median progression-free survival right now is about 4.5 months. And again, as we think about trial design, standard of care options for patients who are in this situation are unfortunately very bad. And the progression-free survival in that population is probably more like 2 months. So this is a trial that has a very high likelihood of being positive because the possibility of long-term response is there, but even for patients who don't get a durable response, they're likely going to benefit more than they would have based on standard chemotherapy or retreatment with an anti–PD-1 agent. Dr. Diwakar Davar: Really, a very important trial to enroll, a trial that is first in many ways. First of a new generation of TCR-T agents, first trial to look at cell therapy in the control arm, a new standard of efficacy, but potentially also if this trial is successful, it will also be a new standard of trial conduct, a new kind of trial, of a set of trials that will be done in the second-line immunotherapy-refractory space. So let's pivot to the last trial that we were going to discuss, which was Abstract 2501. Abstract 2501 is a first-in-human phase 1/2 trial evaluating BNT142, which is the first-in-class mRNA-encoded bispecific targeting Claudin-6 and CD3 in patients with Claudin-positive tumors. We'll talk a little bit about this, but maybe let's start by talking a little bit about Claudin-6. So Claudin-6 is a very interesting new target. It's a target that's highly expressed in GI and ovarian tumors. There are a whole plethora of Claudin-6-targeting agents, including T-cell bispecifics and Claudin-6-directed CAR-Ts that are being developed. But BNT142 is novel. It's a novel lipid nanoparticle LNP-encapsulated mRNA. The mRNA encodes an anti–Claudin-6 CD3 bispecific termed RiboMAB-021. And it then is administered to the patient. The BNT142-encoding mRNA LNPs are taken up by the liver and translated into the active drug. So Jason, tell us a little bit about this agent. Why you think it's novel, if you think it's novel, and let's talk a little bit then about the results. Dr. Jason Luke: So I certainly think this is a novel agent, and I think this is just the first of what will probably become a new paradigm in oncology drug development. And so you alluded to this, but just to rehash it quickly, the drug is encoded as genetic information that's placed in the lipid nanoparticle and then is infused into the patient. And after the lipid nanoparticles are taken up by the liver, which is the most common place that LNPs are usually taken up, that genetic material in the mRNA starts to be translated into the actual protein, and that protein is the drug. So this is in vivo generation, so the patient is making their own drug inside their body. I think it's a really, really interesting approach. So for any drug that could be encoded as a genetic sequence, and in this case, it's a bispecific, as you mentioned, CD3-Claudin-6 engager, this could have a tremendous impact on how we think about pharmacology and novel drug development moving into the future in oncology. So I think it's an extremely interesting drug, the like of which we'll probably see only more moving forward. Dr. Diwakar Davar: Let's maybe briefly talk about the results. You know, the patient population was heavily pretreated, 65 or so patients, mostly ovarian cancer. Two-thirds of the patients were ovarian cancer, the rest were germ cell and lung cancer patients. But let's talk a little bit about the efficacy. The disease control rate was about 58% in the phase 1 population as a whole, but 75% in the ovarian patient population. Now tell us a little bit about the interesting things about the drug in terms of the pharmacokinetics, and also then maybe we can pivot to the clinical activity by dose level. Dr. Jason Luke: Well, so they did present in their presentation at ASCO a proportionality showing that as higher doses were administered, that greater amounts of the drug were being made inside the patient. And so that's an interesting observation, and it's an important one, right? Suggesting that the pharmacology that we classically think of by administering drugs by IV, for example, would still be in play. And that did translate into some level of efficacy, particularly at the higher dose levels. Now, the caveat that I'll make a note of is that disease control rate is an endpoint that I think we have to be careful about because what that really means is sometimes a little bit unclear. Sometimes patients have slowly growing tumors and so on and so forth. And the clinical relevance of disease control, if it doesn't last at least 6 months, I think is probably pretty questionable. So I think these are extremely interesting data, and there's some preliminary sense that getting the dose up is going to matter because the treatment responses were mostly observed at the highest dose levels. There's also a caveat, however, that across the field of CD3 bispecific molecules like this, there's been quite a bit of heterogeneity in terms of the response rate, with some of them only really generating stable disease responses and other ones having more robust responses. And so I think this is a really interesting initial foray into this space. My best understanding is this molecule is not moving forward further after this, but I think that this really does set it up to be able to chase after multiple different drug targets on a CD3 bispecific backbone, both in ovarian cancer, but then basically across all of oncology. Dr. Diwakar Davar: Perfect. This is a very new sort of exciting arena where we're going to be looking at, in many ways, these programmable constructs, whether we're looking at in vivo-generated, in this case, a T-cell bispecific, but we've also got newer drugs where we are essentially giving drugs where people are generating in vivo CAR T, and also potentially even in vivo TCR-T. But certainly lots of new excitement around this entire class of drugs. And so, what we'd like to do at this point in time is switch to essentially the fact that we've got a very, very exciting set of data at ASCO 2025. You've heard from Dr. Luke regarding the advances in both early drug development but also in advanced cutaneous melanoma. And Jason, as always, thank you so much for sharing your very valuable and great, fantastic insights with us on the ASCO Daily News Podcast. Dr. Jason Luke: Well, thanks again for the opportunity. Dr. Diwakar Davar: And thank you to our listeners for taking your time to listen today. You will find the links to the abstracts that we discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers:    Dr. Diwakar Davar    @diwakardavar    Dr. Jason Luke @jasonlukemd Follow ASCO on social media:     @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn   Disclosures:     Dr. Diwakar Davar:      Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences     Consulting or Advisory Role: Instil Bio, Vedanta Biosciences     Consulting or Advisory Role (Immediate family member): Shionogi     Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences     Research Funding (Inst.): Zucero Therapeutics     Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy     Dr. Jason Luke:     Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX     Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine     Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure     Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)     Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss important advances in the treatment of prostate, bladder, and kidney cancers that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I am the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute and editor-in-chief of the ASCO Daily News.  I am delighted to be joined by Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical program director of the GU Center at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing some key abstracts in GU oncology that were presented at the 2025 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode.  Jeanny, it is great to have you on the podcast. Dr. Jeanny Aragon-Ching: Oh, thank you so much, Neeraj. Dr. Neeraj Agarwal: Jeanny, let's begin with some prostate cancer abstracts. Let's begin with Abstract 5017 titled, “Phase 1 study results of JNJ-78278343 (pasritamig) in metastatic castration-resistant prostate cancer.” Can you walk us through the design and the key findings of this first-in-human trial? Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So this study, presented by Dr. Capucine Baldini, introduces pasritamig, a first-in-class T-cell redirecting bispecific antibody that simultaneously binds KLK2 on prostate cancer cells and CD3 receptor complexes on T cells. KLK2 is also known as human kallikrein 2, which is selectively expressed in prostate tissue. And for reference, KLK3 is what we now know as the PSA, prostate-specific antigen, therefore making it an attractive and specific target for therapeutic engagement. Now, while this was an early, first-in-human, phase 1 study, it enrolled 174 heavily pretreated metastatic CRPC patients. So many were previously treated with ARPIs, taxanes, and radioligand therapy. So given the phase 1 nature of this study, the primary objective was to determine the safety and the RP2D, which is the recommended phase 2 dose. Secondary objectives included preliminary assessment of antitumor activity. So, pasritamig was generally well tolerated. There were no treatment-related deaths. Serious adverse events were rare. And in the RP2D safety cohort, where patients received the step-up dosing up to 300 mg of IV every 6 weeks, the most common treatment-related adverse events were low-grade infusion reactions. There was fatigue and grade 1 cytokine release syndrome, what we call CRS. And no cases of neurotoxicity, or what we call ICANS, the immune effector cell-associated neurotoxicity syndrome, reported. Importantly, the CRS occurred in just about 8.9% of patients. All were grade 1. No patients required tocilizumab or discontinued treatment due to adverse events. So, this suggests a favorable safety profile, allowing hopefully for outpatient administration without hospitalization, which will be very important when we're thinking about bispecifics moving forward. In terms of efficacy, pasritamig showed promising activity. About 42.4% of evaluable patients achieved a PSA50 response. Radiographic PFS was about 6.8 months. And among patients with measurable disease, the objective response rate was about 16.1% in those with lymph node or bone metastases, and about 3.7% in those with visceral disease, with a median duration of response of about 11.3 months. So, altogether, this data suggests that pasritamig may offer a well-tolerated and active new potential option for patients with metastatic CRPC.   Again, as a reminder, with the caveat that this is still an early phase 1 study. Dr. Neeraj Agarwal: Thank you, Jeanny. These are promising results for a bispecific T-cell engager, pasritamig, in prostate cancer. I agree, the safety and durability observed here stand out, and this opens the door for further development, possibly even in earlier disease settings.  So, shifting now from immunotherapy to the evolving role of genomics in prostate cancer. So let's discuss Abstract 5094, a real-world, retrospective analysis exploring the prognostic impact of homologous recombination repair gene mutations, especially BRCA1 and BRCA2 mutations, in metastatic hormone-sensitive prostate cancer. Can you tell us more about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Sure, Neeraj. So this study was presented by Dr. David Olmos, represents one of the largest real-world analyses we have evaluating the impact of homologous recombination repair, or what we would call HRR, alterations in metastatic hormone-sensitive prostate cancer. So, this cohort included 556 men who underwent paired germline and somatic testing. Now, about 30% of patients had HRR alterations, with about 12% harboring BRCA1 or BRCA2 mutations and 16% having alterations in other HRR genes. Importantly, patients were stratified via CHAARTED disease volume, and outcomes were examined across treatment approaches, including ADT alone, doublet therapy, and triplet therapy. The prevalence of BRCA and HRR alterations were about similar between the metastatic hormone-sensitive prostate cancer and the metastatic castrate-resistant prostate cancer, with no differences observed, actually, between the patients with high volume versus low volume disease.  So, the key finding was that BRCA and HRR alterations were associated with poor clinical outcomes in metastatic hormone-sensitive prostate cancer. And notably, the impact of these alterations may actually be even greater in metastatic hormone-sensitive prostate cancer than previously reported in metastatic CRPC. So, the data showed that when BRCA mutations are present, the impact of the volume of disease is actually limited. So, poor outcomes were observed across the board for both high-volume and low-volume groups. So, the analysis showed that patients with HRR alterations had significantly worse outcomes compared to patients without HRR alterations. Median radiographic progression-free survival was about 20.5 months for the HRR-altered patients versus 30.6 months for the non-HRR patients, with a hazard ratio of 1.6. Median overall survival was 39 months for HRR-altered patients compared to 55.7 months for the non-HRR patients, with a hazard ratio of 1.5. Similar significant differences were observed when BRCA-mutant patients were compared with patients harboring non-BRCA HRR mutations. Overall, poor outcomes were independent of treatment of ARPI or taxanes. Dr. Neeraj Agarwal: Thank you, Jeanny. So, these data reinforce homologous recombination repair mutations as both a predictive and prognostic biomarker, not only in the mCRPC, but also in the metastatic hormone-sensitive setting as well. It also makes a strong case for incorporating genomic testing early in the disease course and not waiting until our patients have castration-resistant disease. Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. And I think this really brings home the point and the lead up to the AMPLITUDE trial, which is LBA5006, a phase 3 trial that builds on this very concept of testing with a PARP inhibitor, niraparib, in the hormone-sensitive space. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. So, the AMPLITUDE trial, a phase 3 trial presented by Dr. Gerhardt Attard, enrolled 696 patients with metastatic hormone-sensitive prostate cancer and HRR gene alterations. 56% of these patients had BRCA1 and BRCA2 mutations. Patients were randomized to receive abiraterone with or without niraparib, a PARP inhibitor. The majority of patients, 78% of these patients, had high-volume metastatic hormone-sensitive prostate cancer, and 87% of these patients had de novo metastatic HSPC. And 16% of these patients received prior docetaxel, which was allowed in the clinical trial. So, with a median follow-up of nearly 31 months, radiographic progression-free survival was significantly prolonged with the niraparib plus abiraterone combination, and median was not reached in this arm, compared to abiraterone alone, which was 29.5 months, with a hazard ratio of 0.63, translating to a 37% reduction in risk of progression or death. This benefit was even more pronounced in the BRCA1 and BRCA2 subgroup, with a 48% reduction in risk of progression, with a hazard ratio of 0.52. Time to symptomatic progression also improved significantly across all patients, including patients with BRCA1, BRCA2, and HRR mutations. Although overall survival data remain immature, early trends favored the niraparib plus abiraterone combination. The safety profile was consistent with prior PARP inhibitor studies, with grade 3 or higher anemia and hypertension were more common but manageable. Treatment discontinuation due to adverse events remained low at 11%, suggesting that timely dose modifications when our patients experience grade 3 side effects may allow our patients to continue treatment without discontinuation. These findings support niraparib plus abiraterone as a potential new standard of care in our patients with metastatic hormone-sensitive prostate cancer with HRR alterations, and especially in those who had BRCA1 and BRCA2 mutations. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. This trial is especially exciting because it brings PARP inhibitors earlier into the treatment paradigm. Dr. Neeraj Agarwal: Exactly. And it is exciting to see the effect of PARP inhibitors in the earlier setting.  So Jeanny, now let's switch gears a bit to bladder cancer, which also saw several impactful studies. Could you tell us about Abstract 4502, an exploratory analysis from the EV-302 trial, which led to approval of enfortumab vedotin plus pembrolizumab for our patients with newly diagnosed metastatic bladder cancer? So here, the authors looked at the outcomes in patients who achieved a confirmed complete response with EV plus pembrolizumab. Dr. Jeanny Aragon-Ching: Sure, Neeraj. So, EV-302 demonstrated significant improvements in progression-free and overall survival for patients previously treated locally advanced or metastatic urothelial cancer, I'll just call it metastatic UC, as a frontline strategy, establishing EV, which is enfortumab vedotin, plus pembro, with pembrolizumab as standard of care in this setting.  So, this year at ASCO, Dr Shilpa Gupta presented this exploratory responder analysis from the phase 3 EV-302 trial. Among 886 randomized patients, about 30.4% of patients, this is about 133, in the EV+P arm, and 14.5% of the patients in the chemotherapy arm, achieved a confirmed complete response. They call it the CCR rates. So for patients who achieved this, median PFS was not reached with EV+P compared to 26.9 months with chemotherapy, with a hazard ratio of 0.36, translating to a 64% reduction in the risk of progression. Overall survival was also improved. So the median OS was not reached in either arm, but the hazard ratio favored the EV+P at 0.37, translating to a 63% reduction in the risk of death. The median duration of complete response was not reached with EV+P compared to 15.2 months with chemotherapy. And among those patients who had confirmed CRs at 24 months, 78% of patients with the EV+P arm remained progression-free, and around 95% of the patients were alive, compared to 54% of patients who were progression-free and 86% alive of the patients in the chemotherapy arm. Safety among responders were also consistent with prior reports. Grade 3 or higher treatment-related adverse events occurred in 62% of EV+P responders and 72% of chemotherapy responders. Most adverse events were managed with dose modifications, and importantly, no treatment-related deaths were reported among those who were able to achieve complete response.  So these findings further reinforce EV and pembro as the preferred first-line therapy for metastatic urothelial carcinoma, offering a higher likelihood of deep, durable responses with a fairly manageable safety profile. Dr. Neeraj Agarwal: Thank you for the great summary, Jeanny. These findings underscore the depth and durability of responses achievable with this combination and also suggest that achieving a response may be a surrogate for long-term benefit in patients with metastatic urothelial carcinoma.  So now, let's move to Abstract 4503, an exploratory ctDNA analysis from the NIAGARA trial, which evaluated perioperative durvalumab, an immune checkpoint inhibitor, in muscle-invasive bladder cancer. So what can you tell us about this abstract? Dr. Jeanny Aragon-Ching: Absolutely, Neeraj. So, in NIAGARA, presented by Dr. Tom Powles, the addition of perioperative durvalumab to neoadjuvant chemotherapy, gem/cis, significantly improved event-free survival, overall survival, and pathologic complete response in patients with cisplatin-eligible muscle-invasive bladder cancer. Recall that this led to the U.S. FDA approval of this treatment regimen on March 28, 2025.  So, a planned exploratory analysis evaluated the ctDNA dynamics and their association with clinical outcomes, which was the one presented recently at ASCO. So, the study found that the incidence of finding ctDNA positivity in these patients was about 57%. Following neoadjuvant treatment, this dropped to about 22%, with ctDNA clearance being more common in the durvalumab arm, about 41%, compared to the chemotherapy control arm of 31%. Notably, 97% of patients who remained ctDNA positive prior to surgery failed to achieve a pathologic CR. So, this indicates a strong association between ctDNA persistence and lack of tumor eradication. So, postoperatively, only about 9% of patients were ctDNA positive. So, importantly, durvalumab conferred an event-free survival benefit regardless of ctDNA status at both baseline and post-surgery. Among patients who were ctDNA positive at baseline, durvalumab led to a hazard ratio of 0.73 for EFS. So, this translates to a 27% reduction in the risk of disease recurrence, progression, or death compared to the control arm. In the post-surgical ctDNA-positive group, the disease-free survival was also improved with a hazard ratio of 0.49, translating to a 51% reduction in the risk of recurrence.  So, these findings underscore the prognostic value of ctDNA and suggest that durvalumab provides clinical benefit irrespective of molecular residual disease status. So, the data also supports that ctDNA is a promising biomarker for future personalized strategies in the perioperative treatment of muscle-invasive bladder cancer. Dr. Neeraj Agarwal: Thank you, Jeanny. It is great to see that durvalumab is improving outcomes in these patients regardless of ctDNA status. However, based on these data, presence of ctDNA in our patients warrants a closer follow-up with imaging studies, because these patients with positive ctDNA seem to have a higher risk of recurrence. Dr. Jeanny Aragon-Ching: I agree, Neeraj.  Let's round out the bladder cancer discussion with Abstract 4518, which reported the interim results of SURE-02, which is a phase 2 study evaluating neoadjuvant sacituzumab govitecan plus pembrolizumab in cisplatin-ineligible muscle-invasive bladder cancer. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure, Jeanny. So, Dr Andrea Necchi presented interim results from the SURE-02 trial. This is a phase 2 study evaluating neoadjuvant sacituzumab govitecan plus pembrolizumab, followed by a response-adapted bladder-sparing treatment and adjuvant pembrolizumab in patients with muscle-invasive bladder cancer.  So, in this interim analysis, 40 patients were treated and 31 patients were evaluable for efficacy. So, the clinical complete response rate was 38.7%. All patients achieving clinical complete response underwent bladder-sparing approach with a repeat TURBT instead of radical cystectomy. Additionally, 51.6% of patients achieved excellent pathologic response with a T stage of 1 or less after neoadjuvant therapy. The treatment was well tolerated, with only 12.9% of patients experiencing grade 3 or higher adverse events without needing dose reduction of sacituzumab. Molecular profiling, interestingly, showed that clinical complete response correlated with luminal and genomically unstable subtypes, while high stromal gene expression was associated with lack of response.  These results suggest that sacituzumab plus pembrolizumab combination has promising activity in this setting, and tolerability, and along with other factors may potentially allow a bladder preservation approach in a substantial number of patients down the line. Dr. Jeanny Aragon-Ching: Yeah, agree with you, Neeraj. And the findings are very provocative and support completing the full trial enrollment and further exploration of this strategy in muscle-invasive bladder cancer in order to improve and provide further bladder-sparing strategies. Dr. Neeraj Agarwal: Agree. So, let's now turn to the kidney cancer, starting with Abstract 4505, the final overall analysis from CheckMate-214 trial, which evaluated nivolumab plus ipilimumab, so dual checkpoint inhibition strategy, versus sunitinib in our patients with metastatic clear cell renal cell carcinoma. Dr. Jeanny Aragon-Ching: Yeah, absolutely, Neeraj. So, the final 9-year analysis of the phase 3 CheckMate-214 trial confirms the long-term superiority of nivolumab and ipilimumab over sunitinib for first-line treatment of advanced metastatic renal cell carcinoma. So, this has a median follow-up of 9 years. Overall survival remains significantly improved with the combination. So, in the ITT patient population, the intention-to-treat, the hazard ratio for overall survival was 0.71. So, this translates to a 29% reduction in the risk of death. 31% of patients were alive at this 108-month follow-up compared to 20% only in those who got sunitinib. So, similar benefits were observed in the intermediate- and poor-risk groups with a hazard ratio of 0.69, and 30% versus 19% survival at 108 months.  Importantly, a delayed benefit was also seen in those favorable-risk patients. So, the hazard ratio for overall survival improved from 1.45 in the initial report and now at 0.8 at 9 years follow-up, with 35% of patients alive at 108 months compared to 22% in those who got sunitinib. Progression-free survival also favored the nivo-ipi arm across all risk groups. At 96 months, the probability of remaining progression-free was about 23% compared to 9% in the sunitinib arm in the ITT patient population, 25% versus 9% in the intermediate- and poor-risk patients, and 13% compared to 11% in the favorable-risk patients. Importantly, at 96 months, 48% of patients in the nivo-ipi responders remained in response compared to just 19% in those who got sunitinib. And in the favorable-risk group, 36% of patients who responded remained in response, although data were not available for sunitinib in this subgroup.  So, this data reinforces the use of nivolumab and ipilimumab as a durable and effective first-line effective strategy for standard of care across all risk groups for advanced renal cell carcinoma. Dr. Neeraj Agarwal: Thank you, Jeanny. And of course, since ipi-nivo data were presented, several other novel ICI-TKI combinations have emerged. And I'm really hoping to see very similar data with TKI-ICI combinations down the line. It is really important to note that we are not seeing any new safety signals with the ICI combinations or ICI-based therapies, which is very reassuring given the extended exposure. Dr. Jeanny Aragon-Ching: Absolutely agree with you there, Neeraj.  Now, going on and moving on to Abstract 4514, which is the KEYNOTE-564 trial, and they reported on the 5-year outcomes of adjuvant pembrolizumab in clear cell RCC in patients who are at high risk for recurrence. Can you tell us a little bit more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. So, the KEYNOTE-564 trial established pembrolizumab monotherapy as the first adjuvant regimen to significantly improve both disease-free survival and overall survival compared to placebo after surgery for patients with clear cell renal cell carcinoma. So, Dr Naomi Haas presented the 5-year update from this landmark trial.  A total of 994 patients were randomized to receive either pembrolizumab or placebo. The median follow-up at the time of this analysis was approximately 70 months. Disease-free survival remained significantly improved with pembrolizumab. The median DFS was not reached with pembrolizumab compared to 68.3 months with placebo, with a hazard ratio of 0.71, translating to a 29% reduction in risk of recurrence. At 5 years, 60.9% of patients receiving pembrolizumab remained disease-free compared to 52.2% with placebo. Overall survival also favored pembrolizumab. The hazard ratio for OS was 0.66, translating to a 34% reduction in risk of death, with an estimated 5-year overall survival rate of 87.7% with pembrolizumab compared to 82.3% for placebo. Importantly, these benefits were consistent across all key subgroups, including patients with sarcomatoid features. In addition, no new serious treatment-related adverse events have been reported in the 3 years since treatment completion.  So, these long-term data confirm pembrolizumab as a durable and effective standard adjuvant therapy for patients with resected, high-risk clear cell renal cell carcinoma. Dr. Jeanny Aragon-Ching: Thank you for that wonderful summary, Neeraj. Dr. Neeraj Agarwal: That wraps up our kidney cancer highlights. Any closing thoughts, Jeanny, before we conclude? Dr. Jeanny Aragon-Ching: It's been so wonderful reviewing these abstracts with you, Neeraj. So, the 2025 ASCO Annual Meeting showcased a lot of transformative data across GU cancers, from first-in-class bispecifics to long-term survival in RCC. And these findings are already shaping our clinical practices. Dr. Neeraj Agarwal: I agree. And we have covered a broad spectrum of innovations in GU cancers with strong clinical relevance.  So, thank you, Jeanny, for joining me today and sharing your insights.  And thank you to our listeners for joining us. You will find links to the abstracts discussed today in the transcript of this episode. If you find these conversations valuable, please take a moment to rate, review, and subscribe to the ASCO Daily News Podcast wherever you listen. Thank you so much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:    Dr. Neeraj Agarwal     @neerajaiims     Dr. Jeanny Aragon-Ching   Follow ASCO on social media:       @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn       Disclosures:   Dr. Neeraj Agarwal:   Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas  Dr. Jeanny Aragon-Ching:   Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono   Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,    Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics

Dr. Vamsi Velcheti and Dr. Nate Pennell discuss novel treatment approaches in small cell and non-small cell lung cancer that were featured at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host of the ASCO Daily News Podcast. I'm a professor of medicine and chief of hematology and oncology at the Mayo Clinic in Jacksonville, Florida. The 2025 ASCO Annual Meeting featured some exciting advancements in small cell lung cancer, targeted therapies for non-small cell lung cancer, and other novel [treatment] approaches. Today, I'm delighted to be joined by Dr. Nate Pennell to discuss some of the key abstracts that are advancing the lung cancer field. Dr. Pennell is the co-director of the Cleveland Clinic Lung Cancer Program and also the vice chair of clinical research at the Taussig Cancer Institute. Our full disclosures are available in the transcript of this episode. Nate, it's great to have you back on the podcast. Thanks so much for being here. Dr. Nate Pennell: Thanks, Vamsi. Always a pleasure. Dr. Vamsi Velcheti: Let's get started, and I think the first abstract that really caught my attention was Abstract 8516, “The Randomized Trial of Relevance of Time of Day of Immunotherapy for Progression-Free and Overall Survival in Patients With Non-Small Cell Lung Cancer.” What are your thoughts about this, Nate? Dr. Nate Pennell: I agree. I thought this was one of the most discussed abstracts, certainly in the lung cancer session, but I think even outside of lung cancer, it got some discussion. So, just to put this in perspective, there have been a number of publications that have all been remarkably consistent, and not just in lung cancer but across multiple cancer types, that immunotherapy, immune checkpoint inhibitors, are commonly used. And all of them have suggested, when looking at retrospective cohorts, that patients who receive immune checkpoint inhibitors earlier in the day – so in the morning or before the early afternoon – for whatever reason, appear to have better outcomes than those who get it later in the day, and this has been repeated. And I think many people just sort of assumed that this was some sort of strange association and that there was something fundamentally different from a prognostic standpoint in people who came in in the morning to get their treatment versus those who came later in the afternoon, and that was probably the explanation. The authors of this randomized trial actually decided to test this concept. And so, about 210 patients with previously untreated advanced non-small cell lung cancer were randomly assigned to get chemo and immune checkpoint inhibitor – either pembrolizumab or sintilimab – and half of them were randomly assigned to get the treatment before 3 PM in the afternoon, and half of them were assigned to get it after 3 PM in the afternoon. And it almost completely recapitulated what was seen in the retrospective cohorts. So, the median progression-free survival in those who got earlier treatment was 13.2 months versus only 6.5 months in those who got it later in the day. So, really enormous difference with a hazard ratio of 0.43, which was statistically significant. And perhaps even more striking, the median overall survival was not reached in the early group versus 17.8 months in the late group with a hazard ratio of 0.43, also highly statistically significant. Even the response rate was 20% higher in the early patients; 75% response rate compared to 56% in the late-time-of-day patients. So very consistent across all measures of efficacy with pretty good matched characteristics across the different groups. And so, I have to tell you, I don't know what to make of this. I certainly was a skeptic about the retrospective series, but now we have a prospective randomized trial that shows essentially the same thing. So, maybe there is a difference between getting treated in the morning, although I have yet to hear someone give a very good mechanistic explanation as to why this would be. What were your thoughts on this? Dr. Vamsi Velcheti: It's indeed fascinating, Nate, and I actually think this was a very interesting abstract. Really, I was caught off guard looking at the data. I mean, if it were a drug, we would be so excited, right? I mean, with those kind of survival benefits. I don't know. I think circadian rhythm probably has something to do with it, like different cytokine profiles at the time of administration. I mean, who knows? But I think it's a randomized trial, and I think I would expect to see a mad rush for treatment appointments early in the morning given this, and at least I want my patients to come in first thing in the morning. It'll be interesting to see. Dr. Nate Pennell: It's important to point out that in this study, everyone got chemo and immunotherapy. And, at least in our cancer center, most patients who are getting platinum-doublet chemotherapy and immunotherapy actually do get treated earlier in the day already, just because of the length of the infusion appointment that's needed. So it really is oftentimes people getting single-agent immunotherapy who are often getting the later, shorter visits. But if you have a choice, I think it would be very reasonable to have people treated earlier in the day. And I do think most of the impressions that I got from people about this is that they would like to see it reproduced but certainly well worth further investigation. And I personally would like to see more investigation into what the rationale would be for this because I still can't quite figure out, yes, if you got it at, say, you know, 5 PM, that's later in the day and I can understand that maybe your immune system is somewhat less receptive at that point than it would be in the morning. But because these checkpoint inhibitors have such long half-lives, it's still in your system the next morning when your immune system is supposedly more receptive. So I don't quite understand why that would be the case. Well, let's move on to the next study. I would like to hear your thoughts on Abstract 8515, “Plasma-Guided, Adaptive First-Line Chemoimmunotherapy for Non-Small Cell Lung Cancer.” Dr. Vamsi Velcheti: Yeah, this was another abstract that seems to be really interesting in my opinion. I think there's kind of a lot of emphasis lately on ctDNA and MRD-based assays to monitor disease. In the lung cancer space, we haven't had a lot of clinical trials looking at this prospectively, and this was one of those pilot studies where they looked at circulating free DNA (cfDNA)-based response-adaptive strategy for frontline patients who are PD-L1 positive. So, patients started with pembrolizumab monotherapy, and based on plasma molecular response after 2 cycles, those patients without response received early treatment intensification with a platinum doublet. So the approach essentially was to reduce the chemotherapy exposure in patients who respond to immunotherapy. And only about 17.5% of the patients on the trial received chemotherapy based on lack of molecular response. So, in this trial, what they found was patients with the cfDNA response had a markedly improved PFS of 16.4 months versus 4.8 months. So essentially, like, this is a really nice study to set a foundation on which we have to do larger studies to incorporate molecular markers trying to look at cfDNA response to inform treatment strategy, either escalation or de-escalation strategies. So, I thought it was a very interesting study. Dr. Nate Pennell: Yeah. I mean, we always have this question for patients, “Should they get immunotherapy alone or combined with chemo?” and I think this certainly is intriguing, suggesting that there may be ways you can monitor people and perhaps rescue those that aren't going to respond to single agent. I'd like to see a randomized trial against, you know, this strategy, perhaps against everyone getting, say, chemoimmunotherapy or make sure that you're not potentially harming people by doing this strategy. But I agree, it's time to move beyond just observing that cell-free DNA is prognostic and important and start using it to actually guide treatment. Dr. Vamsi Velcheti: Yeah, and I would just caution though, like, you know, I think we need more data, but, however, it's certainly a very interesting piece of data to kind of help inform future trials. So, there was another abstract that caught my attention, and I think this would be a very interesting abstract in the EGFR space. Abstract 8506, "Patritumab Deruxtecan (HER3-DXd) in Resistant EGFR-Mutant Advanced Non-Small Cell Lung Cancer Patients After Third-Generation EGFR TKI," it's the HERTHENA-Lung02 study. What do you think about the results of this study? Dr. Nate Pennell: Yeah, this was, I would say, very widely anticipated and ultimately a little disappointing, despite being a positive trial. So, these are patients with EGFR-mutant non-small cell lung cancer who have progressed after a third-generation EGFR TKI like osimertinib. This is really an area of major unmet need. We do have drugs like amivantamab in this space, but still definitely an area where essentially patients move from having a highly effective oral therapy to being in the realm of chemotherapy as their best option. So, this HER3 antibody-drug conjugate, patritumab deruxtecan, had some good single-arm data for this. And we're sort of hoping this would become an available option for patients. This trial was designed against platinum-doublet chemotherapy in this setting and with a primary endpoint of progression-free survival. And it actually was positive for improved progression-free survival compared to chemo with a hazard ratio of 0.77. But when you look at the medians, you can see that the median PFS was only 5.8 versus 5.4 months. It was really a modest difference between the two arms. And on the interim analysis, it appeared that there will not be a difference in overall survival between the two arms. In fact, the hazard ratio at the interim analysis was 0.98 for the two arms. So based on this, unfortunately, the company that developed the HER3-DXd has withdrawn their application to the FDA for approval of the drug, anticipating that they probably wouldn't get past approval without that overall survival endpoint. So, unfortunately, probably not, at least for the near future, going to be a new option for these patients. Dr. Vamsi Velcheti: Yeah, I think this is a space that's clearly an unmet need, and this was a big disappointment, I should say. I think all of us were going into the meeting anticipating some change in the standard of care here. Dr. Nate Pennell: Yeah, I agree. It was something that I was telling patients, honestly, that I was expecting this to be coming, and so now, definitely a bit of a disappointment. But it happens and, hopefully, it will still find perhaps a role or other drugs with a similar target. Certainly an active area. Well, let's leave the EGFR-mutant space and move into small cell. There were a couple of very impactful studies. And one of them was Abstract 8006, “Lurbinectedin Plus Atezolizumab as First-Line Maintenance Treatment in Patients With Extensive-Stage Small Cell Lung Cancer, Primary Results from the Phase III IMforte Trial.” So, what was your impression of this? Dr. Vamsi Velcheti: Yeah, I think this is definitely an interesting study, and small cell, I remember those days when we had barely any studies of small cell at ASCO, and now we have a lot of exciting developments in the small cell space. It's really good to see. The IMforte trial is essentially like a maintenance lurbinectedin trial with atezolizumab maintenance. And the study was a positive trial. The primary endpoint was a PFS, and the study showed improvement in both PFS and OS with the addition of lurbinectedin to atezolizumab maintenance. And definitely, it's a positive trial, met its primary endpoint, but I always am a little skeptical of adding maintenance cytotoxic therapies here in this setting. In my practice, and I'd like to hear your opinion, Nate, most patients with small cell after 4 cycles of a platinum doublet, they're kind of really beaten up. Adding more cytotoxic therapy in the maintenance space is going to be tough, I think, for a lot of patients. But also, most importantly, I think this rapidly evolving landscape for patients with small cell lung cancer with multiple new, exciting agents, actually like some FDA-approved like tarlatamab, also like a lot of these emerging therapeutics like I-DXd and other ADCs in this space. You kind of wonder, is it really optimal strategy to bring on like another cytotoxic agent right after induction chemotherapy, or do you kind of delay that? Or maybe have like a different strategy in terms of maintenance. I know that the tarlatamab maintenance trial is probably going to read out at some point too. I think it's a little challenging. The hazard ratio is also 0.73. As I said, it's a positive trial, but it's just incremental benefit of adding lurbi. And also on the trial, we need to also pay attention to the post-progression second-line treatments, number of patients who received tarlatamab or any other investigational agents.  So I think it's a lot of questions still. I'm not quite sure I'd be able to embrace this completely. I think a vast majority of my patients might not be eligible anyway for cytotoxic chemotherapy maintenance right away, but yeah, it's tough. Dr. Nate Pennell: Yeah. I would call this a single and not a home run. It definitely is real. It was a real overall survival benefit. Certainly not surprising that a maintenance therapy would improve progression-free survival. We've known that for a long time in small cell, but first to really show an overall survival benefit. But I completely agree with you. I mean, many people are not going to want to continue further cytotoxics after 4 cycles of platinum-doublet chemo. So I would say, for those that are young and healthy and fly through chemo without a lot of toxicity, I think certainly something worth mentioning. The problem with small cell, of course, is that so many people get sick so quickly while on that observation period after first-line chemo that they don't make it to second-line treatment. And so, giving everyone maintenance therapy essentially ensures everyone gets that second-line treatment. But they also lose that potentially precious few months where they feel good and normal and are able to be off of treatment. So, I would say this is something where we're really going to have to kind of sit and have that shared decision-making visit with patients and decide what's meaningful to them. Dr. Vamsi Velcheti: Yeah, I agree. The next abstract that was a Late-Breaking Abstract, 8000, “Overall Survival of Neoadjuvant Nivolumab Plus Chemotherapy in Patients With Resectable Non-Small Cell Lung Cancer in CheckMate-816.” This was a highly anticipated read-out of the OS data from 816. What did you make of this abstract? Dr. Nate Pennell: Yeah, I thought this was great. Of course, CheckMate-816 changed practice a number of years ago when it first reported out. So, this was the first of the neoadjuvant or perioperative chemoimmunotherapy studies in resectable non-small cell lung cancer. So, just to review, this was a phase 3 study for patients with what we would now consider stage II or stage IIIA resectable non-small cell lung cancer. And they received three cycles of either chemotherapy or chemotherapy plus nivolumab, and that was it. That was the whole treatment. No adjuvant treatment was given afterwards. They went to resection. And patients who received the chemoimmunotherapy had a much higher pathologic complete response rate and a much better event-free survival. And based on this, this regimen was approved and, I think, at least in the United States, widely adopted.  Now, since the first presentation of CheckMate 816, there have been a number of perioperative studies that have included an adjuvant component of immunotherapy – KEYNOTE-671, the AEGEAN study – and these also have shown improved outcomes. The KEYNOTE study with pembrolizumab also with an overall survival benefit. And I think people forgot a little bit about CheckMate-816. So, this was the 5-year overall survival final analysis. And it did show a statistically and, I think, clinically meaningful difference in overall survival with the 3 cycles of neoadjuvant chemo-nivo compared to chemo with a hazard ratio of 0.72. The 5-year overall survival of 65% in the chemo-IO group versus 55% with the chemo alone. So a meaningful improvement. And interestingly, that hazard ratio of 0.72 is very similar to what was seen in the peri-operative pembro study that included the adjuvant component. So, very much still relevant for people who think that perhaps the value of those neoadjuvant treatments might be really where most of the impact comes from this type of approach. They also gave us an update on those with pathologic complete response, showing really astronomically good outcomes. If you have a pathologic complete response, which was more than a quarter of patients, the long-term survival was just phenomenal. I mean, 95% alive at 5 years if they were in that group and suggesting that in those patients at least, the adjuvant treatment may not be all that important.  So, I think this was an exciting update and still leaves very much the open question about the importance of continuing immunotherapy after surgery after the neoadjuvant component. Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think the million-dollar question is: “Is there like a population of patients who don't have complete response but like maybe close to complete response?” So, would you like still consider stopping adjuvant IO? I probably would not be comfortable, but I think sometimes, you know, we all have patients who are like very apprehensive of continuing treatments. So, I think that we really need more studies, especially for those patients who don't achieve a complete CR. I think trying to find strategies for like de-escalation based on MRD or other risk factors. But we need more trials in that space to inform not just de-escalation, but there are some patients who don't respond at all to a neoadjuvant IO. So, there may be an opportunity for escalating adjuvant therapies. So, it is an interesting space to watch out for. Dr. Nate Pennell: No, absolutely. Moving to KRAS-mutant space, so our very common situation in patients with non-small cell lung cancer, we had the results of Abstract 8500, “First-Line Adagrasib With Pembrolizumab in Patients With Advanced or Metastatic KRASG12C-Mutated Non-Small Cell Lung Cancer” from the phase 2 portion of the KRYSTAL-7 study. Why was this an interesting and important study? Dr. Vamsi Velcheti: First of all, there were attempts to kind of combine KRASG12C inhibitors in the past with immune checkpoint inhibitors, notably sotorasib with pembrolizumab. Unfortunately, those trials have led to like a lot of toxicity, with increased especially liver toxicity, which was a major issue. This is a phase 2 study of adagrasib in combination with pembrolizumab, and this is a study in the frontline setting in patients with the G12C-mutant metastatic non-small cell lung cancer. And across all the PD-L1 groups, the ORR was 44%, and the median PFS was 11 months, comparable to the previous data that we have seen with adagrasib in this setting. So it's not like a major improvement in clinical efficacy. However, I think the toxicity profile that we were seeing was slightly better than the previous trials in combination with sotorasib, but you still have a fair amount of transaminitis even in the study. At this point, this is not ready for clinical primetime. I don't think we should be using sotorasib or adagrasib in the frontline or even in the second line in combination with checkpoint inhibitors. Combining these drugs with checkpoint inhibitors in the clinical practice might lead to adverse outcomes. So, we need to wait for more data like newer-generation G12C inhibitors which are also being studied in combination, so we'll have to kind of wait for more data to emerge in this space. Dr. Nate Pennell: I agree, this is not immediately practice changing. This is really an attempt to try to combine targeted treatment with immune checkpoint inhibitor. And I agree with you that, you know, it does appear to be perhaps a little bit better tolerated than some of the prior combinations that have tried in this space. The outcomes overall were not that impressive, although in the PD-L1 greater than 50%, it did have a better response rate perhaps than you would expect with either drug alone. And I do think that the company is focusing on that population for a future randomized trial, which certainly would inform this question better. But in the meantime, I agree with you, there's a lot of newer drugs that are coming along that potentially may be more active and better tolerated. And so, I'd say for now, interesting but we'll wait and see. Dr. Vamsi Velcheti: Yeah, so now moving back again to small cell. So, there was a Late-Breaking Abstract, 8008. This is a study of tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer. They presented the primary analysis of the phase III DeLLphi-304 study. What do you think about this? Dr. Nate Pennell: Yeah, I thought this was really exciting. This was, I would say, perhaps the most important lung study that was presented. Tarlatamab is, of course, the anti-DLL3 bispecific T-cell engager compound, which is already FDA approved based on a prior single-arm phase II study, which showed a very nice response rate as a single agent in previously treated small cell lung cancer and relatively manageable side effects, although somewhat unique to solid tumor docs in the use of these bispecific drugs in things like cytokine release syndrome and ICANS, the neurologic toxicities. So, this trial was important because tarlatamab was approved, but there were also other chemotherapy drugs approved in the previously treated space. And so, this was a head-to-head second-line competition comparison between tarlatamab and either topotecan, lurbinectedin, or amrubicin in previously treated small cell patients with a primary endpoint of overall survival. So, a very well-designed trial. And it did show, I think, a very impressive improvement in overall survival with a median overall survival in the tarlatamab group of 13.6 months compared to 8.3 months with chemotherapy, hazard ratio of 0.6. And progression-free survival was also longer at 4.2 months versus 3.2 months, hazard ratio of 0.72. In addition to showing improvements in cancer-related symptoms that were improved in tarlatamab compared to chemotherapy, there was actually also significantly lower rates of serious treatment-related adverse events with tarlatamab compared to chemotherapy. So, you do still see the cytokine release syndrome, which is seen in most people but is manageable because these patients are admitted to the hospital for the first two cycles, as well as a significant number of patients with neurologic side effects, the so-called ICANS, which also can be treated with steroids. And so, I think based upon the very significant improvement in outcomes, I would expect that this should become our kind of standard second-line treatment since it seems to be much better than chemo. However, tarlatamab is definitely a new drug that a lot of places are not used to using, and I think a lot of cancer centers, especially ones that aren't tied to a hospital, may have questions about how to deal with the CRS. So, I'm curious your thoughts on that. Dr. Vamsi Velcheti: Yeah, thank you, Nate. And I completely agree. I think the data looked really promising, and I've already been using tarlatamab in the second-line space. The durability of response and overall, having used tarlatamab quite a bit - like, I participated in some of the early trials and also used it as standard of care - tarlatamab has unique challenges in terms of like need for hospitalization for monitoring for the first few treatments and make sure, you know, we monitor those patients for CRS and ICANS. But once you get past that initial administration and monitoring of CRS, these patients have a much better quality of life, they're off chemotherapy, and I think it's really about the logistics of actually administering tarlatamab and coordination with the hospital and administration in the outpatient setting. It's definitely challenging, but I think it definitely can be done and should be done given what we are seeing in terms of clinical efficacy here. Dr. Nate Pennell: I agree. I think hospital systems now are just going to have to find a way to be able to get this on formulary and use it because it clearly seems to be more effective and generally better tolerated by patients. So, should move forward, I think. Finally, there's an abstract I wanted to ask you about, Abstract 8001, which is the “Neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone in resectable epidermal growth factor receptor-mutated non-small cell lung cancer: The NeoADAURA Study”. And this is one that I think was also fairly highly anticipated. So, what are your thoughts? Dr. Vamsi Velcheti: You know, I wasn't probably surprised with the results, and I believe we were all expecting a positive trial, and we certainly were handed a positive trial here. It's a phase III trial of osimertinib and chemotherapy or osimertinib in the neoadjuvant space followed by surgery, followed by osimertinib. It's a global phase 3 trial and very well conducted, and patients with stage II to stage IIIB were enrolled in the study. And in the trial, patients who had a neoadjuvant osimertinib with or without chemotherapy showed a significant improvement in major pathologic response rates over chemotherapy alone. And the EFS was also positive for osimertinib and chemotherapy, osimertinib monotherapy as well compared to chemotherapy alone. So overall, the study met its primary endpoint, and I think it sheds light on how we manage our patients with early-stage lung cancer. I think osimertinib, we know that osimertinib is already FDA approved in the adjuvant space, but what we didn't really know is how was osimertinib going to work in the neoadjuvant space. And there are always situations, especially for stage III patients, where we are on the fence about, are these patients already close to being metastatic? They have, like, almost all these patients have micrometastatic disease, even if they have stage III. As we saw in the LAURA data, when you look at the control arm, it was like a very short PFS. Chemoradiation does nothing for those patients, and I think these patients have systemic mets, either gross or micrometastatic disease at onset. So, it's really important to incorporate osimertinib early in the treatment course. And I think, especially for the locally advanced patients, I think it's even more important to kind of incorporate osimertinib in the neoadjuvant space and get effective local control with surgery and treat them with adjuvant. I'm curious to hear your thoughts, Nate. Dr. Nate Pennell: I am a believer and have long been a believer in targeted adjuvant treatments, and, you know, it has always bothered me somewhat that we're using our far and away most effective systemic therapy; we wait until after they go through all their pre-op treatments, they go through surgery, then they go through chemotherapy, and then finally months later, they get their osimertinib, and it still clearly improves survival in the adjuvant setting. Why not just start the osimertinib as soon as you know that the patient has EGFR-mutant non-small cell lung cancer, and then you can move on to surgery and adjuvant treatment afterwards? And I think what was remarkable about this study is that all of these patients almost - 90% in each arm - went to surgery. So, you weren't harming them with the neoadjuvant treatment. And clearly better major pathologic response, nodal downstaging, event-free survival was better. But I don't know that this trial is ever going to show an overall survival difference between neoadjuvant versus just surgery and adjuvant treatment, given how effective the drug is in the adjuvant setting. Nonetheless, I think the data is compelling enough to consider this, certainly for our N2-positive, stage IIIA patients or a IIIB who might be otherwise surgical candidates. I think based on this, I would certainly consider that. Dr. Vamsi Velcheti: Yeah, and especially for EGFR, like even for stage IIIB patients, in the light of the LAURA study, those patients who do not do too well with chemoradiation. So you're kind of delaying effective systemic therapy, as you said, waiting for the chemoradiation to finish. So I think probably time to revisit how we kind of manage these locally advanced EGFR patients. Dr. Nate Pennell: Yep, I agree. Dr. Vamsi Velcheti: Nate, thank you so much for sharing your fantastic insights today on the ASCO Daily News Podcast. It's been an exciting ASCO again. You know, we've seen a lot of positive trials impacting our care of non-small cell lung cancer and small cell lung cancer patients. Dr. Nate Pennell: Thanks for inviting me, Vamsi. Always a pleasure to discuss these with you. Dr. Vamsi Velcheti: And thanks to our listeners for your time today. You will find links to all of the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review, subscribe wherever you get your podcast. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today's speakers:    Dr. Vamsi Velcheti   @VamsiVelcheti    Dr. Nathan Pennell   @n8pennell   Follow ASCO on social media:     @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn   ASCO on BlueSky   Disclosures:   Dr. Vamsi Velcheti:   Honoraria: ITeos Therapeutics   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus   Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Nathan Pennell:     Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron    Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi 

Dr. Shaalan Beg and Dr. Kristen Ciombor discuss practice-changing studies in GI cancers and other novel treatment approaches that were presented at the 2025 ASCO Annual Meeting. Transcript Dr. Shaalan Beg: Hello, I'm Dr. Shaalan Beg, welcoming you to the ASCO Daily News Podcast. I'm a medical oncologist and an adjunct associate professor at UT Southwestern Medical Center in Dallas, Texas. There were some remarkable advances in gastrointestinal cancers that were presented at the 2025 ASCO Annual Meeting, and I'm delighted to be joined by Dr. Kristen Ciombor to discuss some exciting GI data. Dr. Ciombor is the Ingram Associate Professor of Cancer Research and a co-leader of Translational Research and the Interventional Oncology Research Program at the Vanderbilt Ingram Cancer Center. Our full disclosures are available in the transcript of this episode. Dr. Ciombor, it's great to have you on the podcast today. Dr. Kristen Ciombor: Thanks, Dr Beg. It's great to be here. Dr. Shaalan Beg: Alright, let's kick it off. Big year for GI cancers. We'll start off with LBA1. This was the ATOMIC study sponsored by NCI and the National Clinical Trials Network (NCTN) and the Alliance group. This is a randomized study of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for stage III mismatch repair deficient colorectal cancer. Dr. Kristen Ciombor: I think this study was really definitely practice-changing, as you can tell because it was a Plenary. But I do have some concerns in terms of how we're actually going to implement this and whether this is the final answer in this disease subtype. So, as you said, the patients were enrolled with stage III resected mismatch repair deficient colon cancer, and then they were randomized to either modified FOLFOX6 with or without atezolizumab. And that's where it starts to become interesting because not many of us give FOLFOX for 6 months like was done in this study. Obviously, the study was done over many years, so that was part of that answer, but also the patients received atezolizumab for a total of 12 months. So the question, I think, that comes from this abstract is, is this practical and is this the final answer? I do think that this is practice-changing, and I will be talking to my patients with resected mismatch repair deficient colon cancer about FOLFOX plus atezolizumab. I think the big question is, do these patients need chemotherapy? And can we do a neoadjuvant approach instead? And that's where we don't have all the answers yet. Dr. Shaalan Beg: Yeah, but it has been great to see immunotherapy make its way into the adjuvant space after having made such a big impact in the metastatic space, but still some unanswered questions in terms of the need for chemotherapy and then the duration of therapy, which I guess we'll have to stay tuned in for the next couple of years to to get a lot of those questions answered. Dr. Kristen Ciombor: Yeah, but a big congratulations to the study team, to the NCTN, the NCI. I mean, this is really a great example of federally funded research that needs to continue. So, great job by the study team. The DFS 10% difference is really very large and certainly a practice-changing study. Dr. Shaalan Beg: Yeah, and and sticking with colon cancer, and and this another federally funded study, but this time funded by a Canadian cancer clinical trials group was LBA3510. This is the CHALLENGE study. It's a randomized phase 3 trial of the impact of a structured exercise program on disease-free survival for stage III or high-risk stage II colon cancer. This study got a lot of buzz, a lot of mainstream press coverage, and a lot of discussions on what that means for us for the patients who we're going to be seeing next week in our clinic. What was your takeaway? Dr. Kristen Ciombor: Yeah, this is a really interesting study, and I was so glad to see it presented because this partially answers one of the questions that patients always have for us in clinic, right? You know, once they've completed their standard chemotherapy and surgery, what else can they do to help prevent recurrence? And so we've always known and sort of extrapolated that healthy lifestyle habits are good, but now we have data, particularly in these patients. Most of them were stage III colon cancer patients, those had high-risk stage II cancer. And basically, the goal was to increase their physical activity by at least 10 MET hours per week. So, my big question, of course, as I came into this presentation was, “Okay, what does that mean exactly? How does that translate to real life?” And really what the author presented and explained was that basically most patients could hit their target by adding a 45- to 60-minute brisk walk 3 to 4 times a week. So I think this is very approachable.  Now, in the confines of the study, this was a structured exercise program, so it wasn't just patients doing this on their own. But I do think kind of extrapolating from that, that this is very achievable for most patients. And not only did this prevent recurrence of their prior cancer, but actually the rate of new primary cancer diagnoses, was less, which is really interesting, especially in the breast and prostate cancer. So this was a really interesting, and I think practice-changing study as well, especially given that this is something that most patients can do. Dr. Shaalan Beg: Yeah, and there was a lot of discussion in the hallways after the presentation in terms of how this really changes our existing practice because most folks already recommend exercise as a way for improving outcomes in cancer patients. So we've already been doing that. Now we have some data on how much it can impact the benefit. But there was some discussion about what the actual degree of impact was. There was a drop-off rate in terms of how long folks were able to stick with this exercise regimen. But you've seen this in clinic when someone have their surgery, they have their chemotherapy, they've been so intimately involved with the oncology world, with the oncology practice, and they somehow feel that they're being let loose into this mean, angry world without any guidance and they're looking for something to do. “What more can I do in terms of my lifestyle?” And then here we have very solid data, as solid as can be for an intervention like exercise, showing that there is an impact and you can give a prescription for exercise when someone wraps up their chemotherapy for colon cancer, thanks to the study. Dr. Kristen Ciombor: Yeah. It was a great study. Dr. Shaalan Beg: Moving to gastroesophageal cancer, another late-breaking abstract. This is LBA5. The MATTERHORN trial was a phase 3 trial of durvalumab plus FLOT for resectable GE junction and gastric cancer. And again, another area where immunotherapy has made an impact, and here we're seeing it move closer for earlier-stage disease. What was your take-home for the MATTERHORN trial? Dr. Kristen Ciombor: Yeah, so this study looked at neoadjuvant perioperative durvalumab plus our current standard chemotherapy of FLOT versus placebo plus FLOT. And this was a large study, almost 1,000 patients were randomized. And the primary endpoint was event-free survival, and it was definitely met in favor of the D + FLOT arm, as Dr. Klempner discussed after Dr Janjigian's presentation. I do think there are still some unanswered questions here. Overall survival is not yet mature, so we do have to wait and see how that shakes out. But it's very interesting and kind of is reflective of what, as you said, we're looking at earlier and earlier lines of therapy, particularly with immunotherapy, in these GI cancer spaces. So it makes a lot of sense to test this and and to look at this. So the toxicity was pretty similar to what we would expect. Primary endpoint was met, but again, we'll have to wait and see what the survival data looks like. Dr. Shaalan Beg: Yeah, and in oncology, we know, especially for treatment that does add additional cost, it does add additional potential toxicity that we want to see that overall survival nudged. I did see some polls on social media asking folks whether their practices changed from this, and I think the results were favoring adding durvalumab for this group of patients but understanding that there are caveats to the addition of treatments and the eventual FDA approval in that indication as well. Dr. Kristen Ciombor: Exactly. I completely agree with that. Dr. Shaalan Beg: All right. How about we stick with gastroesophageal cancer? LBA4002 was trastuzumab deruxtecan versus ramucirumab plus paclitaxel for second-line treatment in HER2-positive unresectable or metastatic gastric cancer or GE junction cancer. This was the DESTINY-Gastric04 study. And again, antibody-drug conjugates making a big impact across different diseases. And here we have more data in the HER2-positive gastric cancer space. Your thoughts on this study? Dr. Kristen Ciombor: Yeah, so this is a really important space in gastroesophageal cancer because the HER2 positivity rate is fairly high as compared to some of our other tumor types. So, I do think one of the important things was that patients did have biopsy confirmation of HER2 status, which was very important, and then they were randomized to either T-DXd versus the kind of second-line standard of ramucirumab-paclitaxel. So this was a great practical study and really answers a question that we had for a while in terms of does anti-HER2 therapy in the second-line really impact and improve survival. So we did see a statistically significant improvement favoring T-DXd. I do think it's always important to look at toxicity, though, too. And there was about almost 14% rate of interstitial lung disease, which of course is the most feared toxicity from some of these antibody-drug conjugates, especially T-DXd. So I do think it's important to keep that in mind, but this is definitely a great addition to the armamentarium for these HER2-positive patients. Dr. Shaalan Beg: And pancreas cancer was on the stage after a very long time with a positive clinical trial. This is Abstract 4006. These were preliminary results from a phase 2 study of elraglusib in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel alone for previously untreated metastatic pancreas cancer. This is a frontline clinical trial of gemcitabine/nab-paclitaxel plus/minus the study drug. There were other cohorts in this study as well, but they reported the results of their part 3B arm. And great to see some activity in the pancreas space. And your thoughts? Dr. Kristen Ciombor: Yeah, we definitely need better treatments in pancreas cancer. This was a very welcome presentation to see. The elraglusib is an inhibitor of GSK-3beta, and it's thought that that mediates drug resistance and EMT. And so this is, I think, a perfect setting to test this drug. So patients basically were randomized. Patients with metastatic pancreas cancer were randomized 2: 1 to gemcitabine/nab-paclitaxel plus or minus this elraglusib. So, what we saw was that overall survival was better with the addition of this new drug. And overall, not only the 1-year overall survival, but also median overall survival.  The thing that was interesting, though, was that we saw that the overall survival rates were 9.3 months with the combination versus 7.2 months with just gemcitabine/nab-paclitaxel. And that's a little bit lower than we've seen in other studies. So, not sure what was going on there. Was it the patients that were a bit sicker? Was it a patient selection, you know, thing? I'm not really sure how to explain that so much. Also, the toxicity profile was much higher in terms of visual impairment, with over 60% of patients being treated with the combination versus 9% with gemcitabine/nab-paclitaxel. So these were mild, grade 1 and 2, but still something to be cautious about. Dr. Shaalan Beg: And especially with this being a phase 2 trial, making sure that in a larger study we're able to better evaluate the toxicity and see if the control arm in the larger confirmatory study performs differently will be really important before this compound makes it to the clinic in our space. But very exciting to see these kinds of results for pancreas adenocarcinoma. Dr. Kristen Ciombor: Yeah. Dr. Shaalan Beg: We've talked, it seems, a couple of times on this podcast about the BREAKWATER clinical trial. We did hear PFS and updated OS data, updated overall survival data on first-line encorafenib plus cetuximab plus modified FOLFOX6 for BRAF-mutated colorectal cancer. This was LBA3500. And eagerly anticipated results – we have all previously heard the progression-free survival results – but here we heard updated overall survival results, and very well-received study it seemed from the audience that time. So what are your takeaways on the updated results for BREAKWATER? Dr. Kristen Ciombor: In my opinion, this was one of the most practice-confirming studies. As you mentioned, we've already seen some of the preliminary data of BREAKWATER at prior meetings. But really what was particularly impactful for me was the median overall survival with the BREAKWATER regimen. So, again, patients received FOLFOX, encorafenib cetuximab in the first line if they had BRAF-mutated V600E-mutated colorectal cancer. And the median PFS was 12.8 months, which was actually really remarkable in this traditionally very aggressive, poor prognosis subtype of tumors. So, by seeing a median overall survival of 30.3 months was just incredible, in my opinion. Just a few years ago, that was considered the median overall survival for all comers for metastatic colorectal cancer. And we know the median overall survival was more in the less than 12 months range for BRAF. So this was incredibly impactful, and I think should be absolutely practice-changing for anyone who is eligible for this regimen.  I think again, where the practice meets the study is what's kind of important to think about too, how long did patients get FOLFOX, and certainly it adds toxicity to add a BRAF-targeted regimen on top of FOLFOX already. So, one of the other interesting things about the study, though, was that even though it didn't complete treatment, they actually did look at encorafenib/cetuximab alone and in the first line without chemotherapy. And those preliminary results actually looked okay, especially for patients who might not be able to tolerate chemotherapy, which we certainly see in practice. So, overall, definitely more data. And I agree that it's certainly practice-changing. Dr. Shaalan Beg: And it completely, as you mentioned, changes the outlook for a person who's diagnosed with BRAF-mutated metastatic colon cancer today versus even 7 or 8 years ago. Dr. Kristen Ciombor: And we're seeing this over and over in other subtypes too, but how you choose to treat the patient up front really matters. So really giving the right regimen up front is the key here. Dr. Shaalan Beg: And along the same lines, Abstract 3501 wanted to answer the question on whether people with MSI-high metastatic colorectal cancer need double checkpoint inhibitor therapy or is single therapy enough. So this [CheckMate-8HW] study compared nivo plus ipi with nivo alone, nivo monotherapy for MSI-high metastatic colorectal cancer. And we've known that both of these are fairly active regimens, but we also know the chance of immune-related adverse events is significantly higher with combination therapy. So this was a much-needed study for this group of patients. And what were your takeaways here? Dr. Kristen Ciombor: This, of course, has been really nivo-ipi in the first-line MSI-high metastatic colorectal cancer is now a standard of care. And not everybody is eligible for it, and there could be reasons, toxicity reasons, and other things too. But as we've been seeing for the last couple of years, immunotherapy clearly beats chemo in this space. And now looking at doublet versus single immunotherapy treatment in the first line, I think really nivo-ipi does beat out monotherapy. I will say, however, there is a caveat in that we still haven't seen the nivo-ipi versus nivo in the first line. So what has been presented thus far has been across all lines of therapy, and that does muddy the waters a little bit. So definitely looking forward and and we've asked this many times and based on the statistical plan and and what not, you know, we just haven't seen that data yet. But I do think it's becoming increasingly important to consider doublet immunotherapy for these patients as long as there are no contraindications. With the again, with the caveat that we have to have these toxicity discussions in the clinic with patients because many patients can tolerate it, you know, this regimen fairly well, but there can be very severe toxicities. So, I think an informed discussion should really be had with each patient before moving forward. Dr. Shaalan Beg: Yeah, informed decision, making them aware of the potential of real significant toxicities, immune-related toxicities with double therapy. But I am curious in your practice, how often do you see people choosing doublet therapy as frontline? Dr. Kristen Ciombor: So patients are really savvy, and a lot of times they've heard this data before or have come across it in patient advocacy groups and other things, and it's really nice to be able to have that conversation of the risk versus benefit. So I will say not all of my patients choose doublet, and many of them are still cured with immunotherapy monotherapy. So the big question there is, will we ever understand who actually needs the doublet versus who can still be cured or have very good long-term outcomes with just the single agent? And that has not been answered yet. Dr. Shaalan Beg: What a great point. So the last abstract I was hoping we could talk about is POD1UM-303 or the INTERAACT2 subgroup analysis and impact of delayed retifanlimab treatment for patients with squamous cell carcinoma of the anal canal. What were your thoughts here? Dr. Kristen Ciombor: This was a study, actually we saw at ESMO, we saw the primary data at ESMO last year, and this was an update with some exploratory analyses. But this was really an important study because once again, we're looking at immunotherapy in later lines of therapy. That's how we started looking at and investigating immunotherapy, and now we're moving it up and up in the treatment course. So this was a study of carboplatin/paclitaxel plus or minus retifanlimab. Actually it was retifanlimab versus placebo. And it was a positive study, as we heard last year. This actually led to FDA approval of this regimen last month, just before ASCO, and it has now been incorporated in the NCCN guidelines as the preferred first-line option.  So what I thought was important from the additional data presented at ASCO was looking at the different subgroups, it did not appear that patients with liver mets or not had different outcomes. So that was really good to see because sometimes in colon cancer we see that immunotherapy doesn't work as well when patients have liver mets. And interestingly, because we use immunotherapy in anal cancer without any biomarkers, unlike with colon cancer or some of the other tumor types, also the authors looked at PD-L1 status, and it did look like maybe patients did a little bit better if they had higher PD-L1 expression, but patients still could benefit even if they were PD-L1 negative. So that was important, I think, and we will continue to see further data come out from this study. I want to mention also that EA2176 just completed accrual, so that was carbo-taxol plus or minus nivolumab. And so we should be seeing that data sometime soon, which will hopefully also confirm the ongoing role for immunotherapy in the first-line setting for anal cancer. Dr. Shaalan Beg: That was a fantastic review. Thank you, Dr Ciombor. Thanks for sharing your valuable insights with us today on the ASCO Daily News Podcast. Dr. Kristen Ciombor: Thanks for having me here. Dr. Shaalan Beg: And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. And if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe, wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today's speakers:   Dr. Shaalan Beg  @ShaalanBeg  Dr. Kristen Ciombor @KristenCiombor Follow ASCO on social media:    @ASCO on Twitter   @ASCO on BlueSky  ASCO on Facebook    ASCO on LinkedIn    Disclosures:   Dr. Shaalan Beg:   Consulting or Advisory Role: Ipsen, Cancer Commons, Foundation Medicine, Science37, Nant Health, Lindus Health Speakers' Bureau: Sirtex Research Funding (Inst.): Delfi Diagnostics, Universal Diagnostics, Freenome Dr. Kristen Ciombor: Consulting or Advisory Role: Pfizer, Incyte, Exelixis, Bayer, ALX Oncology, Tempus, Agenus, Taiho Oncology, Merck, BeiGene Research Funding (Inst.): Pfizer, Boston Biomedical, MedImmune, Onyx, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Incyte, Amgen, Sanofi, Bristol-Myers Squibb, Array BioPharma, Incyte, Daiichi Sankyo, Nucana, Abbvie, Merck, Pfizer/Calthera, Genentech, Seagen, Syndax Travel, Accommodations, Expenses: Incyte, Tempus

Dr. Allison Zibelli and Dr. Rebecca Shatsky discuss advances in breast cancer research that were presented at the 2025 ASCO Annual Meeting, including a potential new standard of care for HER2+ breast cancer, the future of ER+ breast cancer management, and innovations in triple negative breast cancer therapy. Transcript Dr. Allison Zibelli: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Allison Zibelli, your guest host of the podcast today. I'm an associate professor of medicine and a breast medical oncologist at the Sidney Kimmel Comprehensive Cancer Center at Jefferson Health. There was a substantial amount of exciting breast cancer data presented at the 2025 ASCO Annual Meeting, and I'm delighted to be joined by Dr. Rebecca Shatsky today to discuss some of these key advancements. Dr. Shatsky is an associate professor of medicine at UC San Diego and the head of breast medical oncology at the UC San Diego Health Moores Cancer Center, where she also serves as the director of the Breast Cancer Clinical Trials Program and the Inflammatory and Triple-Negative Breast Cancer Program.  Our full disclosures are available in the transcript of this episode. Dr. Shatsky, it's great to have you on the podcast today. Dr. Rebecca Shatsky: Thanks, Dr. Zibelli. It's wonderful to be here. Dr. Allison Zibelli: So, we're starting with DESTINY-Breast09, which was trastuzumab deruxtecan and pertuzumab versus our more standard regimen of taxane, trastuzumab pertuzumab for first-line treatment of metastatic HER2-positive breast cancer. Could you tell us a little bit about the study? Dr. Rebecca Shatsky: Yeah, absolutely. So, this was a long-awaited study. When T-DXd, or trastuzumab deruxtecan, really hit the market, a lot of these DESTINY-Breast trials were started around the same time. Now, this was a global, randomized, phase 3 study presented by Dr. Sara Tolaney from the Dana-Farber Cancer Institute of Harvard in Boston. It was assessing essentially T-DXd in the first-line setting for metastatic HER2-positive breast cancer in addition to pertuzumab. And that was randomized against our standard-of-care regimen, which was established over a decade ago by the CLEOPATRA trial, and we've all been using that internationally for at least the past 10 years. So, this was a large trial, and it was one-to-one-to-one of patients getting T-DXd plus pertuzumab, T-DXd alone, or THP, which mostly is used as docetaxel and trastuzumab and pertuzumab every three weeks for six cycles. And this was in over 1,000 patients; it was 1,159 patients with metastatic HER2-positive breast cancer. This was a very interesting trial. It was looking at the use of trastuzumab deruxtecan, but patients were started on this treatment for their first-line metastatic HER2-positive breast cancer with no end date to their T-DXd. So, it was, you know, you were started on T-DXd every 3 weeks until progression. Now, CLEOPATRA is a little bit different than that, though, as we know. So, CLEOPATRA has a taxane plus trastuzumab and pertuzumab. But generally, patients drop the taxane after about six to seven cycles because, as we know, you can't be really on a taxane indefinitely. You get pretty substantial neuropathy as well as cytopenias, other things that end up happening. And so, in general, that regimen has sort of a limited time course for its chemotherapy portion, and the patients maintained after the taxane is dropped on their trastuzumab and their pertuzumab, plus or minus endocrine therapy if the investigator so desires. And the primary endpoint of the trial was progression-free survival by blinded, independent central review (BICR) in the intent-to-treat population. And then it had its other endpoints as overall survival, investigator-assessed progression-free survival, objective response rates, and duration of response, and of course, safety. As far as the results of this trial, so, I think that most of us key opinion leaders in breast oncology were expecting that this was going to be a positive trial. And it surely was. I mean, this is a really, really active drug, especially in HER2-positive disease, of course. So, the DESTINY-Breast03 data really established that, that this is a very effective treatment in HER2-positive metastatic breast cancer. And this trial really, again, showed that. So, there were 383 patients that ended up on the trastuzumab plus deruxtecan plus pertuzumab arm, and 387 got THP, the CLEOPATRA regimen. What was really interesting also to note of this before I go on to the results was that 52% of patients on this trial had de novo metastatic disease. And that's pretty unusual for any kind of metastatic breast cancer trial. It kind of shows you, though, just how aggressive this disease is, that a lot of patients, they present with de novo metastatic disease. It's also reflecting the global nature of this trial where maybe the screening efforts are a little bit less than maybe in the United States, and more patients are presenting as later stage because to have a metastatic breast cancer trial in the United States with 52% de novo metastatic disease doesn't usually happen. But regardless, the disease characteristics were pretty well matched between the two groups. 54% of the patients were triple positive, or you could say hormone-positive because whether they were PR positive or ER positive and PR negative doesn't really matter in this disease. And so, the interim data cutoff was February of this year, of 2025. So, the follow-up so far has been about 29 months, so the data is still really immature, only 38% mature for progression-free survival interim analysis. But what we saw is that T-DXd plus pertuzumab, it really improved progression-free survival. It had a hazard ratio that was pretty phenomenal at 0.56 with a confidence interval that was pretty narrow of 0.44 to 0.71. So, very highly statistically significant data here. The progression-free survival was consistent across all subgroups. Overall survival, very much immature at this time, but of course, the trend is towards an overall survival benefit for the T-DXd group. The median durable response with T-DXd plus pertuzumab exceeded 3 years. Now, importantly, though, I want to stress this, is grade 3 or above treatment-emergent adverse events occurred in both subgroups pretty equally. But there were 2 deaths in the T-DXd group due to interstitial lung disease. And there was a 12.1% adjudicated drug-induced interstitial lung disease/pneumonitis event rate in the T-DXd group and only 1%, and it was grade 1-2, in the THP group. So, that's really the caveat of this therapy, is we know that a percentage of patients are going to get interstitial lung disease, and that some may have very serious adverse events from it. So, that's always something I keep in the back of my mind when I treat patients with T-DXd. And so, overall, the conclusions of the trial were pretty much a slam dunk. T-DXd plus pertuzumab, it had a highly statistically significant and clinically meaningful improvement in progression-free survival versus the CLEOPATRA regimen. And that was across all subgroups for first-line metastatic HER2-positive breast cancer here. And so, yeah, the data was pretty impressive. Just to go into the overall response rate, because that's always super important as well, you had 85.1% of patients having a confirmed overall RECIST response rate in the T-DXd plus pertuzumab group and a 78.6 in the CLEOPATRA group. The complete CR rate, complete response was 15.1% in the T-DXd group and 8.5 in the CLEOPATRA regimen. And it was really an effective regimen in this group, of course. Dr. Allison Zibelli: So, the investigators say at the end of their abstract that this is the new standard of care. Would you agree with that statement? Dr. Rebecca Shatsky: Yeah, that was a bold statement to make because I would say in the United States, not necessarily at the moment because the quality of life here, you have to think really hard about. Because one thing that's really important about the DESTINY-Breast09 data is that this was very much an international trial, and in many of the countries where patients enrolled on this, they were not able to access T-DXd off trial. And so, for them, this means T-DXd now or potentially never. And so, that is a really big difference whereas internationally, that may mean standard of care. However, in the US, patients have no issues accessing T-DXd in the second- or third-line settings. And right now, it's the standard of care in the second line in the United States, with all patients basically getting this second-line therapy except for some unique patients where they may be doing a PATINA trial regimen, which we saw at San Antonio Breast Cancer in 2024 of the triple-positive patients getting hormonal therapy plus palbociclib, which had a really great durable response. That was super impressive as well. Or there is the patient that the investigator can pick KADCYLA because the patient really wants to preserve their hair or maybe it's more indolent disease. But the quality of life on T-DXd indefinitely in the first-line setting is a big deal because, again, that CLEOPATRA regimen allows patients to drop their chemotherapy component about five to six months in. And with this, you're on a drug that feels very chemo-heavy indefinitely. And so, I think there's a lot more to investigate as far as what we're going to do with this data in the United States because it's a lot to commit a patient in the first-line metastatic setting. These de novo metastatic patients, some of them may be cured, honestly, on the HER2-targeting regimen. That's something we see these days. Dr. Allison Zibelli: So, very interesting trial. I'm sure we'll be talking about this for a long time.  So, let's move on to SERENA-6, which was, I thought, a very interesting trial. This trial took patients with ER positive, advanced breast cancer after six months on an AI (aromatase inhibitor) and a CDK4/6 inhibitor. They did ctDNA every two to three months, and when they saw an ESR1 mutation emerge, they changed half of the patients to camizestrant plus CDK4/6 and kept the other half on the AI plus CDK4/6. Can you talk about that trial a little bit, please? Dr. Rebecca Shatsky: Yeah, so this was a big trial at ASCO25. This was presented as a Plenary Session. So, this was camizestrant plus a CDK4/6 inhibitor, and it could have been any of the three, so palbo, ribo, or abemaciclib in the first-line metastatic hormone-positive population, and patients were on an AI with that. They were, interestingly, tested by ctDNA at baseline to see if they had an ESR1 mutation. So, that was an interesting feature of this trial. But patients had to have already been on their CDK4/6 inhibitor plus AI for at least 6 months to enroll. And then, as you mentioned, they got ctDNA testing every 2 to 3 months. This was also a phase 3, double-blind, international trial. And I do want to highlight again, international here, because that's important when we're considering some of this data in the U.S. because it influences some of the results. So, this was presented by Dr. Nick Turner of the Royal Marsden in the UK. So, just a little bit of background for our listeners on ESR1 mutations and why they're important. This is the most common, basically, acquired resistance mutation to patients being treated with aromatase inhibitors. We know that treatment with aromatase inhibitors can induce this. It makes a conformational change in the estrogen receptor that makes the estrogen receptor constitutively active, which allows the cell to signal despite the influence of the aromatase inhibitor to decrease the estrogen production so that the ligand binding doesn't matter as much as far as the cell signaling and transcription is concerned. And camizestrant, you know, as an oral SERD, just to explain that a little bit too; these are estrogen receptor degraders. The first-in-class of a selective estrogen receptor degrader to make it to market was fulvestrant. And that's really been our standard-of-care estrogen degrader for the past 25 years, almost 25 years. And so, a lot of us are just looking for some of these oral SERDs to replace that. But regardless, they do tend to work in the ESR1-mutated population. And we know that patients on aromatase inhibitors, the estimates of patients developing an ESR1 mutation, depending on which study you look at, somewhere between 30% to 50% overall, patients will develop this mutation with hormone-positive metastatic breast cancer. There is a small percentage of patients that have these at baseline without even treatment of an aromatase inhibitor. The estimates of that are somewhere between 0.5 and up to 5%, depending on the trial you look at and the population. But regardless, there is a chance someone on their CDK4/6 inhibitor plus AI at 6 months' time course could have had an ESR1 mutation at that time. But anyway, so they got this ctDNA every 2 to 3 months, and once they were found to develop an ESR1 mutation, the patients were then switched to the oral SERD. AstraZeneca's version of the oral SERD is camizestrant, 75 mg daily. And then their type of CDK4/6 inhibitor was maintained, so they didn't switch the brand of their CDK4/6 inhibitor, importantly. And that was looked at then for progression-free survival, but these were patients with measurable disease by RECIST version 1.1. And the data cut off here was November of 2024. This was a big trial, you know, and I think that that's influential here because this was 3,256 patients, and that's a lot of patients. So, they were all eligible. And then 315 patients ended up being randomized to switch to camizestrant upon presence of that ESR1 mutation. So, that was 157 patients. And then the other half, so they were randomized 1:1, they continued on their AI without switching to an oral SERD. That was 158 patients. They were matched pretty well. And so, their baseline characteristics, you know, the two subgroups was good. But this was highly statistically significant data. I'm not going to diminish that in any way. Your hazard ratio was 0.44. Highly statistically significant confidence intervals. And you had a median progression-free survival in those that switched to camizestrant of 16 months, and then the non-switchers was 9.2 months. So, the progression-free survival benefit there was also consistent across the subgroups. And so, you had at 12 months, the PFS rate was 60.7% for the non-treatment group and 33.4% in the treatment group. What's interesting, though, is we don't have overall survival data. This is really immature, only 12% mature as far as overall survival. And again, because this was an international trial and patients in other countries right now do not have the access to oral SERDs that the United States does, the crossover rate, they were not allowed to crossover, and so, a very few patients, when we look at progression-free survival 2 and ultimately overall survival, were able to access an oral SERD in the off-trial here and in the non-treatment group. And so, that's really important as far as we look at these results. Adverse events were pretty minimal. These are very safe drugs, camizestrant and all the other oral SERDs. They have some mild toxicities. Camizestrant is known for something weird, which is called photopsia, which is some flashing lights in the periphery of the eye, but it doesn't seem to have any serious clinical significance that we know of. It has a little bit of bradycardia, but it's otherwise really well tolerated. You know, I hate to say that because that's very subjective, right? I'm not the one taking the drug. But it doesn't have any serious adverse events that would cause discontinuation. And that's really what we saw in the trial. The discontinuation rates were really low. But overall, I mean, this was a positive trial. SERENA-6 showed that switching to camizestrant at the first sign of an ESR1 mutation on CDK4/6 inhibitor plus AI improved progression-free survival. That's all we can really say from it right now. Dr. Allison Zibelli: So, let's move on to ASCENT-04, which was a bit more straightforward. Sacituzumab govitecan plus pembrolizumab versus chemotherapy plus pembrolizumab in PD-L1-positive, triple-negative breast cancer. Could you talk about that study? Dr. Rebecca Shatsky: Yeah, so this was also presented by the lovely Sara Tolaney from Dana-Farber. And this study made me really excited. And maybe that's because I'm a triple-negative breast cancer person. I mean, not to say that I don't treat hundreds of patients with hormone- positive, but our unmet needs in triple negative are huge because this is a disease where you have got to throw your best available therapy at it as soon as you can to improve survival because survival is so poor in this disease. The average survival with metastatic triple-negative breast cancer in the United States is still 13-18 months, and that's terrible. And so, for full disclosure, I did have this trial open at my site. I was one of the site PIs. I'm not the global PI of the study, obviously. So, what this study was was for patients who had had at least a progression-free survival of 6 months after their curative intent therapy or de novo metastatic disease. They were PD-L1 positive as assessed by the Dako 22C3 assay of greater than or equal to a CPS score of 10. So, that's what the KEYNOTE-355 trial was based on as well. So, standard definition of PD-L1 positive in breast cancer here. And basically, these patients were randomized 1:1 to either their sacituzumab govitecan plus pembrolizumab, day 1 they got both therapies, and then day 8 just the saci, as is standard for sacituzumab. And then the other group got the KEYNOTE-355 regimen. So, that is pembrolizumab with – your options are carbogem there, paclitaxel or nab-paclitaxel. And it's up to investigator's decision which upon those they decided. They followed these patients for disease progression or unacceptable toxicity. It was really an impressive trial in my opinion because we know already that this didn't just improve progression-free survival, because survival is so poor in this disease, of course, we know that it improved overall survival. It's trending towards that very much, and I think that's going to be shown immediately. And then the objective response rates were better, which is key in this disease because in the first-line setting, you've got a lot of people who, especially your relapsed TNBC that don't respond to anything. And you lose a ton of patients even in the first-line setting in this disease. And so, this was 222 patients to chemotherapy and pembro and 221 to sacituzumab plus pembro. Median follow-up has only been 14 months, so it's still super early here. Hazard ratio so far of progression-free survival is 0.65, highly statistically significant, narrow confidence intervals. And so, the median duration of response here for the saci group was 16.5 months versus 9.2 months. So, you're getting a 7-month progression-free survival benefit here, which in triple negative is pretty fantastic. I mean, this reminds me of when we saw the ASCENT data originally come out for sacituzumab, and we were all just so happy that we had this tool now that doubled progression-free and overall survival and made such a difference in this really horrible disease where patients do poorly. So, OS is technically immature here, but it's really trending very heavily towards improvement in overall survival. Importantly, the treatment-related adverse events in this, I mean, we know sacituzumab causes neutropenia, people who are experienced with this drug know how to manage it at this point. There wasn't any really unexpected treatment-related adverse events. You get some people with sacituzumab who have diarrhea. It's usually pretty manageable with some Imodium. So, it was cytopenias predominantly in this disease in this population that were highlighted as far as adverse events. But I'm going to be honest, like I was surprised that this wasn't the plenary over the SERENA-6 data because this, in my mind, there we have a practice-changing trial. I will immediately be trying to use this in my PD-L1 population because, to be honest, as a triple-negative breast cancer clinical specialist, when I get a patient with metastatic triple-negative breast cancer who's PD-L1 positive, I think, "Oh, thank God," because we know that part of the disease just does better in general. But now I have something that really could give them a durable response for much longer than I ever thought possible when I started really heavily treating this disease. And so, this was immediately practice-changing for me. Dr. Allison Zibelli: I think that it's pretty clear that this is at least an option, if not the option, for this group of patients. Dr. Rebecca Shatsky: Yeah, the duration of responses here was – it's just really important because, I mean, I do think this will make people live longer. Dr. Allison Zibelli: So, moving on to the final study that we're going to discuss today, neoCARHP (LBA500), which was neoadjuvant taxane plus trastuzumab, pertuzumab, plus or minus carbo(platin) in HER2-positive early breast cancer. I think this is a study a lot of us have been waiting for. What was the design and the results of this trial? Dr. Rebecca Shatsky: I was really excited about this as well because I'm one of those people that was waiting for this. This is a Chinese trial, so that is something to take note of. It wasn't an international trial, but it was a de-escalation trial which had become really popular in HER2-positive therapy because we know that we're overtreating HER2-positive breast cancer in a lot of patients. A lot of patients we're throwing the kitchen sink at it when maybe that is not necessary, and we can really de-escalate and try to personalize therapy a little bit better because these patients tend to do well. So, the standard of care, of course, in HER2-positive curative intent breast cancer with tumors that are greater than 2 cm is to give them the TCHP regimen, which is docetaxel, carboplatin, trastuzumab, and pertuzumab. And that was sort of established by several trials in the NeoSphere trial, and now it's been repeated in a lot of different studies as well. And so, that's really the standard of care that most people in the United States use for HER2-positive curative intent breast cancer. This was a trial to de-escalate the carboplatin, which I was super excited about because many of us who treat this disease a lot think carbo is the least important part of the therapy you're giving there. We don't really know that it's necessary. We've just been doing it for a long time, and we know that it adds a significant amount of toxicity. It causes thrombocytopenia, it causes severe nausea, really bad cytopenias that can be difficult in the last few cycles of this to manage. So, this trial was created. It randomized patients one to one with stage 2 and 3 HER2-positive breast cancer to either get THP, a taxane, pertuzumab, trastuzumab, similar to the what we do in first-line metastatic HER2-positive versus the whole TCHP with a carboplatin AUC of 6, which is what's pretty standard. And it was a non-inferiority trial, so important there. It wasn't to establish superiority of this regimen, which none of us, I think, were looking for it to. And it was a modified intent-to-treat population. And so, all patients got at least one cycle of this to be assessed as a standard for an intent-to-treat trial. And so, they assumed a pCR rate of about 62.8% for both groups. And, of course, it included both HER2-positive triple positives and ER negatives, which are, you know, a bit different diseases, to be honest, but we all kind of categorize them and treat them the same. And so, this trial was powered appropriately to detect a non-inferiority difference. And so, we had about 380 patients treated on both arms, and there was an absolute difference of only 1.8% of those treated with carbo versus those without. Which was fantastic because you really realized that de-escalation here may be something we can really do. And so, the patients who got, of course, the taxane regimen had fewer adverse events. They had way fewer grade 3 and 4 adverse events than the THP group. No treatment-associated deaths occur, which is pretty standard for- this is a pretty safe regimen, but it causes a lot of hospitalizations due to diarrhea, due to cytopenias, and neutropenic fever, of course. And so, I thought that this was something that I could potentially enact, you know, and be practice-changing. It's hard to say that when it's a trial that was only done in China, so it's not necessarily the United States population always. But I think for patients moving forward, especially those with, say, a 2.5 cm tumor, you know, node negative, those, I'd feel pretty comfortable not giving them the carboplatin here. Notes that I want to make about this population is that the majority were stage 2 and not stage 3. They weren't necessarily your inflammatory HER2-positive breast cancer patients. And that the taxane that was utilized in the trial is a little different than what we use in the United States. The patients were allowed to get nab-paclitaxel, which we don't have FDA approval for in the first-line curative intent setting for HER2-positive breast cancer in the United States. So, a lot of them got abraxane, and then they also got paclitaxel. We tend to use docetaxel every 3 weeks in the United States. So, just to point out that difference. We don't really know if that's important or not, but it's just a little bit different to the population we standardly treat. Dr. Allison Zibelli: So, are there patients that you would still give TCHP to? Dr. Rebecca Shatsky: Yeah, great question. I've been asked that a lot in the past like week since ASCO. I'd say in my inflammatory breast cancer patients, that's a group I do tend to sometimes throw the kitchen sink at. Now, I don't actually use AC in those because I know that that was the concern, but I think the TRAIN-2 trial really showed us you don't need to use Adriamycin in HER2-positive disease unless it's like refractory. So, I don't know that I would throw this on my stage 3C or inflammatory breast cancer patients yet because the majority of this were not stage 3. So, in your really highly lymph node positive patients, I'm a little bit hesitant to de-escalate them from the start. This is more of a like, if there's serious toxicity concerns, dropping carbo is absolutely fine here. Dr. Allison Zibelli: All right, great.  Thank you, Dr. Shatsky, for sharing your valuable insights with us on the ASCO Daily News Podcast today. Dr. Rebecca Shatsky: Thanks so much, Dr. Zibelli and ASCO Daily News. I really want to thank you for inviting me to talk about this today. It was really fun, and I hope you find my opinions on some of this valuable. And so, I just want to thank everybody and my listeners as well. Dr. Allison Zibelli: And thank you to our listeners for joining us today. You'll find the links to all the abstracts discussed today in the transcript of this episode. Finally, if you like this podcast and you learn things from it, please take a moment to rate, review, and describe because it helps other people find us wherever you get your podcasts. Thank you again. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today's speakers Dr. Allison Zibelli Dr. Rebecca Shatsky @Dr_RShatsky Follow ASCO on social media:  @ASCO on Twitter  @ASCO on Bluesky  ASCO on Facebook  ASCO on LinkedIn   Disclosures: Dr. Allison Zibelli: No relationships to disclose Dr. Rebecca Shatsky: Consulting or Advisory Role: Stemline, Astra Zeneca, Endeavor BioMedicines, Lilly, Novartis, TEMPUS, Guardant Health, Daiichi Sankyo/Astra Zeneca, Pfizer Research Funding (Inst.): OBI Pharma, Astra Zeneca, Greenwich LifeSciences, Briacell, Gilead, OnKure, QuantumLeap Health, Stemline Therapeutics, Regor Therapeutics, Greenwich LifeSciences, Alterome Therapeutics  

Dr. John Sweetenham and Dr. Marc Braunstein highlight top research on hematologic malignancies from the 2025 ASCO Annual Meeting, including abstracts on newly diagnosed chronic phase CML, relapsed B-cell lymphoma, and multiple myeloma. Transcript Dr. John Sweetenham: Hello, and welcome to the ASCO Daily News Podcast. I'm your host, Dr. John Sweetenham. On today's episode, we'll be discussing promising advances in newly diagnosed chronic phase CML, relapsed B-cell lymphoma, multiple myeloma, and other hematologic malignancies that were presented at the 2025 ASCO Annual Meeting. Joining me for this discussion is Dr. Marc Braunstein, a hematologist and oncologist at the NYU Perlmutter Cancer Center. Our full disclosures are available in the transcript of this episode.  Marc, there were some great studies in the heme space at this year's Annual Meeting, and it's great to have you back on the podcast to highlight some of these advances. Dr. Marc Braunstein: Yes, I agree, John, and thank you so much for inviting me again. It's great to be here.  Dr. John Sweetenham: Let's start out with Abstract 6501. This was a study that reported on the primary endpoint results of the phase 3B ASC4START trial, which assessed asciminib versus nilotinib in newly diagnosed chronic phase CML. And the primary endpoint of this, as you know, was time to treatment discontinuation because of adverse events. Can you give us your insights into this study? Dr. Marc Braunstein: Absolutely. So, like you mentioned, you know, asciminib is an allosteric inhibitor of the BCR-ABL kinase that has activity in CML, and that includes patients with the T315I mutation that confers resistance to first- and second-generation TKIs. So, the ASC4FIRST study, which was published last year in the New England Journal of Medicine, showed superior efficacy of asciminib compared to investigator-selected first- or second-generation TKIs, actually leading to the FDA approval of asciminib in first-line CML. So, the authors of that study presented data at this year's ASCO meeting from the phase 3 ASC4START comparing safety and time to discontinuation due to adverse events of asciminib versus nilotinib, a second-generation TKI. So, 568 patients with newly diagnosed CML were randomized one-to-one to once-daily asciminib or twice-daily nilotinib. So, at a median follow-up of 9.7 months, about 11% in the asciminib group and 17% in the nilotinib group discontinued treatment, with significantly fewer discontinuations with asciminib due to adverse events. There was also a secondary endpoint of major molecular response, which was also better with asciminib. For example, the MR 4.5, which is a deep response, was 2.5% versus 0.4% favoring asciminib by week 12. So, I think in conclusion, these results build on the ASC4FIRST study, making the case for the superior safety and efficacy of asciminib versus other first- or second-generation TKIs in newly diagnosed CML. Dr. John Sweetenham: Thanks, Marc. Do you think this is going to change practice? Dr. Marc Braunstein: I think so. I think there are still some questions to be answered, such as what resistance mutations occur after first-line treatment with asciminib. But I think the sum of these studies really make the case for using asciminib upfront in CML. Dr. John Sweetenham: Okay, great. Thank you. And let's move on to our second abstract. This was Abstract 7015 and was reported from Mass General Hospital. And this was a study in patients with relapsed and refractory diffuse large B-cell lymphoma and reported the 2-year results of the so-called STARGLO study. This is a comparison of glofitamab, a T-cell engaging bispecific antibody, with gemcitabine and oxaliplatin in this group of patients. Can you tell us a little bit about your impressions of this study? Dr. Marc Braunstein: Absolutely. So just for background, the treatment landscape for relapsed/refractory large B-cell lymphoma is expanding, now with two bispecific antibodies targeting CD20 that are approved after two or more lines of therapy. Among these, glofitamab was approved in 2023 based on phase 2 data showing an objective response rate of 52%, with 39% complete responses in relapsed/refractory large B-cell lymphoma patients after a median of three prior lines of therapy. Distinguishing glofitamab from epcoritamab, the other approved bispecific, glofitamab was given for 12 cycles and then stopped. Additionally, when combined with gemcitabine and oxaliplatin in the phase 3 STARGLO study, there was significantly improved overall survival compared to rituximab plus gemcitabine and oxaliplatin in transplant-ineligible relapsed/refractory large B-cell lymphoma patients at a median follow-up of 11 months.  The authors of that study published last year in Lancet now present at ASCO this year the 2-year follow-up of the STARGLO study. Two hundred and seventy-four patients with a median of one prior line of therapy were randomized two-to-one to glofitamab plus GemOx versus rituximab plus GemOx, with the primary endpoint of overall survival. Here, the median overall survival was not reached versus 13.5 months, with a median PFS also significantly improved at about 14 months versus 4 months in the control. CRS of note in the glofitamab arm was mostly grade 1 or 2, with only about 2.3% grade 3 events. And three of the four patients had grade 1 or 2 neurotoxicity. So, John, putting this into context, I think it's encouraging that we now have randomized data showing the superiority of a bispecific plus chemotherapy over rituximab plus chemotherapy in transplant-ineligible patients. And while only 8% of the patients in the STARGLO study had prior anti-CD19 CAR T-cell therapy, I think this regimen could be considered in those patients who are ineligible for transplant or CAR T-cell therapy. Dr. John Sweetenham: Yeah, I agree. I think a couple of other compelling numbers to me were the fact that around 55% of these patients were alive at 2 years in the group who'd received glofitamab, and that almost 90% of those having that arm of the study who had a CR at the end of treatment were alive at 12 months. So, clearly, it's an active agent and also a kind of great off-the-shelf fixed-duration alternative in these relapsed and refractory patients. Dr. Marc Braunstein: I agree, and I would also note that the phase 3 SKYGLO study is looking at glofitamab plus Pola-R-CHP versus Pola-R-CHP alone. So, we may even be using these eventually in the first-line setting. Dr. John Sweetenham: Absolutely. Let's stay on the theme of diffuse large B-cell lymphoma and look at one other abstract in that space, which was Abstract 7000. This was a study from the HOVON group in the Netherlands, which looked at the prospective validation of end-of-treatment circulating tumor DNA in the context of a national randomized trial. What are your thoughts on this? Dr. Marc Braunstein: So, non-invasive liquid biopsies to detect and monitor cancers via circulating tumor-derived DNA or ctDNA, you know, is really emerging as a valuable tool in both solid and liquid tumors to understand disease biology, and also for drug development. So, to date, the most established application of ctDNA in lymphoma, I would say, is really for monitoring of minimal residual disease. So, in this correlative study by Steven Wang and colleagues in the HOVON group, they evaluated the prognostic significance of MRD status as assessed by ctDNA following first-line treatment with curative intent with either R-CHOP or dose-adjusted R-EPOCH. At the end of treatment, encouragingly, 76% of patients were MRD-negative, and 24% were MRD-positive. Now, of note, MRD-positive status at the end of treatment predicted inferior progression-free survival at 2 years, with only 28% of patients who are MRD-positive being progression-free versus 88% who are MRD-negative. And in fact, all the patients who failed to achieve a complete response after first-line treatment and were MRD-positive ultimately relapsed. So, circulating tumor cells are rarely found in large B-cell lymphomas, and so this study really builds on accumulating data that ctDNA has clinical value to detect residual disease with a non-invasive approach. So, there are many implications of how we could potentially use this to detect early signs of relapse, to potentially escalate treatment for consolidation if patients remain MRD-positive. So, I think this will eventually become utilized in clinical practice. Dr. John Sweetenham: Yeah, I agree. I think it's interesting that it provided an independent assessment of response, which was independent, in fact, of the results of PET-CT scanning and so on, which I think was very interesting to me. And the authors of the abstract actually commented in their presentation that they think this should be integrated as part of the standard response assessment now for patients with large B-cell lymphoma. Would you agree with that? Dr. Marc Braunstein: I would. For one thing, it allows repeated sampling. It's a non-invasive approach; it doesn't necessarily require a bone marrow biopsy, and it may have more sensitivity than conventional response measures. So, I think having a standardized system to assess ctDNA will be helpful, and definitely, I think this will be a valuable biomarker of disease response. Dr. John Sweetenham: Okay, great. Thanks. We're going to change gear again now, and we're going to highlight two abstracts in the multiple myeloma space. The first one of these is Abstract 7507. And this abstract reported on the long-term results of the CARTITUDE study for patients with relapsed and refractory multiple myeloma. What are your comments on this presentation? Dr. Marc Braunstein: So, this study actually got a lot of press, and I've already had multiple patients asking me about CAR T-cells as a result. Just as some background, CAR T-cells targeting BCMA, which is pretty much universally expressed on malignant plasma cells in myeloma, have really shown remarkable responses, especially in heavily pretreated patients, showing superior progression-free survival in both later and earlier phases of the disease, including in randomized studies in patients with second-line or beyond. So, the CARTITUDE-1 was really the original Phase 1/2 study of ciltacabtagene autoleucel, one of the two approved anti-BCMA CAR T-cell products, which was investigated in patients with a median of six to seven prior lines of therapy. So, these were patients who were pretty heavily pretreated. So, in the study presented by Voorhees at this year's ASCO meeting, this was the long-term follow-up at a median of 5 years from the one-time CAR infusion in these patients with a median of five prior lines of therapy. And remarkably, of the 97 patients, 33% remained progression-free at 5 years plus, without needing any further myeloma treatment during that time. And among those 33% of patients, 23% had high-risk cytogenetics, which we know are notoriously difficult to achieve responses in. What was interesting that they presented as correlative studies was there were some biomarkers that were distinguishing the patients who had the long PFS, including enrichment of more naive T-cells in the product, lower neutrophil-to-T-cell ratio, higher hemoglobin and platelets at baseline, and higher CAR T-cell levels relative to soluble BCMA levels. And the fact that they reported a median overall survival of 61 months in these really heavily pretreated patients, I think these data are impressive. I think we're going to continue to be using CAR T even earlier in the disease status than fifth or sixth line, as it was studied in CARTITUDE-1. There are even ongoing studies looking at first-line treatment with CAR T-cells. Dr. John Sweetenham: So, do you think that those 33% of patients who are disease-free at 5 years, do you think any of those are cured?  Dr. Marc Braunstein: That was one of the headlines in the press. I think if we're going to discuss things like "operational cures," where we're transforming myeloma into really a chronic disease, where patients can live practically a normal life expectancy, I think the measure of 5 years, especially in this population that was explored in CARTITUDE-1, I think we can call that close to a cure. Dr. John Sweetenham: Okay. Well, thank you. Exciting data, for sure. We're going to conclude today with another abstract in the multiple myeloma space. And this was Abstract 7500, which looked at an MRD, minimal residual disease-driven strategy following induction and transplant-eligible newly diagnosed multiple myeloma patients and reported on the primary endpoints of the phase 3 MIDAS trial. Can you walk us through this one, Marc? Dr. Marc Braunstein: Absolutely. It is a bit more complicated than the prior one we discussed because this is a randomized study with four arms. So, I'll start by saying that anti-CD38-based quadruplet regimens continue to show superior outcomes in both transplant-eligible and -ineligible newly diagnosed multiple myeloma patients. The MIDAS study mentioned is an open-label phase 3 trial with four arms in transplant-eligible newly diagnosed myeloma patients.  And initially, these patients were all treated with quadruplet therapy with the anti-CD38 antibody isatuximab combined with carfilzomib, lenalidomide, and dexamethasone in 718 newly diagnosed myeloma patients. So, they received the quadruplet regimen for six cycles and then were randomized based on their MRD status at 10 to the negative fifth following six cycles of induction. And that first randomization, if they were MRD-negative, was to either consolidation with six more cycles of the quadruplet regimen or transplant, autologous transplant, plus two cycles additionally of the quadruplet regimen. And both arms were followed by lenalidomide maintenance. The primary endpoint was MRD negativity at 10 to the negative sixth prior to entering the lenalidomide maintenance component. And in addition, the patients who were MRD-positive after induction were randomized to transplant plus two cycles of consolidation or a tandem autologous transplant. So, the median follow-up of the study was about 16 months, and the pre-maintenance rate of MRD negativity was high, between 84 to 86% between the two arms who were MRD-negative, which was not significantly different. And as far as the 233 patients who were MRD-positive, the pre-maintenance MRD negativity was also not significantly different at 40% for those who received autologous transplant, and 32% who received a tandem transplant. So, there's a lot of debate in the myeloma field about the evolving role of autologous transplant and whether transplant still plays a significant role in patients who are either MRD-negative after induction or who have deep remissions and are of standard risk. So, I think these data suggest that patients who are MRD-negative after induction with a quadruplet regimen studied here, which was Isa-KRd, plus consolidation, may possibly be able to forego consolidation with autologous transplant. And likewise, for those patients who are MRD-positive after induction, tandem transplant didn't seem to provide much of a benefit compared to single transplant, which is consistent with prior studies such as the StaMINA study. Dr. John Sweetenham: So, where do you think this leaves us, Marc? Are we going to need more studies before we have any definitive guidance on whether an autologous transplant is still appropriate for those patients who are MRD-negative? Dr. Marc Braunstein: Well, as clinicians, we want to do what's best for our patient. And in myeloma, the best we can do is to get as deep remissions as possible, meaning MRD negativity. And so, I think it's clear from the MIDAS study and others that quadruplet regimens provide the deepest remissions when given upfront. We can debate the role of autologous transplant. I think certainly the role of tandem autologous transplant is fading. But as far as a single autologous transplant as consolidation, I think it's reasonable as a goal to try to achieve MRD negativity after the transplant, especially for patients who remain MRD-positive after induction. Dr. John Sweetenham: Okay, great. Marc, thanks as always for sharing your insights on the heme malignancies studies from the ASCO meeting this year and for joining us on the ASCO Daily News Podcast. Always appreciate hearing your thoughtful and balanced input on these. Dr. Marc Braunstein: My pleasure. Thank you, John. Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's guest:  Dr. John Sweetenham Dr. Marc Braunstein   @docbraunstein     Follow ASCO on social media:   @ASCO on Twitter  ASCO on Bluesky  ASCO on Facebook   ASCO on LinkedIn     Disclosures:  Dr. John Sweetenham:  Consulting or Advisory Role: EMA Wellness  Dr. Marc Braunstein:  Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp  Speakers' Bureau: Janssen Oncology  Research Funding (Institution): Janssen, Celgene/BMS

Dr. John Sweetenham and Dr. Erika Hamilton highlight key abstracts that were presented at ASCO25, including advances in breast and pancreatic cancers as well as remarkable data from the use of structured exercise programs in cancer care. Transcript Dr. Sweetenham: Hello, and welcome to the ASCO Daily News Podcast. I'm your host, Dr. John Sweetenham. Today, we'll be discussing some of the key advances and novel approaches in cancer care that were presented at the 2025 ASCO Annual Meeting. I'm delighted to be joined again by the chair of the Meeting's Scientific Program, Dr. Erika Hamilton. She is a medical oncologist and director of breast cancer and gynecologic cancer research at the Sarah Cannon Research Institute in Nashville, Tennessee.  Our full disclosures are available in the transcript of this episode. Dr. Hamilton, congratulations on a fantastic meeting. From the practice-changing science to the world-renowned speakers at this year's Meeting, ASCO25 really reflected the amazing progress we're seeing in oncology today and the enormous opportunities that lie ahead of us. And thanks for coming back on to the podcast today to discuss some of these advances. Dr. Hamilton: Thanks, Dr. Sweetenham. I'm happy to join you today. It really was an impactful ASCO Annual Meeting. I probably am biased, but some great research was presented this year, and I heard lots of great conversations happening while we were there. Dr. Sweetenham: Yeah, absolutely. There was a lot of buzz, as well as a lot of media buzz around the meeting this year, and I think that's probably a good place to start. So I'd like to dive into abstract number LBA3510. This was the CHALLENGE trial, which created a lot of buzz at the meeting and subsequently in the media. This is the study that was led by the NCI Canada Clinical Trials Group, which was the first randomized phase 3 trial in patients with stage III and high-risk stage II colon cancer, which demonstrated that a post-treatment structured exercise program is both feasible and effective in improving disease-free survival in this patient group. The study was performed over a long period of time and in many respects is quite remarkable. So, I wonder if you could give us your thoughts about this study and whether you think that this means that our futures are going to be full of structured exercise programs for those patients who may benefit. Dr. Hamilton: It's a fantastic question. I think that this abstract did create a lot of buzz. We were very excited when we read it. It was highlighted in one of the Clinical Science Symposium sessions. But briefly, this was a phase 3 randomized trial. It was conducted at 55 centers, so really a broad experience, and patients that had resected colon cancer who completed adjuvant therapy were allowed to participate. There were essentially 2 groups: a structured exercise program, called ‘the exercise group,' or health education materials alone, so that was called just ‘the health education group.' And this was a 3-year intervention, so very high quality. The primary end point, as you mentioned, was disease-free survival. This actually accrued from 2009 to 2024, so quite a lift, and almost 900 patients underwent randomization to the exercise group or the health education group. And at almost 8 years of follow-up, we saw that the disease-free survival was significantly longer in the exercise group than the health education group. This was essentially 80.3% of patients were disease-free in exercise and 73.9% in the health education group. So a difference of over 6 percentage points, which, you know, at least in the breast cancer world, we make decisions about whether to do chemotherapy or not based on these kind of data. We also looked at overall survival in the exercise group and health education group, and the 8-year overall survival was 90.3% in the exercise group and 83.2% in the health education group. So this was a difference of 7.1%. Still statistically significant. I think this was really a fantastic effort over more than a decade at over 50 institutions with almost 900 patients, really done in a very systematic, high-intervention way that showed a fantastic result. Absolutely generalizable for patients with colon cancer. We have hints in other cancers that this is beneficial, and frankly, for our patients for other comorbidities, such as cardiovascular, etc., I really think that this is an abstract that deserved the press that it received. Dr. Sweetenham: Yeah, absolutely, and it is going to be very interesting, I think, over the next 2 or 3 years to see how much impact this particular study might have on programs across the country and across the world actually, in terms of what they do in this kind of adjuvant setting for structured exercise. Dr. Hamilton: Absolutely.  So let's move on to Abstract 3006. This was an NCI-led effort comparing genomic testing using ctDNA and tissue from patients with less common cancers who were enrolled in but not eligible for a treatment arm of the NCI-MATCH trial. Tell us about your takeaways from this study. Dr. Sweetenham: Yeah, so I thought this was a really interesting study based, as you said, on NCI-MATCH. And many of the listeners will probably remember that the original NCI-MATCH study screened almost 6,000 patients to assess eligibility for those who had an actionable mutation. And it turned out that about 60% of the patients who went on to the study had less common tumors, which were defined as anything other than colon, rectum, breast, non–small cell lung cancer, or prostate cancer. And most of those patients lacked an eligible mutation of interest and so didn't get onto a trial therapy. But with a great deal of foresight, the study group had actually collected plasma samples from these patients so that they would have the opportunity to look at circulating tumor DNA profiles with the potential being that this might be another way for testing for clinically relevant mutations in some of these less common cancer types. So initially, they tested more than 2,000 patients, and to make a somewhat complicated story short, there was a subset of five histologies with a larger representation in terms of sample size. And these were cholangiocarcinoma, small cell lung cancer, esophageal cancer, pancreatic, and salivary gland cancer. And in those particular tumors, when they compared the ctDNA sequencing with the original tumor, there was a concordance there of around 84%, 85%. And in the presentation, the investigators go on to list the specific mutated genes that were identified in each of those tumors. But I think that the other compelling part of this study from my perspective was not just that concordance, which suggests that there's an opportunity there for the use of ctDNA instead of tumor biopsies in some of these situations, but what was also interesting was the fact that there were several clinically relevant mutations which were detected only in the circulating tumor DNA. And a couple of examples of those included IDH1 for cholangiocarcinoma, BRAF and p53 in several histologies, and microsatellite instability was most prevalent in small cell lung cancer in the ctDNA. So I think that what this demonstrates is that liquid biopsy is certainly a viable screening option for patients who are being assessed for matching for targeted therapies in clinical trials. The fact that some of these mutations were only seen in the ctDNA and not in the primary tumor specimen certainly suggests that there's some tumor heterogeneity. But I think that for me, the most compelling part of this study was the fact that many of these mutations were only picked up in the plasma. And so, as the authors concluded, they believe that a comprehensive gene profiling with circulating tumor DNA probably should be included as a primary screening modality in future trials of targeted therapy of this type. Dr. Hamilton: Yeah, I think that that's really interesting and mirrors a lot of data that we've been seeing. At least in breast cancer, you know, we still do a biopsy up front to make sure that our markers, we're still treating the right disease that we think we are. But it really speaks to the utility of using ctDNA for serial monitoring and the emergence of mutations. Dr. Sweetenham: Absolutely. And you mentioned breast cancer, and so I'd like to dwell on that for a moment here because obviously, there was a huge amount of exciting breast cancer data presented at the meeting this year. And in particular, I'd like to ask you about LBA1008, the DESTINY-Breast09 clinical trial, which I think has the potential to establish a new first-line standard of care for metastatic HER2+ breast cancer. And that's an area where we haven't seen a whole lot of innovation for around a decade now. So can you give us some of the highlights of this trial and what your thinking is, having seen the results? Dr. Hamilton: Yeah, absolutely. So this was a trial in the first-line metastatic HER2 setting. So this was looking at trastuzumab deruxtecan. We certainly have had no shortage of reports around this drug, initially approved for later lines. DESTINY-Breast03 brought it into our second-line setting for HER2+ disease and we're now looking at DESTINY-Breast09 in first-line. So this actually was a 3-arm trial where patients were randomized 1:1:1 against standard taxane/trastuzumab/pertuzumab in one arm; trastuzumab deruxtecan with pertuzumab in another arm; and then a third arm, trastuzumab deruxtecan alone. And what we did not see reported was that trastuzumab deruxtecan-alone arm. But we did have reports from the trastuzumab deruxtecan plus pertuzumab versus the chemo/trastuzumab/pertuzumab. And what we saw was a statistically significant improvement in median progression-free survival, 26.9 months up to 40.7, so an improvement of 13.8 months, over a year in PFS. Not to mention that we're now in the 40-month range for PFS in first-line disease. Really, across all subgroups, we really weren't able to pick out a subset of patients that did not benefit. We did see about a 12% ILD rate with trastuzumab deruxtecan. That really is on par with what we've seen in other studies, around 10%-15%. I think that this is going to become a new standard of care in the first-line. I think it did leave some unanswered questions. We saw some data from the PATINA trial this past San Antonio Breast, looking at the addition of endocrine therapy with or without a CDK4/6 inhibitor, palbociclib, for those patients that also have ER+ disease, after taxane has dropped out in the first-line setting. So how we're going to kind of merge all this together is, I suspect that there are going to be patients that we or they just don't have the appetite to continue 3 to 4 years of trastuzumab deruxtecan. And so we're probably going to be looking at a maintenance-type strategy for them, maybe integrating the PATINA data there. But how we really put this into practice in the first-line setting and if or when we think about de-escalating down from trastuzumab deruxtecan to antibody therapy are some lingering questions. Dr. Sweetenham: Okay, so certainly is going to influence practice, but watch this space for a little bit longer, it sounds as though that's what you're saying. Dr. Hamilton: Absolutely.  So let's move on to GI cancer. Abstract 4006 reported preliminary results from the randomized phase 2 study of elraglusib in combination with gemcitabine/nab-paclitaxel versus the chemo gemcitabine/nab-paclitaxel alone in patients with previously untreated metastatic pancreatic cancer. Can you tell us more about this study? Dr. Sweetenham: Yeah, absolutely. As you mentioned, elraglusib is actually a first-in-class inhibitor of GSK3-beta, which has multiple potential actions in pancreatic cancer. But the drug itself may be involved in mediating drug resistance as well as in some tumor immune response modulation. Some of that's not clearly understood, I believe, right now. But certainly, preclinical data suggests that the drug may be effective in preclinical models and may also be effective in combination with chemotherapy and potentially with immune-modulating agents as well. So this particular study, as you said, was an open-label, randomized phase 2 study in which patients with pancreatic cancer were randomized 2:1 in favor of the elraglusib plus GMP—gemcitabine and nab-paclitaxel—versus the chemotherapy alone. And upon completion of the study, which is not right now, median overall survival was the primary end point, but there are a number of other end points which I'll talk about in just a moment. But the sample size was planned to be around 207 patients. The primary analysis included 155 patients in the combination arm versus 78 patients in the gemcitabine/nab-paclitaxel arm. Overall, the 1-year overall survival rate was 44.1% for the patients in the elraglusib-containing arm versus 23.0% in the patients receiving gemcitabine/nab-paclitaxel only. When they look at the median overall survival, it was 9.3 months for the experimental arm versus 7.2 months for chemotherapy alone. So put another way, there's around a 37% reduction in the risk of death with the use of this combination arm. The treatment was overall well-tolerated. There were some issues with grade 1 to 2 transient visual impairment in a large proportion of the patients. The most common treatment-related adverse effects with the elraglusib/GMP combination was transient visual impairment, which affected around 60% of the patients. Most of the more serious treatment-related adverse events included neutropenia, anemia, and fatigue in 50%, 25%, and 16% of the patients, respectively. So the early results from this study show a significant benefit for 1-year overall survival and for median overall survival with, as I mentioned above, a significant reduction in the risk of death. The authors went on to mention that the median overall survival for the control arm in this study is somewhat lower than in other comparable trials, but they think that this may be related to a more advanced disease burden in this particular study. Of interest to me was that right now: there is no apparent difference in progression-free survival between the 2 arms of this study. The authors described this as potentially indicating that this may be related in some way to immune modulation and immune effects on the tumor, which, if I'm completely honest, I don't totally understand. And so, the improvement in overall survival, as far as I can see at the moment, is not matched by an improvement in progression-free survival. So I think we probably need to wait for more time to elapse to see what happens with the study. And so, I think it certainly is an interesting study, and the results are intriguing, but I think it's probably a little early for it to actually shift the treatment paradigm in this disease. Dr. Hamilton: Fantastic. I think we've been waiting for advances in pancreatic cancer for a long time, but this, not unlike others, we learn more and then learn more we don't realize, so. Dr. Sweetenham: Right. Let's shift gears at this point and talk about a couple of other abstracts in kind of a very different space. Let's start out with symptom management for older adults with cancer. We know that undertreated symptoms are common among the older patient population, and Abstract 11002 reported on a randomized trial that demonstrated the effects of remote monitoring for older patients with cancer in terms of kind of symptoms and so on. Can you tell us a little bit about this study and whether you think this approach will potentially improve care for older patients? Dr. Hamilton: Yeah, I really liked this abstract. It was conducted through the Veterans Affairs, and it was based in California, which I'm telling you that because it's going to have a little bit of an implication later on. But essentially, adults that were 75 years or older who were Medicare Advantage beneficiaries were eligible to participate. Forty-three clinics in Southern California and Arizona, and patients were randomized either into a control group of usual clinic care alone, or an intervention group, which was usual care plus a lay health worker-led proactive telephone-based weekly symptom assessment, and this was for 12 months using the validated Edmonton Symptom Assessment System. So, there was a planned enrollment of at least 200 patients in each group. They successfully met that. And this lay health worker reviewed assessments with a physician assistant, who conducted follow-up for symptoms that changed by 2 points from a prior assessment or were rated 4 or greater. So almost a triage system to figure out who needed to be reached out to and to kind of work on symptoms. What I thought was fantastic about this was it was very representative of where it enrolled. There were actually about 50% of patients enrolled here that were Hispanic or Latinos. So some of our underserved populations and really across a wide variety of tumor types. They found that the intervention group had 53% lower odds of emergency room use, 68% lower odds of hospital use than the control group. And when they translated this to actual total cost of care, this was a savings of about $12,000 U.S. per participant and 75% lower odds of a death in an acute care facility. So I thought this was really interesting for a variety of reasons. One, certainly health care utilization and cost, but even more so, I think any of our patients would want to prevent hospitalizations and ER visits. Normally, that's not a fantastic experience having to feel poorly enough that you're in the emergency room or the hospital. And really showing in kind of concrete metrics that we were able to decrease this with this intervention. In terms of sustainability and scalability, I think the question is really the workforce to do this. Obviously, you know, this is going to take dedicated employees to have the ability to reach out to these patients, etc., but I think in value-based care, there's definitely a possibility of having reimbursement and having the funds to institute a program like this. So, definitely thought-provoking, and I hope it leads to more interventions. Dr. Sweetenham: Yeah, we've seen, over several years now, many of these studies which have looked at remote symptom monitoring and so on in this patient population, and many of them do show benefits for that in kinds of end points, not the least in this study being hospitalization and emergency room avoidance. But I think the scalability and personnel issue is a huge one, and I do wonder at some level whether we may see some AI-based platforms coming along that could actually help with this and provide interactions with these patients outside of actual real people, or at least in combination with real people. Dr. Hamilton: Yeah, that's a fantastic point.  So let's talk a little bit about clinical trials. So eligibility assessment for oncology clinical trials, or prescreening, really relies on manual review of unstructured clinical notes. It's time-consuming, it's prone to errors, and Abstract 1508 reported on the final analysis of a randomized trial that looked at the effect of human-AI teams prescreening for clinical trial eligibility versus human-only or AI-only prescreening. So give us more good news about AI. What did the study find? Dr. Sweetenham: Yeah, this is a really, a really interesting study. And of course, any of us who have ever been involved in clinical trials will know that accrual is always a problem. And I think most centers have attempted, and some quite successfully managed to develop prescreening programs so that patients are screened by a health care provider or health care worker prior to being seen in the clinic, and the clinical investigator will then already know whether they're going to be eligible for a trial or not. But as you've already said, it's a slow process. It's typically somewhat inefficient and requires a lot of time on the part of the health care workers to actually do this in a successful way. And so, this was a study from Emory University where they took three models of ways in which they could assess the accuracy of the prescreening of charts for patients who are going to be considered for clinical trials. One of these was essentially the regular way of having two research coordinators physically abstract the charts. The second one was an AI platform which would extract longitudinal EHR data. And then the third one was a combination of the two. So the AI would be augmented by the research coordinator or the other way around. As a gold standard, they had three independent oncology reviewers who went through all of these charts to provide what they regarded as being the benchmark for accuracy. In a way, it's not a surprise to me because I think that a number of other systems which have used this combination of human verification of AI-based tools, it actually ultimately concluded that the combination of the two in terms of chart accuracy was for the most part better than either one individually, either the research coordinator or the AI alone. So I'll give you just a few examples of where specifically that mattered. The human plus AI platform was more accurate in terms of tumor staging, in terms of identifying biomarker testing and biomarker results, as well as biomarker interpretation, and was also superior in terms of listing medications. There are one or two other areas where either the AI alone was somewhat more accurate, but the significant differences were very much in favor of a combination of human + AI screening of these patient charts. So, in full disclosure, this didn't save time, but what the authors reported was that there were definite efficiency gains, and presumably this would actually become even more improved once the research coordinators were somewhat more comfortable and at home with the AI tool. So, I thought it was an interesting way of trying to enhance clinical trial accrual up front by this combination of humans and technology, and I think it's going to be interesting to see if this gets adopted at other centers in the future. Dr. Hamilton: Yeah, I think it's really fascinating, all the different places that we can be using AI, and I love the takeaway that AI and humans together are better than either individually. Dr. Sweetenham: Absolutely.  Thanks once again, Dr. Hamilton, for sharing your insights with us today and for all of the incredible work you did to build a robust program. And also, congratulations on what was, I think, a really remarkable ASCO this year, one of the most exciting for some time, I think. So thank you again for that. Dr. Hamilton: Thanks so much. It was really a pleasure to work on ASCO 2025 this year. Dr. Sweetenham: And thank you to our listeners for joining us today. You'll find links to all the abstracts we discussed today in the transcript of this episode. Be sure to catch up on all of our coverage from the Annual Meeting. You can catch up on my daily reports that were published each day of the Annual Meeting, featuring the key science and innovations presented. And we'll have wrap-up episodes publishing in June, covering the full spectrum of malignancies from ASCO25. If you value the insights you hear on the ASCO Daily News Podcast, please remember to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   More on today's speakers: Dr. John Sweetenham   Dr. Erika Hamilton @erikahamilton9   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Bluesky  ASCO on Facebook   ASCO on LinkedIn     Disclosures:     Dr. John Sweetenham:     No relationships to disclose    Dr. Erika Hamilton: Consulting or Advisory Role (Inst): Pfizer, Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Ellipses Pharma, Olema Pharmaceuticals, Stemline Therapeutics, Tubulis, Verascity Science, Theratechnologies, Accutar Biotechnology, Entos, Fosun Pharma, Gilead Sciences, Jazz Pharmaceuticals, Medical Pharma Services, Hosun Pharma, Zentalis Pharmaceuticals, Jefferies, Tempus Labs, Arvinas, Circle Pharma, Janssen, Johnson and Johnson   Research Funding (Inst): AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stem CentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Millenium, TapImmune, Inc., Lilly, Pfizer, Lilly, Pfizer, Tesaro, Boehringer Ingelheim, H3 Biomedicine, Radius Health, Acerta Pharma, Macrogenics, Abbvie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceuticals, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Zenith Epigentics, Arvinas, Harpoon, Black Diamond, Orinove, Molecular Templates, Seattle Genetics, Compugen, GI Therapeutics, Karyopharm Therapeutics, Dana-Farber Cancer Hospital, Shattuck Labs, PharmaMar, Olema Pharmaceuticals, Immunogen, Plexxikon, Amgen, Akesobio Australia, ADC Therapeutics, AtlasMedx, Aravive, Ellipses Pharma, Incyte, MabSpace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pieris Pharmaceuticals, Pionyr, Repetoire Immune Medicines, Treadwell Therapeutics, Accutar Biotech, Artios, Bliss Biopharmaceutical, Cascadian Therapeutics, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, Relay Therapeutics, Tolmar, Torque, BeiGene, Context Therapeutics, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Cullinan Oncology, Bristol-Myers Squib, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetics, Silverback Therapeutics, Stemline Therapeutics

JCO PO author Dr. Philip Philip at Henry Ford Cancer Institute and Wayne State University shares insights into his JCO PO article, “Incorporating Circulating Tumor DNA Testing Into Clinical Trials: A Position Paper by the National Cancer Institute GI Oncology Circulating Tumor DNA Working Group.” Host Dr. Rafeh Naqash and Dr. Philip discuss how prospective trials are required to clarify the role of ctDNA as a valid surrogate end point for progression-free or overall survival in GI cancers. Transcript Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, we are excited to be joined by Dr. Philip Philip, Chair of Hematology and Oncology, as well as leader of GI and Neuroendocrine Oncology. He's also the Professor of Oncology and Pharmacology, as well as Co-Leader of the Pancreatic Cancer Program and Medical Director of the Cancer Clinical Trial and Translational Research Office at the Henry Ford Cancer Institute at Wayne State University. Dr. Philip is also the Senior Corresponding Author of the JCO Precision Oncology article entitled, "Incorporating Circulating Tumor DNA Testing into Clinical Trials: A Position Paper by the National Cancer Institute GI Oncology Circulating Tumor DNA Working Group." At the time of this recording, our guest's disclosures will be linked in the transcript. Dr. Philip, welcome to our podcast, and thank you so much for joining us today. Dr. Philip Philip: Thank you so much, Dr. Naqash, for providing me this opportunity to be discussing this with you. Dr. Rafeh Naqash: This is a very timely and interesting topic. We've done a couple of podcasts on ctDNA before, but none that is an opinion piece or a guidance piece based on what you guys have done. Could you tell us what led to this perspective piece or guidance manuscript being published? There is some background to this. Could you tell us, for the sake of our listeners, what was the initial thought process of why you all wanted to do this? Dr. Philip Philip: The major reason for this was the fact that investigators were considering using ctDNA as a primary endpoint in clinical trials. Obviously, you hear my focus will be on gastrointestinal cancers. So, the idea was, can we use ctDNA instead of using the traditional endpoints such as disease-free survival, progression-free survival, or overall survival? And the question was, do we have enough data to support that in patients with gastrointestinal cancers? Now, the article obviously goes over some review of the data available, but the core of the article was not to do a comprehensive review of ctDNA use and the evidence so far, although we used that in really putting our recommendations. So, we really had to evaluate available data. But the focus was, what are the gaps? What do we need to do? And are we ready to use ctDNA as a primary endpoint in clinical trials? Dr. Rafeh Naqash: Thank you for giving us that background. Obviously, a very broad, complicated topic with a bunch of emerging data that you've highlighted. But most importantly, for the sake of, again, trainees and listeners, could you help us understand the difference between tumor-informed and non-tumor-based ctDNA assessments? Dr. Philip Philip: Sure. So, the tumor-informed is simply meaning that you're taking the genomic makeup or the DNA fingerprint of the cancer in a given patient, and you create a profile, and then use that profile to see whether that DNA is present in the blood. So, it's very simple. It's like barcoding DNA and then going and looking for it in the blood, which means that you have to have the primary tumor. When I say primary tumor, you need to have the tumor to start off with. It doesn't really apply, maybe easily, if you just have a fine-needle aspirate and things like that. So, you really have to have a good amount of the tumor for you to be able to do that. So, that's a tumor-informed, and from the name, you can easily understand how it's done, compared to the other one, which is uninformed, whereby off-the-shelf probes are used to look for tumor DNA. And again, they're based on prior experience and prior identification of the key DNA changes that will be seen in tumors. So, that's the difference between the two in terms of the principle of the test. The uninformed will not require you to send the original tumor that you're trying to test. However, the informed, you do. The turnaround time is, again, a bit different because, as you would expect, it's shorter in the uninformed. And the reason for that, again, is the initial preparation of the profile that is going to be used in the future when you do serial testing. The sensitivity has been a bit of a discussion. Initially, people have thought that tumor-informed assays are more sensitive, more specific, more sensitive, et cetera. But in our review, we come to the conclusion saying that we don't think that's going to be a major difference. And there are obviously improvements happening in both types of assays. The sensitivities have been improving. So, at this point in time, we do feel that you have two types of assays, and we didn't feel strongly about recommending one over the other. Dr. Rafeh Naqash: Thank you for that description. You mentioned something about sensitivity, specificity. Obviously, many of us who have ordered both tumor-informed and tumor-uninformed, we understand the differences with respect to the timing. The tumor-informed one can take more time. The uninformed one, being a sort of a liquid biopsy, may not necessarily have as much of a turnaround time. Could you briefly speak to those limitations or advantages in the context of the two versions? Dr. Philip Philip: I just really want to also highlight that when we say turnaround time, so for the tumor-informed assays, the first assay that we do will be requiring a turnaround time. But once the pattern has been set and the profile has been documented, the subsequent testing doesn't require much in the way of waiting. However, when you're using this for the minimal residual disease, then you have a window of opportunity to work at. That's number one. So, it means that in patients who have resected cancer, you may end up having to wait longer than the tumor-uninformed assay, especially if you don't have easy access to your material for the baseline material to send. And also, what we'd like to do is not do the test immediately after the operation or soon after the operation. Give it some time. There's a window where you can work at, and starting minimally two weeks after the surgery. But in my experience, I'd like to wait at least four weeks just to make sure that we got an accurate reading. Sometimes when you do it very early after surgery, because of the effect of the surgery and the release of the normal DNA is also, it may dilute the tumor DNA, and then you may get a false negative. So, basically, it depends on the clinical situation. And your question is, is one better to be used than the other? I think ultimately, it ends up with the turnaround time not being as much of an issue. It might be in certain situations, depending on when you see the patients after the operation or any definitive treatment you've done and you want to look for minimal residual disease. But in general, I don't think that's going to be a real major issue. Dr. Rafeh Naqash: I remember discussing this with one of the tumor-informed platforms with regards to this barcode you mentioned. They generate a fingerprint of sorts for the tumor on the tissue, then they map it out in the blood and try to assess it longitudinally. And one of the questions and discussions we had was around the fact that most of the time, these barcoded genes are not the driver genes. If you have a KRAS mutant tumor, it's not going to be the KRAS gene that they map out. It's something that is specific. So, is there a possibility that when you are mapping out, let's say, a metastatic tumor where there is truncal and subclonal mutations at different sites, that you capture something that is not necessarily truncal, and that does not necessarily reflect some other metastatic site having a recurrence? So basically, over time, you don't see a specific mutational pattern or the signature on the tumor-informed, and then you see something on the scan which makes you think, "Well, it was not the right test," but actually it could be a different subclone or a clone mutation at a different site. Is there a concept that could help us understand that better? Dr. Philip Philip: I think you raise a very important point. Although, I have to say from my practical experience, that is not a common thing to see. In fact, for some reason, we don't see it that often in any frequency that should, at this point in time, make us concerned about the serial testing. But what you were mentioning is a real challenge which can happen. Now, the question is, how often does the clonal evolution or the divergence happen to the point that it's going to be like a false negative, is what you're saying. At this point in time, we don't really have good information on that, or any good information, practical information. And when we went through the literature and we were looking for the evidence, that wasn't something which was there clearly telling us. Although, this is something that has to be studied further prospectively. And I don't know of a study, but I might be missing it, I don't know of a study which is systematically looking at this. Although it's a very valid hypothesis and theoretical basis for it, but in real life, we still have to see how much does it really interfere with the validity of this kind of testing. Dr. Rafeh Naqash: Which brings us to the more important discussion around your manuscript. And I think that the overarching theme here is the consensus panel that you guys had recommended that ctDNA-based metrics be used as a co-primary endpoint. Could you tell us, for early-phase trials, maybe phase two studies for that matter, could you tell us what were some of the aspects that led to this consensus being formed from your working group? Dr. Philip Philip: Well, there were a number of reasons, in any order of priority, but one of them is we don't have a good sense of dynamics of the ctDNA. And again, remember this article was about gastrointestinal cancers. Maybe we know more about colon cancer, but, or colorectal cancer, but we don't know that well about the upper GI, like gastroesophageal, pancreatic, et cetera. So, we don't know what is the false negative percentages. And in fact, we know that there are certain sites of the disease, metastases, that do not lead to enough shedding of the DNA into the circulation. So, that was something else. I mean, false negativity, not knowing exactly what the dynamics are, especially in different disease types. So, that was another reason, which we felt that it may not be at this time primetime to really have those ctDNA tests as a primary endpoint. We wanted to make sure that, on the other hand, we wanted to make sure that people consider including ctDNA more like a secondary endpoint so that we can gain the information that we're lacking, at least the ones I mentioned to you. So, that was an important point of our discussions and deliberations when we were writing the article. Dr. Rafeh Naqash: And I myself have been on both sides of the aisle where - I treat people with lung cancer, you mentioned appropriately that most of the data that we have for ctDNA is generated from GI cancers, especially colorectal - on the lung cancer side, I myself had a patient with an early-stage cancer, had treatment, surgery, immunotherapy, and then had ctDNA that was tumor-informed, was positive four to five months before the imaging actually showed up. And on the other side, I've also had an individual where early-stage lung cancer, surgery, immunotherapy, and then had PET scans that showed a positive finding, but the ctDNA, tumor-informed ctDNA, was negative multiple times. So, I've seen both aspects of it, and your paper tries to address some of these questions on how to approach a negative, radiologically negative imaging but positive ctDNA potentially, and vice versa. Could you elaborate upon that a little bit? Dr. Philip Philip: Well, obviously, we do see this in practice. Again, I do GI oncology. I have patients who, you do ctDNA. I mean, my advice to anyone, when you order a test, you have to make sure that you know what you're going to do with the test, because that's the most important thing. You get a positive test, you do something. You get a negative test, you do something. But most importantly, our patients who you're following up, they are very anxious for a diagnosis they have that is not- I mean, it's cancer. If you're doing these tests, if we get continuous, repeatedly negative testing, then you really have to also tell the patient that there's a false negativity. And I mentioned to you earlier, there are certain sites of disease, like peritoneal, they may not be producing enough, or there are some tumors, their biology is such that they don't release as much to be detected in the blood. Now, one day we will get maybe a more sensitive test, but I'm talking about the tests we have now. On the other hand, if you get a positive testing, you have to make a distinction for ctDNA in the minimal residual disease situation. If you get a positive test, there is enough evidence that the patient has a worse prognosis. There's evidence for that. No one can dispute that. Again, I'm talking about colorectal cancer where there are a lot of data for that. So, in that situation, there are studies that are looking, if you get a positive test in someone who you're not intending to give any adjuvant treatment, there are studies looking into that, both in terms of intensifying, like chemotherapy, in certain patients. And also, there's work being done, if you have a negative test in someone who has stage III disease, for example, or definitely stage II disease, they may not need to give them chemo. Those things are happening. But in metastatic disease, it's a different situation. Or even in someone who has received surgery, adjuvant chemotherapy, in those patients where they, whether they're now under, in the surveillance mode, those patients, if you have a positive, it may be positive. I had a recent patient like those, eight months before we saw anything on the scans. So, the question is, if you have a positive test, is there any advantage in giving them treatment, systemic treatment? Of course, we're assuming that the PET scan is negative. So, is there really any advantage in giving someone treatment ahead of time, before you see the imaging changes? That kind of data, in my opinion, is not really available or strong. You can always think of it in different ways, explain it in different ways. It's minimal disease, maybe you get a better response. But I don't know if we really can justify at this time. Therefore, in my practice, my own practice, I do not treat just a positive ctDNA. Again, that's different than after surgery when you're thinking of whether to give adjuvant treatment, no adjuvant treatment. But someone who's finished treatments and then you're just serially monitoring the disease, those patients, I do not treat them with chemotherapy. And that was something which, based on the literature we reviewed, there was nothing out there to definitely- I mean, if you see something positive, you will do a scan earlier, you will talk to the patient, examine the patient, whatever. But if there's nothing there, starting a treatment, that's not justified at this point in time. Now, you need to do a study like that. Definitely, you need to do a study. But I can tell you that from my experience, having been involved with study design and all that, it's not an easy trial to do. It's going to be a trial- at a minimum, it will take many patients, it will take longer time to complete, and there are a number of variables there. If someone is willing to put a lot of money into it, it can be done. But I can tell you that that kind of intention to do a study like that has been very much a challenge at this time. Dr. Rafeh Naqash: Of course, as you mentioned, the follow-up time that you need for a study like that is going to be very long to get to meaningful outcomes. Dr. Philip Philip: You need to be very patient to do such a study. But the problem with a very long study is that things change, standard of care changes with time, and the assays will change. So, that's why we don't have that kind of data. I'm not sure if there are people in the community or in the academic centers who do treat based on only positive ctDNA. The other thing is that you really have to always consider the psychological impact of these tests on patients and caregivers. Sometimes it can be really very stressful, burdensome to people to sit there just waiting for the disease to show up on a scan. And therefore, in my opinion, I'm not saying definitely don't use it in that situation, I'm just saying that you have to personalize it also, to see the patient who you would like to do it and then other patients who may not do it, or you think that it's not good for them to do it. And the patient also has to understand the outcome of the test and how you're going to be interpreting it. Dr. Rafeh Naqash: That's a lot of great insights, Dr. Philip, and I know you've been involved in trial designs. I'm sure NCT and cooperative groups are actively thinking and incorporating ctDNA-based metrics as one of the endpoints in their trial. I know of a GU study that's, I think it's an Alliance study, trying to de-escalate treatment based on ctDNA. I have one of my colleagues who's also a GU investigator at OU, he's doing a ctDNA-based, tumor-informed-based de-escalation. So, obviously, more and more data, hopefully, that'll be generated in the next couple of years. Dr. Philip Philip: But remember, these studies are not using it as an endpoint. They're using it as a means of optimizing treatment, which is a bit different. So, as an endpoint, can you do a phase III trial of, let's say, a thousand patients, and your primary endpoint is not survival, but you're saying, "Can I reduce the ctDNA, clear it earlier, or whatever?" That's the sort of thing this article was about. We can't do that at this time. Dr. Rafeh Naqash: I totally understand. Thank you for explaining the difference, and hopefully more to come in this space in the next couple of years. I briefly wanted to touch upon your personal career and journey based on all that you've done and accomplished. Could you tell us about how you started, what your journey has been like, and how that connects with what you're doing right now, including mentoring other trainees and junior faculty? Dr. Philip Philip: Well, when I was in high school, I wanted to be an engineer, but I grew up in Baghdad, and all my friends wanted to do medicine, so I went with the tide, so I did medicine. I don't regret that. I would do it again if I had the opportunity. The reason why I did oncology was, I left the country and did a PhD in clinical pharmacology at the University of London. And that really got me, it was a topic which included, which was on cancer. So, I really got interested in a disease that is really a lot of science, and things are new, or were new at the time. And if I want to look back what I was doing, the beginning of my training in the 80s, second half of the 80s, and now, it's unbelievable how things have changed. But one of the things which I really have to say is that almost all my life I've been in what we call academic institutions. But I firmly believe that for people, whether academic or not, you have to be a very good, astute clinician, because many of the things we do, really, we're trying to put the patients in the center. It's not only doing fancy science, it's to do things that help the patients. And you can bring in bits and pieces of fancy science or less fancy science, but that's something which is really extremely important for us to think about, being a very good clinician, very good doctor, because medicine is a science, whether you're practicing as a solo practitioner or you're part of a large academic center. It's the way you think, the way you interrogate things that you're not sure of, the way you collaborate, the way you learn every day. I mean, at my age, I still don't like to miss any tumor board, because in each tumor board, there's something you learn, even if you think that you know everything. So, that's really the whole thing of it, is that be a very good clinician, be open-minded. Always, you have to think of things that, they look interesting, they look somehow unexplained. Always try to help find the solutions and do that. One of the major things that I feel that people should do is being also very focused on things. I mean, you have to also know what you want to do in the next 5, 10, 15 years. Because although everyone is in it in the same way when we start, but there are different things that drive people, people who want to do more of the formal research, like being an academic-like institution. But there are also a lot of people who are very successful outside of a- what we call an academic setting. In the United States, most people are not working in an academic kind of setting. Although, for me, the distinction between academic and community is getting less and less, because if you think that you do phase I trials in academia only, that's not true, because there are, in fact, in the state of Michigan, the most active phase I doctor is not even in academia, he's in private practice. So, you can do all these things. It's a matter of what you like to do, and you really have to make sure you know what you want to do. Because sometimes people are, especially early on, they get a bit confused, “What I want to do.” There's an issue of doing general oncology versus subspecialist. If you're a subspecialist doing only GI, you have to make sure that you really also have some kind of recognition that you're only a GI oncologist, recognition regional, national, international, but some degree of recognition that you feel that people are coming to you for advice as a second opinion or whatever it is. But again, you have to decide what you think you want to be, how you want to be, because there's a lot of options here between community practice, academic practice, industry, and of course, there's always the administrative thing. Some people tend to be more like going into the line of being an administrator. So, there's a lot of options for you. Dr. Rafeh Naqash: Well, thank you again, Dr. Philip, for those pearls of wisdom. I think that was very insightful. I'm sure all the trainees and early-career investigators will find all that advice very helpful. Thank you again for joining us today. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Philip Philip Disclosures Honoraria: Bayer, Ipsen, incyte, Taiho Pharmaceutical, Astellas Pharma, BioNTech SE, Novocure, TriSalus Life Sciences, SERVIER, Seagen Consulting or Advisory Role: Celgene, Ipsen, Merck, TriSalus Life Sciences, Daiichi Sankyo, SynCoreBio, Taiho Pharmaceutical Speakers' Bureau: Incyte Research Funding: Bayer (Inst), incyte (Inst), Merck (Inst), Taiho Pharmaceutical (Inst), novartis (Inst), Regeneron (Inst), Genentech (Inst), halozyme (Inst), Lilly (Inst), Taiho Pharmaceutical (Inst), merus (Inst), BioNTech SE (Inst) Uncompensated Relationships: Rafael Pharmaceuticals, Caris MPI  

Dr. Nathan Pennell and Dr. Cheryl Czerlanis discuss challenges in lung cancer screening and potential solutions to increase screening rates, including the use of AI to enhance risk prediction and screening processes. Transcript Dr. Nate Pennell: Hello, and welcome to By the Book, a monthly podcast series for ASCO Education that features engaging discussions between editors and authors from the ASCO Educational Book. I'm Dr. Nate Pennell, the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research for the Taussig Cancer Center. I'm also the editor-in-chief for the ASCO Educational Book.  Lung cancer is one of the leading causes of cancer-related mortality worldwide, and most cases are diagnosed at advanced stages where curative treatment options are limited. On the opposite end, early-stage lung cancers are very curable. If only we could find more patients at that early stage, an approach that has revolutionized survival for other cancer types such as colorectal and breast cancer.  On today's episode, I'm delighted to be joined by Dr. Cheryl Czerlanis, a professor of medicine and thoracic medical oncologist at the University of Wisconsin Carbone Cancer Center, to discuss her article titled, "Broadening the Net: Overcoming Challenges and Embracing Novel Technologies in Lung Cancer Screening." The article was recently published in the ASCO Educational Book and featured in an Education Session at the 2025 ASCO Annual Meeting. Our full disclosures are available in the transcript of this episode.  Cheryl, it's great to have you on the podcast today. Thanks for being here. Dr. Cheryl Czerlanis: Thanks, Nate. It's great to be here with you. Dr. Nate Pennell: So, I'd like to just start by asking you a little bit about the importance of lung cancer screening and what evidence is there that lung cancer screening is beneficial. Dr. Cheryl Czerlanis: Thank you. Lung cancer screening is extremely important because we know that lung cancer survival is closely tied to stage at diagnosis. We have made significant progress in the treatment of lung cancer, especially over the past decade, with the introduction of immunotherapies and targeted therapies based on personalized evaluation of genomic alterations. But the reality is that outside of a lung screening program, most patients with lung cancer present with symptoms related to advanced cancer, where our ability to cure the disease is more limited.  While lung cancer screening has been studied for years, the National Lung Screening Trial, or the NLST, first reported in 2011 a significant reduction in lung cancer deaths through screening. Annual low-dose CT scans were performed in a high-risk population for lung cancer in comparison to chest X-ray. The study population was comprised of asymptomatic persons aged 55 to 74 with a 30-pack-year history of smoking who were either active smokers or had quit within 15 years. The low-dose CT screening was associated with a 20% relative risk reduction in lung cancer-related mortality. A similar magnitude of benefit was also reported in the NELSON trial, which was a large European randomized trial comparing low-dose CT with a control group receiving no screening. Dr. Nate Pennell: So, this led, of course, to approval from CMS (Centers for Medicare and Medicaid Services) for lung cancer screening in the Medicare population, probably about 10 years ago now, I think. And there are now two major trials showing an unequivocal reduction in lung cancer-related mortality and even evidence that it reduces overall mortality with lung cancer screening. But despite this, lung cancer screening rates are very low in the United States. So, first of all, what's going on? Why are we not seeing the kinds of screening rates that we see with mammography and colonoscopy? And what are the barriers to that here? Dr. Cheryl Czerlanis: That's a great question. Thank you, Nate. In the United States, recruitment for lung cancer screening programs has faced numerous challenges, including those related to socioeconomic, cultural, logistical, and even racial disparities. Our current lung cancer screening guidelines are somewhat imprecise and often fail to address differences that we know exist in sex, smoking history, socioeconomic status, and ethnicity. We also see underrepresentation in certain groups, including African Americans and other minorities, and special populations, including individuals with HIV. And even where lung cancer screening is readily available and we have evidence of its efficacy, uptake can be low due to both provider and patient factors. On the provider side, barriers include having insufficient time in a clinic visit for shared decision-making, fear of missed test results, lack of awareness about current guidelines, concerns about cost, potential harms, and evaluating both true and false-positive test results.  And then on the patient side, barriers include concerns about cost, fear of getting a cancer diagnosis, stigma associated with tobacco smoking, and misconceptions about the treatability of lung cancer. Dr. Nate Pennell: I think those last two are really what make lung cancer unique compared to, say, for example, breast cancer, where there really is a public acceptance of the value of mammography and that breast cancer is no one's fault and that it really is embraced as an active way you can take care of yourself by getting your breast cancer screening. Whereas in lung cancer, between the stigma of smoking and the concern that, you know, it's a death sentence, I think we really have some work to be made up, which we'll talk about in a minute about what we can do to help improve this.  Now, that's in the U.S. I think things are probably, I would imagine, even worse when we leave the U.S. and look outside, especially at low- and middle-income countries. Dr. Cheryl Czerlanis: Yes, globally, this issue is even more complex than it is in the United States. Widespread implementation of low-dose CT imaging for lung cancer screening is limited by manpower, infrastructure, and economic constraints. Many low- and middle-income countries even lack sufficient CT machines, trained personnel, and specialized facilities for accurate and timely screenings. Even in urban centers with advanced diagnostic facilities, the high screening and follow-up care costs can limit access. Rural populations face additional barriers, such as geographic inaccessibility of urban centers, transportation costs, language barriers, and mistrust of healthcare systems. In addition, healthcare systems in these regions often prioritize infectious diseases and maternal health, leaving limited room for investments in noncommunicable disease prevention like lung cancer screening. Policymakers often struggle to justify allocating resources to lung cancer screening when immediate healthcare needs remain unmet. Urban-rural disparities exacerbate these challenges, with rural regions frequently lacking the infrastructure and resources to sustain screening programs. Dr. Nate Pennell: Well, it's certainly an intimidating problem to try to reduce these disparities, especially between the U.S. and low- and middle-income countries. So, what are some of the potential solutions, both here in the U.S. and internationally, that we can do to try to increase the rates of lung cancer screening? Dr. Cheryl Czerlanis: The good news is that we can take steps to address these challenges, but a multifaceted approach is needed. Public awareness campaigns focused on the benefits of early detection and dispelling myths about lung cancer screening are essential to improving participation rates. Using risk-prediction models to identify high-risk individuals can increase the efficiency of lung cancer screening programs. Automated follow-up reminders and screening navigators can also ensure timely referrals and reduce delays in diagnosis and treatment. Reducing or subsidizing the cost of low-dose CT scans, especially in low- or middle-income countries, can improve accessibility. Deploying mobile CT scanners can expand access to rural and underserved areas.  On a global scale, integrating lung cancer screening with existing healthcare programs, such as TB or noncommunicable disease initiatives, can enhance resource utilization and program scalability. Implementing lung cancer screening in resource-limited settings requires strategic investment, capacity building, and policy interventions that prioritize equity. Addressing financial constraints, infrastructure gaps, and sociocultural barriers can help overcome existing challenges. By focusing on cost-effective strategies, public awareness, and risk-based eligibility criteria, global efforts can promote equitable access to lung cancer screening and improve outcomes.  Lastly, as part of the medical community, we play an important role in a patient's decision to pursue lung cancer screening. Being up to date with current lung cancer screening recommendations, identifying eligible patients, and encouraging a patient to undergo screening often is the difference-maker. Electronic medical record (EMR) systems and reminders are helpful in this regard, but relationship building and a recommendation from a trusted provider are really essential here. Dr. Nate Pennell: I think that makes a lot of sense. I mean, there are technology improvements. For example, our lung cancer screening program at The Cleveland Clinic, a few years back, we finally started an automated best practice alert in our EMR for patients who met the age and smoking requirements, and it led to a six-fold increase in people referred for screening. But at the same time, there's a difference between just getting this alert and putting in an order for lung cancer screening and actually getting those patients to go and actually do the screening and then follow up on it. And that, of course, requires having that relationship and discussion with the patient so that they trust that you have their best interests. Dr. Cheryl Czerlanis: Exactly. I think that's important. You know, certainly, while technology can aid in bringing patients in, there really is no substitute for trust-building and a personal relationship with a provider. Dr. Nate Pennell: I know that there are probably multiple examples within the U.S. where health systems or programs have put together, I would say, quality improvement projects to try to increase lung cancer screening and working with their community. There's one in particular that you discuss in your paper called the "End Lung Cancer Now" initiative. I wonder if you could take us through that. Dr. Cheryl Czerlanis: Absolutely. "End Lung Cancer Now" is an initiative at the Indiana University Simon Comprehensive Cancer Center that has the vision to end suffering and death from lung cancer in Indiana through education and community empowerment. We discuss this as a paradigm for how community engagement is important in building and scaling a lung cancer screening program.  In 2023, the "End Lung Cancer Now" team decided to focus its efforts on scaling and transforming lung cancer screening rates in Indiana. They developed a task force with 26 experts in various fields, including radiology, pulmonary medicine, thoracic surgery, public health, and advocacy groups. The result of this work is an 85-page blueprint with key recommendations that any system and community can use to scale lung cancer screening efforts. After building strong infrastructure for lung cancer screening at Indiana University, they sought to understand what the priorities, resources, and challenges in their communities were. To do this, they forged strong partnerships with both local and national organizations, including the American Lung Association, American Cancer Society, and others. In the first year, they actually tripled the number of screening low-dose CTs performed in their academic center and saw a 40% increase system-wide. One thing that I think is the most striking is that through their community outreach, they learned that most people prefer to get medical care close to home within their own communities. Establishing a way to support the local infrastructure to provide care became far more important than recruiting patients to their larger system.  In exciting news, "End Lung Cancer Now" has partnered with the IU Simon Comprehensive Cancer Center and IU Health to launch Indiana's first and only mobile lung screening program in March of 2025. This mobile program travels around the state to counties where the highest incidence of lung cancer exists and there is limited access to screening. The mobile unit parks at trusted sites within communities and works in partnership, not competition, with local health clinics and facilities to screen high-risk populations. Dr. Nate Pennell: I think that sounds like a great idea. Screening is such an important thing that it doesn't necessarily have to be owned by any one particular health system for their patients. I think. And I love the idea of bringing the screening to patients where they are. I can speak to working in a regional healthcare system with a main campus in the downtown that patients absolutely hate having to come here from even 30 or 40 minutes away, and they'd much rather get their care locally. So that makes perfect sense.  So, under the current guidelines, there are certainly things that we can do to try to improve capturing the people that meet those. But are those guidelines actually capturing enough patients with lung cancer to make a difference? There certainly are proposals within patient advocacy communities and even other countries where there's a large percentage of non-smokers who perhaps get lung cancer. Can we expand beyond just older, current and heavy smokers to identify at-risk populations who could benefit from screening? Dr. Cheryl Czerlanis: Yes, I think we can, and it's certainly an active area of research interest. We know that tobacco is the leading cause of lung cancer worldwide. However, other risk factors include secondhand smoke, family history, exposure to environmental carcinogens, and pulmonary diseases like COPD and interstitial lung disease. Despite these known associations, the benefit of lung cancer screening is less well elucidated in never-smokers and those at risk of developing lung cancer because of family history or other risk factors. We know that the eligibility criteria associated with our current screening guidelines focus on age and smoking history and may miss more than 50% of lung cancers. Globally, 10% to 25% of lung cancer cases occur in never-smokers. And in certain parts of the world, like you mentioned, Nate, such as East Asia, many lung cancers are diagnosed in never-smokers, especially in women. Risk-prediction models use specific risk factors for lung cancer to enhance individual selection for screening, although they have historically focused on current or former smokers.  We know that individuals with family members affected by lung cancer have an increased risk of developing the disease. To this end, several large-scale, single-arm prospective studies in Asia have evaluated broadening screening criteria to never-smokers, with or without additional risk factors. One such study, the Taiwan Lung Cancer Screening in Never-Smoker Trial, was a multicenter prospective cohort study at 17 medical centers in Taiwan. The primary outcome of the TALENT trial was lung cancer detection rate. Eligible patients aged 55 to 75 had either never smoked or had a light and remote smoking history. In addition, inclusion required one or more of the following risk factors: family history of lung cancer, passive smoke exposure, history of TB or COPD, a high cooking index, which is a metric that quantifies exposure to cooking fumes, or a history of cooking without ventilation. Participants underwent low-dose CT screening at baseline, then annually for 2 years, and then every 2 years for up to 6 years. The lung cancer detection rate was 2.6%, which was higher than that reported in the NLST and NELSON trials, and most were stage 0 or I cancers. Subsequently, this led to the Taiwan Early Detection Program for Lung Cancer, a national screening program that was launched in 2022, targeting 2 screening populations: individuals with a heavy history of smoking and individuals with a family history of lung cancer.  We really need randomized controlled trials to determine the true rates of overdiagnosis or finding cancers that would not lead to morbidity or mortality in persons who are diagnosed, and to establish whether the high lung detection rates are associated with a decrease in lung cancer-related mortality in these populations. However, the implementation of randomized controlled low-dose CT screening trials in never-smokers has been limited by the need for large sample sizes, lengthy follow-up, and cost.  In another group potentially at higher risk for developing lung cancer, the role of lung cancer screening in individuals who harbor germline pathogenic variants associated with lung cancer also needs to be explored further. Dr. Nate Pennell: We had this discussion when the first criteria came out because there have always been risk-based calculators for lung cancer that certainly incorporate smoking but other factors as well and have discussion about whether we should be screening people based on their risk and not just based on discrete criteria such as smoking. But of course, the insurance coverage for screening, you have to fit the actual criteria, which is very constrained by age and smoking history. Do you think in the U.S. there's hope for broadening our screening beyond NLST and NELSON criteria? Dr. Cheryl Czerlanis: I do think at some point there is hope for broadening the criteria beyond smoking history and age, beyond the criteria that we have typically used and that is covered by insurance. I do think it will take some work to perhaps make the prediction models more precise or to really understand who can benefit. We certainly know that there are many patients who develop lung cancer without a history of smoking or without family history, and it would be great if we could diagnose more patients with lung cancer at an earlier stage. I think this will really count on there being some work towards trying to figure out what would be the best population for screening, what risk factors to look for, perhaps using some new technologies that may help us to predict who is at risk for developing lung cancer, and trying to increase the group that we study to try and find these early-stage lung cancers that can be cured. Dr. Nate Pennell: Part of the reason we, of course, try to enrich our population is screening works better when you have a higher pretest probability of actually having cancer. And part of that also is that our technology is not that great. You know, even in high-risk patients who have CT scans that are positive for a screen, we know that the vast majority of those patients with lung nodules actually don't have lung cancer. And so you have to follow them, you have to use various models to see, you know, what the risk, even in the setting of a positive screen, is of having lung cancer.  So, why don't we talk about some newer tools that we might use to help improve lung cancer screening? And one of the things that everyone is super excited about, of course, is artificial intelligence. Are there AI technologies that are helping out in early detection in lung cancer screening? Dr. Cheryl Czerlanis: Yes, that's a great question. We know that predicting who's at risk for lung cancer is challenging for the reasons that we talked about, knowing that there are many risk factors beyond smoking and age that are hard to quantify. Artificial intelligence is a tool that can help refine screening criteria and really expand screening access. Machine learning is a form of AI technology that is adept at recognizing patterns in large datasets and then applying the learning to new datasets. Several machine learning models have been developed for risk stratification and early detection of lung cancer on imaging, both with and without blood-based biomarkers. This type of technology is very promising and can serve as a tool that helps to select individuals for screening by predicting who is likely to develop lung cancer in the future.  A group at Massachusetts General Hospital, represented in our group for this paper by my co-authors, Drs. Fintelmann and Chang, developed Sybil, which is an open-access 3D convolutional neural network that predicts an individual's future risk of lung cancer based on the analysis of a single low-dose CT without the need for human annotation or other clinical inputs. Sybil and other machine learning models have tremendous potential for precision lung cancer screening, even, and perhaps especially, in settings where expert image interpretation is unavailable. They could support risk-adapted screening schedules, such as varying the frequency and interval of low-dose CT scans according to individual risk and potentially expand lung cancer screening eligibility beyond age and smoking history. Their group predicts that AI tools like Sybil will play a major role in decoding the complex landscape of lung cancer risk factors, enabling us to extend life-saving lung cancer screening to all who are at risk. Dr. Nate Pennell: I think that that would certainly be welcome. And as AI is working its way into pretty much every aspect of life, including medical care, I think it's certainly promising that it can improve on our existing technology.  We don't have to spend a lot of time on this because I know it's a little out of scope for what you covered in your paper, but I'm sure our listeners are curious about your thoughts on the use of other types of testing beyond CT screening for detecting lung cancer. I know that there are a number of investigational and even commercially available blood tests, for example, for detection of lung cancer, or even the so-called multi-cancer detection blood tests that are now being offered, although not necessarily being covered by insurance, for multiple types of cancer, but lung cancer being a common cancer is included in that. So, what do you think? Dr. Cheryl Czerlanis: Yes, like you mentioned, there are novel bioassays such as blood-based biomarker testing that evaluate for DNA, RNA, and circulating tumor cells that are both promising and under active investigation for lung cancer and multi-cancer detection. We know that such biomarker assays may be useful in both identifying lung cancers but also in identifying patients with a high-risk result who should undergo lung cancer screening by conventional methods. Dr. Nate Pennell: Anything that will improve on our rate of screening, I think, will be welcome. I think probably in the future, it will be some combination of better risk prediction and better interpretation of screening results, whether those be imaging or some combination of imaging and biomarkers, breath-based, blood-based. There's so much going on that it is pretty exciting, but we're still going to have to overcome the stigma and lack of public support for lung cancer screening if we're going to move the needle. Dr. Cheryl Czerlanis: Yes, I think moving the needle is so important because we know lung cancer is still a very morbid disease, and our ability to cure patients is not where we would like it to be. But I do believe there's hope. There are a lot of motivated individuals and groups who are passionate about lung cancer screening, like myself and my co-authors, and we're just happy to be able to share some ways that we can overcome the challenges and really try and make an impact in the lives of our patients. Dr. Nate Pennell: Well, thank you, Dr. Czerlanis, for joining me on the By the Book Podcast today and for all of your work to advance care for patients with lung cancer. Dr. Cheryl Czerlanis: Thank you, Dr. Pennell. It's such a pleasure to be with you today. Thank you. Dr. Nate Pennell: And thank you to our listeners for joining us today. You'll find a link to Dr. Czerlanis' article in the transcript of this episode.  Please join us again next month for By the Book's next episode and more insightful views on topics you'll be hearing at the education sessions from ASCO meetings throughout the year, and our deep dives on approaches that are shaping modern oncology. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers:     Dr. Nathan Pennell    @n8pennell   @n8pennell.bsky.social Dr. Cheryl Czerlanis Follow ASCO on social media:     @ASCO on X (formerly Twitter)     ASCO on Bluesky    ASCO on Facebook     ASCO on LinkedIn     Disclosures:    Dr. Nate Pennell:        Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron       Research Funding (Institution): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi    Dr. Cheryl Czerlanis: Research Funding (Institution): LungLife AI, AstraZeneca, Summit Therapeutics

Dr. John Sweetenham shares highlights from Day 3 of the 2025 ASCO Annual Meeting, including new research for the treatment of advanced renal cell carcinoma and 2 studies on novel approaches in non-small cell lung cancer. Transcript Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast, with my takeaways on selected abstracts from Day 3 of the 2025 ASCO Annual Meeting. Today's selection features studies addressing the treatment of advanced renal cell carcinoma and 2 studies exploring novel approaches in non-small cell lung cancer. My disclosures are available in the transcript of this episode. The first abstract is number 4505. This study, led by Dr. Toni Choueiri of the Dana-Farber Cancer Institute, describes the final analysis of the CheckMate 214 trial, which compared the combination of nivolumab and ipilimumab with sunitinib for the first-line treatment of advanced renal cell carcinoma. The ipi-nivo combination is approved for the frontline treatment of intermediate and poor-risk advanced renal cell carcinoma based on the primary analysis of the CheckMate 214 trial, which demonstrated a higher response rate and longer overall survival compared with sunitinib. Today's presentation provided the final safety and efficacy results for the trial with long-term follow-up of more than 9 years.  The intent-to-treat (ITT) population in this trial comprised 550 patients randomized to nivo and ipi versus 546 who received sunitinib. The final analysis showed sustained long-term benefit for the combination therapy. Patients given nivolumab plus ipi had a 29% reduction in the risk for death compared with sunitinib. For patients with intermediate or poor-risk disease, there was a 31% reduction in the risk of death.   The probability of remaining in response through 8 years was more than doubled with nivolumab plus ipilimumab versus sunitinib in the ITT population at 48% versus 19%, and in the intermediate and poor-risk population at 50% versus 23%. The other important observation is that patients with favorable-risk disease appeared to have a 20% reduction in the risk for death at 9 years and more durable responses. This suggests a possible delayed benefit for ipi and nivo in this group since these differences were not seen in the earlier analysis.   No new safety signals emerged with longer follow-up, and the results confirm the use of ipi and nivo as a standard front-line combination therapy in this disease. Since this combination has been in widespread use for some years, the results are not surprising although the subgroup analysis suggesting benefit in favorable-risk patients is likely to inform practice in the future.   Today's second abstract is number is 8506, which was presented by Dr. Tony Mok from the Chinese University of Hong Kong, describing results from the phase 3 HERTHENA-Lung02 trial. This trial compared the antibody-drug conjugate patritumab deruxtecan with platinum-based chemotherapy in patients with EGFR-mutated advanced non-small cell lung cancer following a third-generation tyrosine kinase inhibitor (TKI).  Patritumab deruxtecan, also known as HER3-DXd, comprises a fully human anti-HER3 IgG3 monoclonal antibody conjugated to a topoisomerase 1 inhibitor payload, and showed activity in a previous phase 2 trial in patients relapsing after EGFR TKI and chemotherapy.   In this phase 3 study, this agent was compared with platinum-based chemotherapy in eligible patients with an EGFR-activating mutation who had previously received 1 or 2 EGFR TKIs, at least one of which was a third-generation drug, with relapse or progression after this therapy. Five hundred and eighty-six patients were enrolled, with progression-free survival as the primary endpoint.  The primary analysis showed a 9-month progression-free survival of 29% for the experimental arm compared with 19% for platinum-based chemotherapy, for a hazard ratio of 0.77 and a P value of 0.011. With higher progression-free survival rates at 6 months and 12 months, HER3-DXd also had a better objective response rate (35.2% versus 25.3%) compared with platinum-based chemotherapy (PBC), and HER3-DXd also extended intracranial progression-free survival compared with PBC in patients with brain metastases, with a hazard ratio of 0.75. Grade 3 or more treatment-related adverse events occurred in 73% of patients treated with HER3-DXd and 57% of patients who received PBC. HER3-DXd had a higher rate of grade or more 3 thrombocytopenia, and drug-related interstitial lung disease occurred in 5% of patients in the HER3-DXd arm.   The follow-up will need more time to mature since no overall survival data are currently available, but definitely an agent to watch with interest. Moving on to today's final abstract, 8500, was presented by Dr. Pasi Jänne from the Dana-Farber Cancer Institute, describing results from the phase 2 portion of the KRYSTAL-7 study. This study is exploring the use of a potent KRAS inhibitor, adagrasib, in combination with pembrolizumab in patients with advanced or metastatic KRASG12C- mutated non-small cell lung cancer.  Adagrasib has already received accelerated approval in the U.S. for previously treated locally advanced or metastatic NSCLC with a KRASG12C mutation. A previous report from the KRYSTAL-7 study demonstrated encouraging activity in combination with pembrolizumab in the frontline setting for this patient group who also had more than 50% expression of PD-L1. The presentation today described efficacy and safety data for this drug combination across all PD-L1 expression levels.  One hundred and forty-nine patients with a median age of 67 years were treated with the combination, 104 of whom had PD-L1 expression level results available, representing the so-called biomarker population in this trial. The overall response rate for the entire study population was 44%. In the biomarker population, the overall response rate ranged from 36% in those with less than 1% PD-L1 expression to 61% for those with more than 50% expression. For all patients, the median response duration was just over 26 months, and the median progression-free and overall survival rates were 11 and 18.3 months respectively.    For the biomarker population, the median progression-free and overall survival were highest in those patients with more than 50% PD-L1. No new safety issues emerged from this analysis; the most frequent toxicities were nausea, diarrhea, and increases in transaminases. Immune-related toxicities included pneumonitis, hypothyroidism, and hepatitis. These are important results and the results of the phase 3 portion of KRYSTAL-7, which compares first-line therapy with adagrasib plus pembro versus pembro alone in the KRASG12C mutated/PD-L1 more than 50% group, will be informative. For those patients with lower levels of PD-L1 expression, the authors suggest that the treatment escalation may be beneficial, possibly including the addition of chemotherapy.  That concludes today's report. Thanks for listening and I hope you will join me again tomorrow to hear more top takeaways from ASCO25. If you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review, and subscribe wherever you get your podcasts.  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today's speaker:    Dr. John Sweetenham    Follow ASCO on social media:     @ASCO on Twitter    @ASCO on Bluesky    ASCO on Facebook    ASCO on LinkedIn     Disclosures:   Dr. John Sweetenham:    No relationships to disclose

Dr. John Sweetenham shares highlights from Day 2 of the 2025 ASCO Annual Meeting, including new data on the treatment of ER+/HER2-negative breast cancer and potentially practice-changing results for patients with cutaneous squamous cell carcinoma at high risk of recurrence.  Transcript Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, your host of the ASCO Daily News Podcast, welcoming you to our special coverage of the 2025 ASCO Annual Meeting. Today, I'll be bringing you my takeaways on selected abstracts from Day 2 of the Meeting. My disclosures are available in the transcript of this episode.  Today's selection features important, new data on the treatment of ER-positive, HER2-negative breast cancer, the use of tumor treating fields in combination with chemotherapy for locally advanced pancreatic cancer, and potentially practice-changing results for patients with cutaneous squamous cell carcinoma at high-risk of recurrence.  Our first selected abstract is LBA1000. This important phase 3 study was presented by Dr. Erika Hamilton from the Sarah Cannon Research Institute in Nashville and evaluated the use of a novel agent, vepdegestrant, in patients with ER-positive/HER2-negative breast cancer, which had progressed after first-line endocrine therapy. Vepdegestrant is a selective oral PROTAC estrogen receptor degrader, which targets wild-type and mutant estrogen receptor through a novel mechanism of action which directly harnesses the ubiquitin-proteasome system to degrade ER. It has potential advantages over fulvestrant, a selective ER degrader which has to be administered intramuscularly and has limited benefit in patients who progress after endocrine therapy plus a CDK4/6 inhibitor.  Building on the encouraging results from the initial phase 1/2 study of vepdegestrant, Dr. Hamilton reported results from the VERITAC-2 global phase 3 trial, comparing this agent with fulvestrant. The patients in the study had already received treatment with hormone therapy and a CDK inhibitor and were randomly assigned to receive treatment with either vepdegestrant (313 patients) or fulvestrant (311 patients). The vepdegestrant was taken orally each day, while the fulvestrant was given intramuscularly on days 1 and 15 of the first cycle of treatment and day 1 of each subsequent treatment cycle. Patients were stratified by the presence of wild-type ER or ESR1 mutation. A total of 43.3% of patients had ESR1 mutations; 136 of those were in the vepdegestrant group and 134 in the fulvestrant group.   For patients with ESR1 mutations, vepdegestrant significantly increased progression-free survival compared with fulvestrant. For patients who received vepdegestrant, the median PFS was 5 months versus 2.1 months for those who received fulvestrant. The clinical benefit rate was 42.1% in the vepdegestrant group vs. 20.2% in the fulvestrant group. The overall response rate was 18.6% in the vepdegestrant group compared with only 4% in the fulvestrant group.  The PFS and response benefits of vepdegestrant were largely restricted to the population with ESR1 mutations. Overall survival data are currently immature. The safety profile was favorable, with fewer than 5% of patients having dose reductions or discontinuation due to toxicity. The most frequent toxicities were fatigue, nausea, and elevated transaminases.  The authors concluded that oral vepdegestrant demonstrates statistically significant and clinically meaningful improvement in progression-free survival compared with fulvestrant in this group of patients with ESR1-mutated ER+/HER2- advanced breast cancer who have progressed after endocrine therapy and a CDK inhibitor. Patients with recurrent disease in this context are now routinely tested for ESR1 mutations, and this agent is for sure a potential treatment option for them.  The next study on today's episode, LBA4005, reports on the use of tumor treatment fields for patients with locally advanced pancreatic cancer. Tumor treatment fields are electric fields which disrupt cell division and may also induce an enhanced immune response, using a non-invasive portable device attached to the skin, and are already approved for the treatment of some cancers, including GBM and non-small cell lung cancer. A previous phase 2 trial, PANOVA-2, confirmed the feasibility and safety of using this approach in combination with gemcitabine plus or minus nabpaclitaxel in pancreatic cancer. In today's presentation, Dr. Vincent Picozzi from the Virginia Mason Medical Center in Seattle presented the results of the PANOVA-3 trial, a phase 3 study comparing gemcitabine and nabpaclitaxel with the same chemotherapy plus tumor treatment fields in patients with locally advanced pancreatic adenocarcinoma.  Five hundred and seventy-one eligible patients were enrolled in the study with a total of 405 (198 in the treatment field group and 207 in the standard arm) comprising the modified intent- to-treat population. The duration of chemotherapy treatment was comparable in both study arms, and patients receiving treatment fields had a median exposure of almost 27 weeks.  Statistically significant improvements were observed for several study endpoints, including overall survival (a median of 16.2 versus 14.2 months), distant PFS (at 13.9 versus 11.5 months) and pain-free survival (at 15.2 versus 9.1 months), all in favor of the treatment fields arm. Although quality of life data were not reported in detail, the authors noted a significant improvement in global health status in the treatment fields arm. Safety data showed a higher level of skin adverse events in the treatment fields arm but were otherwise as expected for the GnP combination.  These are quite remarkable results which add to the growing evidence base for tumor treatment fields and are particularly compelling in this patient group given the substantial improvement in pain-free survival. It will be especially interesting to see the mature analysis of the quality-of-life endpoints in a subsequent report.  The final selection today is Abstract 6001, which describes the C-POST trial, a phase 3 trial of adjuvant cemiplimab versus placebo in patients with high-risk cutaneous squamous cell carcinoma of the skin. This study was presented by Dr. Danny Rischin from the Peter MacCallum Cancer Centre in Melbourne, Australia.   Although surgical resection with or without adjuvant radiation is curative in 90% of patients with cutaneous squamous cell carcinoma, high-risk features, including nodal disease, skin and subcutaneous metastases, perineural invasion and bone involvement, predict for an inferior prognosis.  Cemiplimab, a PD-1 targeting antibody is standard therapy for patients with locally advanced or metastatic disease who are not candidates for curative surgical resection or radiation therapy, with an overall response rate of almost 50%.  The C-POST study evaluated the use of cemiplimab as adjuvant therapy following surgery and radiation in high-risk patients, compared with placebo. Treatment was administered at 3-week intervals for 12 weeks, and then 6-week intervals for a further 36 weeks, with a primary endpoint of disease-free survival. Four hundred and fifteen patients were randomized in the study, 209 to cemiplimab and 206 to placebo. With median follow-up at 24 months, Dr. Rischin reported a highly significant improvement in disease-free survival for the cemiplimab arm, 49.4 months for placebo versus not reached for cemiplimab, with improvements also observed in the rates of locoregional recurrence and distant recurrence at 80% and 60% reductions, respectively. No new safety signals were observed.  This study is potentially practice-changing and provides strong evidence that cemiplimab should be considered the new standard of care in this clinical context.  Thanks for listening today and join me again tomorrow to hear more top takeaways from ASCO25. If you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review, and subscribe wherever you get your podcasts.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speaker:   Dr. John Sweetenham   Follow ASCO on social media:    @ASCO on Twitter   @ASCO on Bluesky   ASCO on Facebook   ASCO on LinkedIn    Disclosures:   Dr. John Sweetenham:   No relationships to disclose  

In the first episode of a special daily series during the 2025 ASCO Annual Meeting, Dr. John Sweetenham discusses the results of 2 studies on the treatment of advanced colorectal cancer plus an additional study exploring the association of Medicaid expansion with cancer survival outcomes. Transcript Dr. John Sweetenham: Hello, and welcome to our special coverage of the 2025 ASCO Annual Meeting on the ASCO Daily News Podcast. I'm your host, Dr. John Sweetenham, and I'll be bringing you brief analysis on selected abstracts from each day of the Meeting. My disclosures are available in the transcript of this episode.  Today, I'll be reviewing three abstracts, the first two of which address the treatment of advanced colorectal cancer. Today's first study is Abstract 3501. These data were presented by Dr. Heinz-Josef Lenz from the USC Norris Comprehensive Cancer Center and report on the expanded analysis of the CheckMate-8HW trial. This was a phase 3, international, multicenter trial in patients with MSI-high/MMR-deficient metastatic colorectal cancer, who were randomized between nivolumab (nivo) alone, nivolumab plus ipilumomab (ipi) or investigators' choice of chemotherapy (FOLFOX or FOLFIRI) with or without bevacizumab or cetuximab. The study showed that nivo plus ipi demonstrated superior progression-free survival compared with chemotherapy in the first-line setting and superior progression-free survival compared with nivo alone across all lines of therapy. These results led to the approval of nivo + ipi in the first-line setting in patients with MSI-H/dMMR mCRC in the U.S., the EU, and many other countries.  In today's presentation, Dr. Lenz reported on the expanded analyses of nivo plus ipi versus nivo across all lines of therapy and longer follow-up results for nivo and ipi versus chemo in the first-line setting. With longer follow up (the median is now at 47 months) nivo and ipi continued to show progression-free survival benefit compared with chemotherapy with a median PFS of 54.1 months versus 5.9 months, for a hazard ratio of 0.21.  Additionally, the analysis of the effects on PFS2, defined as the time from randomization to progression after subsequent systemic therapy, start of second subsequent systemic therapy, or death, showed that compared with chemotherapy, first-line nivo and ipi was associated with a 72% reduction in the risk of death or disease progression, despite the fact that 71% of those who progressed following chemotherapy crossed over to receive subsequent immunotherapy. The study also showed that across all lines, nivo and ipi demonstrated superior progression-free survival compared with nivo alone, the median not reached versus 39.3 months, for a hazard ratio of 0.62. No new toxicity signals emerged after further analysis. Most treatment-related adverse events with possible immune etiology were observed within the first six months of therapy. The results for PFS2 are particularly significant. Up to now, there has been some reluctance to use nivo and ipi as first-line therapy, partly because of its toxicity profile and based on the rationale that it would be active after other frontline therapies. The observation in this study that the beneficial effects of nivo and ipi are maintained downstream is compelling. The results suggest that delaying the use of this combination to the second line or later may compromise subsequent PFS and supports the use of nivo and ipi as a standard-of-care frontline option for MSI-H/dMMR metastatic colorectal cancer. Moving on, the next study I'm featuring today is Abstract 3503, presented by Dr. Jeanne Tie from the Peter MacCallum Cancer Centre and the Walter and Eliza Hall Medical Institute of Medical Research from Melbourne, Australia. This study reported the impact of circulating tumor DNA (ctDNA)-guided adjuvant chemotherapy escalation in stage III colon cancer, focused on the primary analysis of the ctDNA-positive cohort from the randomized DYNAMIC-III trial. As background, about 30% of patients with stage III colon cancer will recur following standard-of-care adjuvant therapy with oxaliplatin-based regimens. And current data show that for those patients with high-risk disease, 6 months of chemotherapy is associated with a lower recurrence rate than 3 months. Circulating tumor DNA following initial surgery has been shown to be a strong independent prognostic factor for these patients, but questions remain about how ctDNA can be used for adaptation of treatment. Questions regarding treatment adaptation were addressed in the DYNAMIC-III trials – specifically, does treatment escalation benefit those who are ctDNA positive following surgery, and can therapy be de-escalated for those who are ctDNA negative. The first of these 2 questions – treatment escalation in the positive group – is the subject of this report. One thousand and two patients were randomized in this study, between ctDNA-informed therapy (502) or standard management (500). Of those patients included in the intent to treat cohorts, 129 were ctDNA positive in the ctDNA-informed arm compared with 130 in the standard management arm. Various pre-planned treatment escalation protocols were used, depending on the choice of first-line therapy. With a median follow up of 42.2 months, there was no difference in 3-year relapse free survival between the ctDNA informed group (48%) and the standard management group (52%). There was, however, a highly significant difference in relapse-free survival for patients who cleared ctDNA by the end of treatment compared with those who didn't. The authors concluded that the recurrence risk for this group remains high, at about 50%, after adjuvant therapy and that it increases with higher ctDNA burden, but treatment escalation didn't appear to reduce the recurrence risk. Clearance of ctDNA was associated with a favorable outcome, suggesting that as more effective treatments are developed in the future for this group, ctDNA will likely prove to have major utility. Changing gears now, my final selection for today is Abstract 11006, presented by Dr. Elizabeth Shafer from the American Cancer Society. This study explored the association of Medicaid expansion with 5-year survival after a cancer diagnosis.  Dr. Schafer began her presentation by providing some historical perspective on the impact of the Affordable Care Act on reducing the number of uninsured adults aged less than 65 years in the United States. She then reviewed some recent data on the impact of Medicaid expansion on cancer care, including improved screening rates, improved access to cancer surgery, and an increase in earlier cancer diagnosis. The current study builds on earlier data from the American Cancer Society which showed improved 2-year overall survival for patients with newly diagnosed cancer following Medicaid expansion. The new study reported by Dr. Schafer examined 5-year cause-specific survival in individuals with cancer since Medicaid expansion, analyzed according to cancer type and various demographic and social factors. Using data from more than 813,000 individuals from 26 states that expanded Medicaid compared with more than 610,000 from 12 states that did not, the authors reported that similar improvements in 5-year cause-specific survival were observed in the expansion and the non-expansion states, but when analyzed by other factors, differences in outcome emerged. For example, although similar improvements in survival between expansion and non-expansion states were seen in urban communities, there was a significant improvement of 2.55 percentage points in survival for individuals in rural communities in expansion states compared with those in non-expansion states. Similar trends were observed in high poverty areas, where improvements in survival were superior in expansion versus non-expansion states.  When examined by cancer type, the authors observed greater improvements in 5-year survival for those with pancreatic, lung, and colorectal cancer, possibly due to improvements in screening and early access to treatment.  The authors concluded that those residing in rural and high-poverty areas experienced the most improvement in cause-specific cancer survival following Medicaid expansion. In summary, it's encouraging to see an improving trend in cancer mortality overall, independent of Medicaid expansion, but it's also important to remember that this is yet another study which confirms how implementation of the ACA has improved cancer outcomes and begun to address some of the disparities in cancer care. Join me again tomorrow to hear more top takeaways from ASCO25. And if you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review, and subscribe wherever you get your podcasts.   Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.     Find out more about today's speaker:  Dr. John Sweetenham    Follow ASCO on social media:  @ASCO on Twitter  @ASCO on Bluesky  ASCO on Facebook  ASCO on LinkedIn        Disclosures:  Dr. John Sweetenham:  No relationships to disclose 

Dr. John Sweetenham and Dr. Erika Hamilton discuss top abstracts that will be presented at the 2025 ASCO Annual Meeting, including research on tech innovations that could shape the future of oncology. Transcript Dr. John Sweetenham: Hello, and welcome to the ASCO Daily News Podcast. I'm your host, Dr. John Sweetenham, and I'm delighted to be joined today by Dr. Erika Hamilton, a medical oncologist and director of breast cancer and gynecologic cancer research at the Sarah Cannon Research Institute in Nashville, Tennessee. Dr. Hamilton is also the chair of the 2025 ASCO Annual Meeting Scientific Program, and she's here to tell us about some of the key abstracts, hot topics, and novel approaches in cancer care that will be featured at this year's Annual Meeting. Our full disclosures are available in the transcript of this episode. Dr. Hamilton, it's great to have you on the podcast today, and thanks so much for being here. Dr. Erika Hamilton: Thanks, Dr. Sweetenham. I'm glad to be here. Dr. John Sweetenham: Dr. Hamilton, the Presidential Theme of the Annual Meeting this year is ‘Driving Knowledge to Action: Building a Better Future,' and that's reflected in many of the sessions that will focus on action-oriented guidance to improve care for our patients. And as always, there'll be great presentations on practice-changing abstracts that will change treatment paradigms and transform care. Can you tell us about some of the hot topics this year and what you're particularly excited about? Dr. Erika Hamilton: You're right. Dr. Robin Zon's theme is ‘Driving Knowledge to Action: Building a Better Future,' and you're going to see that theme really interlaced throughout the ASCO program this year. We had a record number of submissions. Over 5,000 abstracts will be published, and there'll be about 3,000 presentations, either in oral format or poster presentations. We have 200 dynamic sessions. Many of the discussants will be highlighting key takeaways and how we can translate action-oriented guidance to better treat our patients to build a better future. Our state-of-the-art science will include a Plenary Session. This will feature presentations as well as discussion of each of the presentations for clinical late-breaking abstracts. We have Clinical Science Symposia that I'm particularly excited about this year. These will feature key abstracts as well as discussions and a foundational talk around the subject. We're covering novel antibody-drug conjugate targets, turning “cold” tumors “hot” to include CAR T, as well as the future of cancer detection. There'll be rapid oral abstracts, case-based panels, and this will also feature interactive audience polling and case discussions. I also want to highlight the community connection opportunities. There will be 13 Communities of Practice that will be meeting on-site during ASCO, and there's also really a plethora of networking opportunities for trainees and early-career professionals, a Women's Networking Center, a patient advocate space, and I'm happy to report there will also be live music out on the terrace this year at ASCO. Dr. John Sweetenham: Well, that's going to be a really great addition. I have to say, I think this is always a special time of year because excitement starts to mount as the meeting gets closer and closer. And once the abstracts are out there, I certainly personally feel that the excitement builds. Talking of abstracts, let's dive into some of the key abstracts for this year's meeting. I'd like to start out by asking you about Abstract 505. This reports on 15-year outcomes for women with premenopausal hormone receptor-positive early breast cancer in the SOFT and TEXT trials. It assesses the benefits of adjuvant exemestane and ovarian function suppression or tamoxifen and ovarian function suppression. So, could you talk us through this and tell us what you think the key takeaways from this abstract are? Dr. Erika Hamilton: Absolutely. This is essentially the SOFT and TEXT trials. They are trials that we've been following for quite some time, evidenced by the 15-year outcome. And I think it really answers two very important questions for us regarding adjuvant endocrine therapy for patients that are facing hormone receptor-positive disease. The benefit of ovarian function suppression for one, and then second, the benefit of exemestane over tamoxifen, which is our SERM [selective estrogen receptor modulator]. So, in terms of the SOFT trial, when we talk about distance recurrence-free interval, which I really think is probably the most meaningful because secondary cancers, et cetera, are not really what we're getting at here. But in terms of distant recurrence-free interval, certainly with tamoxifen, using tamoxifen plus ovarian function suppression adds a little bit. But where we really get additional benefits are by moving to exemestane, an aromatase inhibitor with the ovarian function suppression. So, for example, in SOFT, for distant recurrence-free interval for patients that have received prior chemotherapy, the distance recurrence-free interval was 73.5% with tamoxifen, bumped up just a tiny bit to 73.8% with ovarian function suppression. But when we used both ovarian function suppression and switched to that aromatase inhibitor, we're now talking about 77.6%. It may seem like these are small numbers, but when we talk about an absolute benefit of 4%, these are the type of decisions that we decide whether to offer chemotherapy based on. So, really just optimizing endocrine therapy really can provide additional benefits for these patients. Just briefly, when we turn to TEXT, similarly, when we look at distance recurrence-free interval for our patients that are at highest risk and receive chemotherapy, tamoxifen and ovarian function suppression, 79%; 81% with exemestane and ovarian function suppression. And when we talk about our patients that did not receive chemotherapy, it increased from 91.6% up to 94.6%—very similar that 3% to 4% number. So, I think that this is just very important information when counseling our patients about the decisions that they're going to make for themselves in the adjuvant setting and how much we want to optimize endocrine therapy. Dr. John Sweetenham: Thanks so much for your insight into that. Dr. Erika Hamilton: Yeah, absolutely. So, let's turn to hematologic malignancies. Abstract 6506 reports exciting results on the new agent ziftomenib in relapsed/refractory NPM1-mutant acute myeloid leukemia. This is a phase 1b clinical activity study and safety results. This was the pivotal KOMET-001 study. And my question is, will this new agent fulfill an unmet need in this NPM1 space? Dr. John Sweetenham: Yeah, great question. And I think the answer is almost certainly ‘yes'. So, just as some brief background, NPM1 mutation is known to be a driver of leukemogenesis in around 30% of patients with AML, and it's a poor prognostic factor. And typically, about 50% of these patients will relapse within a year of their first-line therapy, and only around 10% of them will get a subsequent complete remission with salvage therapy. Menin inhibitors, which disrupt the interaction between menin and KMT2A, are known to be active in NPM1-mutated as well as in KMT2A-rearranged AML. And ziftomenib is a selective oral menin inhibitor, which in this study was evaluated at a dose of 600 mg once a day, as you mentioned, a phase 1b/2 study, which is multicenter and presented by Dr. Eunice Wang from Roswell Park. It's a relatively large study of 112 patients who were treated with this standard dose with relatively short median follow-up at this time. The median age was 69 years, and median prior therapies were two, but with a range of one to seven. And I think very importantly, 60% of these patients had previously been treated with venetoclax, and 23% of them had had a prior transplant. Looking at the results overall for this study, the overall response rate was 35%, which is actually quite impressive. Specifically for those patients in the phase 2 part of the study, around 23% achieved a CR [complete remission] or CRh [complete remission with partial hematologic recovery]. What's very interesting in my mind is that the response rates were comparable in venetoclax-naive and venetoclax-exposed patients. And the drug was very well tolerated, with only 3% of patients having to discontinue because of treatment-related adverse events. And I think the authors appropriately conclude that, first of all, the phase 2 primary endpoint in the study was met, and that ziftomenib achieved deep and durable responses in relapsed and refractory NPM1-mutated AML, regardless of prior venetoclax, with good tolerance of the drug. And so, I think putting all of this together, undoubtedly, these data do support the potential use of this agent as monotherapy and as a new option for those patients who have relapsed or refractory NPM1-mutated acute myeloid leukemia. So, let's move on a little bit more now and change the subject and change gears completely and talk about circulating tumor DNA [ctDNA]. This has been a hot topic over a number of years now, and at this year's meeting, there are quite a few impactful studies on the use of ctDNA. We have time to focus on just one of these, and I wanted to get your thoughts on Abstract 4503. This is from the NIAGARA trial, which looks at ctDNA in patients with muscle-invasive bladder cancer who receive perioperative durvalumab. Could you tell us a little bit about this study? Dr. Erika Hamilton: So, this was the phase 3 NIAGARA trial, and this is literally looking for patients with muscle-invasive bladder cancer that are cisplatin-eligible, and the addition of durvalumab to neoadjuvant chemotherapy. So here, this is a planned exploratory analysis of ctDNA and the association with clinical outcomes from NIAGARA. So, this is really the type of study that helps us determine which of our patients are more likely to have a good outcome and which of our patients are more likely not to. There were 1,000 randomized patients in this study, and 462 comprised the biomarker-evaluable population. There were about half in the control arm and half in the durvalumab arm. And overall, the ctDNA-positive rate at baseline was about 57%, or a little over half, and that had decreased to about 22% after neoadjuvant treatment. ctDNA clearance rates from baseline to pre-radical cystectomy was about 41% among those with durvalumab and 31% among those in control. And the non-pCR rate was 97% among patients with pre-cystectomy ctDNA-positive status. So, this really gives us some information about predicting who is going to have better outcomes here. We did see a disease-free survival benefit with perioperative durvalumab, and this was observed in post-cystectomy ctDNA-positive as well as the ctDNA-negative groups. Shifting gears now to GI cancer, Abstract 3506 is a long-term safety and efficacy study of sotorasib plus panitumumab and FOLFIRI for previously treated KRAS G12C-mutated metastatic colorectal cancer. And this is the CodeBreaK-101 study. What are your thoughts on this study? Dr. John Sweetenham: Yeah, thanks. A very interesting study, and this abstract builds upon the phase 3 CodeBreaK-300 trial, which I think has just been published in the Journal of Clinical Oncology. This showed that the combination of sotorasib and panitumumab improved clinical outcomes in patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer. The current abstract, as you mentioned, reports the CodeBreaK-101 trial. And this was a phase 1b trial where FOLFIRI therapy was added to sotorasib and panitumumab in previously treated patients with KRAS G12C-mutated metastatic colorectal cancer. The abstract reports the overall and progression-free survival results, as well as some updated safety and response data. So, in this study, patients with this particular mutation who had received at least one prior systemic treatment but were KRAS G12C inhibitor-naive were enrolled into an expansion cohort of the CodeBreaK-101 protocol. And these patients received what apparently now recommended as the standard phase 2 dose of sotorasib of 960 mg daily, plus panitumumab and a standard dose of FOLFIRI. And the primary endpoint of the study was safety, and secondary endpoints included confirmed response, overall response, and progression-free survival, as assessed by the investigator. And by November of last year, 40 patients had been enrolled into this study. Common treatment-related adverse events were cutaneous; some patients developed neutropenia, and stomatitis was fairly widespread. Discontinuation of sotorasib because of adverse events was only seen in 1% of patients, although patients did have to discontinue because of toxicity from some of the other agents in the combination. Looking at the results of this study, the updated objective response rate was 57.5%, and the disease control rate was estimated at 92%, going on 93%, with a median time to response of 1.6 months and a median response duration of 6 months. After a median follow-up of 29.2 months, the median progression-free survival was 8.2 months, and the overall survival 17.9 months. So, the authors have concluded that this combination, including sotorasib, panitumumab, and FOLFIRI, does appear to show quite promising long-term efficacy in pretreated patients with this specific mutation. The ongoing phase 3 study they mentioned, CodeBreaK-301, is aiming to evaluate this combination against the standard of care in the first-line setting for patients with KRAS G12C-mutated colorectal cancer. So, promising results, and we'd be very interested to see how this particular combination performs in the frontline. Dr. Erika Hamilton: Fantastic. Thanks so much for sharing that. Let's shift gears again and really talk about digital technology. I feel that we're all going to have to get much better with this, and really, there are a lot of promises for our patients coming here. There are a lot of abstracts at ASCO that are focusing on innovations in digital technology, including a really interesting psychosocial digital application for caregivers of patients that are undergoing hematopoietic stem cell transplantation. Can you tell us a little bit about this? It's Abstract 11000. Dr. John Sweetenham: Yeah, absolutely. This abstract certainly caught my eye, and I think it's intriguing for a number of reasons, partly because it's app-based, and partly also because it specifically addresses caregiver burden and caregiver needs in the oncology setting, which I think is especially important. And although the context, the clinical context of this study, is hematopoietic stem cell transplantation, I think it has potential applications way beyond that. We all know that caregivers of patients undergoing stem cell transplantation have significant quality-of-life struggles. They are well-documented to have significant psychological and emotional strain before, during, and after stem cell transplantation. And this abstract describes an application called BMT-CARE, which is aimed at improving caregivers' quality of life, caregiver burden, mood symptoms, and coping skills, and so on. So, this was a single-center, randomized trial from MGH [Massachusetts General Hospital] of this app for stem cell transplant caregivers, compared with usual care in those individuals. And the eligible patients, or eligible individuals, were adults caring for patients with heme malignancy undergoing either an autologous or an allogeneic stem cell transplant. Patients were randomly assigned either to use the app or for usual care. And the app itself—and I think it'll be interesting to actually see this at the meeting and visualize it and see how user-friendly and so on it is—but it comprises five modules, which integrate psychoeducation, behavior change, stress management, and they're delivered through a kind of interactive platform of educational games and videos. And then participants were self-reporting at baseline and then 60 days after transplant. So, around 125 patients were enrolled in this study, of around 174 who were initially approached. So, just over 70% uptake from caregivers, which is, I think, relatively high, and evenly distributed between the two randomized arms. And the majority of the participants were spouses. And at 60 days post-stem cell transplant, the intervention participants reported a better quality of life compared with those who received usual care. If you break this down a little bit more, these participants reported lower caregiving burden, lower incidence of depression, fewer PTSD symptoms, and overall better coping skills. So, the authors conclude that this particular app, a digital health intervention, led to pretty substantial improvements in quality of life for these caregivers. So, intriguing. As I said, it'll be particularly interesting to see how this thing looks during the meeting. But if these kind of results can be reproduced, I think this sort of application has potential uses way beyond the stem cell transplant setting. Dr. Erika Hamilton: Yeah, I find that just so fascinating and very needed. I think that the caregiving role is often underestimated in how important that is for the patient and the whole family, and really giving our caregivers more tools in their toolbox certainly is quite helpful. Dr. John Sweetenham: Absolutely. Well, the meeting is getting closer, and as I mentioned earlier, I think anticipation is mounting. And I wanted to say thanks so much to you for chatting with me today about some of the interesting advances in oncology that we're going to see at this year's meeting. There is a great deal more to come. Our listeners can access links to the studies we've discussed today in the transcript of this episode. I'm also looking forward, Dr. Hamilton, to having you back on the podcast after the Annual Meeting to dive into some of the late-breaking abstracts and some of the other key science that's captured the headlines this year. So, thanks once again for joining me today. Dr. Erika Hamilton: Thanks so much for having me. Pleasure. Dr. John Sweetenham: And thank you to our listeners for joining us today. Be sure to catch my “Top Takeaways from ASCO25.” These are short episodes that will drop each day of the meeting at 5:30 p.m. Eastern Time. So, subscribe to the ASCO Daily News Podcast wherever you prefer to listen, and join me for concise analyses of the meeting's key abstracts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   More on today's speakers: Dr. John Sweetenham   Dr. Erika Hamilton @erikahamilton9   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Bluesky  ASCO on Facebook   ASCO on LinkedIn     Disclosures:     Dr. John Sweetenham:     No relationships to disclose  Dr. Erika Hamilton: Consulting or Advisory Role (Inst): Pfizer, Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Ellipses Pharma, Olema Pharmaceuticals, Stemline Therapeutics, Tubulis, Verascity Science, Theratechnologies, Accutar Biotechnology, Entos, Fosun Pharma, Gilead Sciences, Jazz Pharmaceuticals, Medical Pharma Services, Hosun Pharma, Zentalis Pharmaceuticals, Jefferies, Tempus Labs, Arvinas, Circle Pharma, Janssen, Johnson and Johnson   Research Funding (Inst): AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stem CentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Millenium, TapImmune, Inc., Lilly, Pfizer, Lilly, Pfizer, Tesaro, Boehringer Ingelheim, H3 Biomedicine, Radius Health, Acerta Pharma, Macrogenics, Abbvie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceuticals, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Zenith Epigentics, Arvinas, Harpoon, Black Diamond, Orinove, Molecular Templates, Seattle Genetics, Compugen, GI Therapeutics, Karyopharm Therapeutics, Dana-Farber Cancer Hospital, Shattuck Labs, PharmaMar, Olema Pharmaceuticals, Immunogen, Plexxikon, Amgen, Akesobio Australia, ADC Therapeutics, AtlasMedx, Aravive, Ellipses Pharma, Incyte, MabSpace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pieris Pharmaceuticals, Pionyr, Repetoire Immune Medicines, Treadwell Therapeutics, Accutar Biotech, Artios, Bliss Biopharmaceutical, Cascadian Therapeutics, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, Relay Therapeutics, Tolmar, Torque, BeiGene, Context Therapeutics, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Cullinan Oncology, Bristol-Myers Squib, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetics, Silverback Therapeutics, Stemline Therapeutics

JCO PO author Dr. Dean A. Regier at the Academy of Translational Medicine, University of British Columbia (UBC), and the School of Population and Public Health, BC Cancer Research Institute shares insights into his JCO PO article, “Clinical Effectiveness and Cost-Effectiveness of Multigene Panel Sequencing in Advanced Melanoma: A Population-Level Real-World Target Trial Emulation.” Host Dr. Rafeh Naqash and Dr. Regier discuss the real-world clinical effectiveness and cost-effectiveness of multigene panels compared with single-gene BRAF testing to guide therapeutic decisions in advanced melanoma. Transcript Dr. Rafeh Naqash:Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center in the University of Oklahoma. Today, we are excited to be joined by Dr. Dean A. Regier, Director at the Academy of Translational Medicine, Associate Professor at the School of Population and Public Health, UBC Senior Scientist at the British Columbia Cancer Research Institute, and also the senior author of the JCO Precision Oncology article entitled "Clinical Effectiveness and Cost-Effectiveness of Multigene Panel Sequencing in Advanced Melanoma: A Population-Level Real-World Target Trial Emulation." At the time of this recording, our guest's disclosures will be linked in the transcript. Dean, welcome to our podcast and thank you for joining us today. Dr. Dean Regier:Thank you. I'm delighted to be here. Dr. Rafeh Naqash:So, obviously, you are from Canada, and medicine, or approvals of drugs to some extent, and in fact approvals of gene testing to some extent is slightly different, which we'll come to learn about more today, compared to what we do in the US—and in fact, similarly, Europe versus North America to a large extent as well. Most of the time, we end up talking about gene testing in lung cancer. There is a lot of data, a lot of papers around single-gene panel testing in non-small cell lung cancer versus multigene testing. In fact, a couple of those papers have been published in JCO PO, and it has shown significant cost-effectiveness and benefit and outcomes benefit in terms of multigene testing. So this is slightly, you know, on a similar approach, but in a different tumor type. So, could you tell us first why you wanted to investigate this question? What was the background to investigating this question? And given your expertise in health economics and policy, what are some of the aspects that one tends or should tend to understand in terms of cost-effectiveness before we go into the results for this very interesting manuscript? Dr. Dean Regier:Yeah, of course, delighted to. So, one of the reasons why we're deeply interested in looking at comparative outcomes with respect to single- versus multigene testing— whether that's in a public payer system like Canada or an insurer system, a private system in the United States— is that the question around does multigene versus single-gene testing work, has not typically tested in randomized controlled trials. You don't have people randomized to multigene versus single-gene testing. And what that does, it makes the resulting evidence base, whether it's efficacy, safety, or comparative cost-effectiveness, highly uncertain. So, the consequence of that has been uneven uptake around the world of next-generation sequencing panels. And so if we believe that next-gen sequencing panels are indeed effective for our patients, we really need to generate that comparative evidence around effectiveness and cost-effectiveness. So we can go to payers, whether it be single payer or a private insurer, to say, "Here are the comparative outcomes." And when I say that uptake has been uneven, uptake there's been actually plenty, as you know, publications around that uneven uptake, whether it be in Europe, in the United States, in Canada. And so we're really interested in trying to produce that evidence to create the type of deliberations that are needed to have these types of technologies accessible to patients. And part of those deliberations, of course, is the clinical, but also in some contexts, cost-effectiveness. And so, we really start from the perspective of, can we use our healthcare system data, our learning healthcare system, to generate that evidence in a way that emulates a randomized controlled trial? We won't be able to do these randomized controlled trials for various, like really important and and reasons that make sense, quite frankly. So how can we mimic or emulate randomized controlled trials in a way that allows us to make inference around those outcomes? And for my research lab, we usually think through how do we do causal inference to address some of those biases that are inherent in observational data. So in terms of advanced melanoma, we were really interested in this question because first of all, there have been no randomized controlled trials around next-gen sequencing versus single-gene testing. And secondly, these products, these ICIs, immune checkpoint inhibitors, and BRAF and MEK inhibitors, they are quite expensive. And so the question really becomes: are they effective? And if so, to what extent are they cost-effective? Do they provide a good reason to have information around value for money? Dr. Rafeh Naqash:So now going to the biology of melanoma, so we know that BRAF is one of the tumor-agnostic therapies, it has approvals for melanoma as well as several other tumor types. And in fact, I do trials with different RAF-RAS kinase inhibitors. Now, one of the things that I do know is, and I'm sure some of the listeners know, is the DREAMseq trial, which was a melanoma study that was an NCI Cooperative Group trial that was led by Dr. Mike Atkins from Georgetown a couple of years back, that did show survival benefit of first-line immunotherapy sequencing. It was a sequencing study of whether to do first-line BRAF in BRAF-mutant melanoma followed by checkpoint inhibitors, or vice versa. And the immune checkpoint inhibitors followed by BRAF was actually the one that showed benefit, and the trial had to stop early, was stopped early because of the significant benefit seen. So in that context, before we approach the question of single-gene versus multigene testing in melanoma, one would imagine that it's already established that upfront nivolumab plus ipilimumab, for that matter, doublet checkpoint inhibitor therapy is better for BRAF-mutant melanoma. And then there's no significant other approvals for melanoma for NRAS or KIT, you know, mucosal melanomas tend to have KIT mutations, for example, or uveal melanomas, for that matter, have GNAQ, and there's no targeted therapies. So, what is the actual need of doing a broader testing versus just testing for BRAF? So just trying to understand when you started looking into this question, I'm sure you kind of thought about some of these concepts before you delved into that. Dr. Dean Regier:I think that is an excellent question, and it is a question that we asked ourselves: did we really expect any differences in outcomes between the testing strategies? And what did the real-world implementation, physician-guided, physician-led implementation look like? And so, that was kind of one of the other reasons that we really were interested is, why would we go to expanded multigene panel sequencing at all? We didn't really expect or I didn't expect an overall survival a priori. But what we saw in our healthcare system, what happened in our healthcare system was the implementation in 2016 of this multigene panel. And this panel covered advanced melanoma, and this panel cost quite a bit more than what they were doing in terms of the single-gene BRAF testing. And so when you're a healthcare system, you have to ask yourself those questions of what is the additional value associated with that? And indeed, I think in a healthcare system, we have to be really aware that we do not actually follow to the ideal extent randomized controlled trials or trial settings. And so that's the other thing that we have to keep in mind is when these, whether it's an ICI or a BRAF MEK inhibitor, when these are implemented, they do not look like randomized controlled trials. And so, we really wanted to emulate not just a randomized controlled trial, but a pragmatic randomized controlled trial to really answer those real-world questions around implementation that are so important to decision making. Dr. Rafeh Naqash:Sure. And just to understand this a little better: for us in the United States, when we talk about multigene testing, we generally refer to, these days, whole-exome sequencing with whole-transcriptome sequencing, which is like the nuclear option of of the testings, which is not necessarily cheap. So, when you talk about multigene testing in your healthcare system, what does that look like? Is it a 16-gene panel? Is it a 52-gene panel? What is the actual makeup of that platform? Dr. Dean Regier:Excellent question. Yeah, so at the time that this study is looking at, it was 2016, when we, as BC Cancer—so British Columbia is a population right now of 5.7 million people, and we have data on all those individuals. We are one healthcare system providing health care to 5.7 million people. In 2016, we had what I call our "home-brew" multigene panel, which was a 53-gene panel that was reimbursed as standard of care across advanced cancers, one of them being advanced melanoma. We have evolved since then. I believe in 2022, we are using one of the Illumina panels, the Focus panel. And so things have changed; it's an evolving landscape. But we're specifically focused on the 53-gene panel. It was called OncoPanel. And that was produced in British Columbia through the Genome Sciences Centre, and it was validated in a single-arm trial mostly around validity, etc. Dr. Rafeh Naqash:Thank you for explaining that. So now, onto the actual meat and the science of this project. So, what are some of the metrics from a health economy standpoint that you did look at? And then, methodology-wise, I understand, in the United States, we have a fragmented healthcare system. I have data only from my institution, for that matter. So we have to reach out to outside collaborators and email them to get the data. And that is different for you where you have access to all the data under one umbrella. So could you speak to that a little bit and how that's an advantage for this kind of research especially? Dr. Dean Regier:Yeah. In health economics, we look at the comparative incremental costs against the incremental effectiveness. And when we think about incremental costs, we think not just about systemic therapy or whether you see a physician, but also about hospitalizations, about all the healthcare interactions related to oncology or not that a patient might experience during their time or interactions with the healthcare system. You can imagine with oncology, there are multiple interactions over a prolonged time period depending on survival. And so what we try to do is we try to—and the benefit of the single-payer healthcare system is what we do is we link all those resource utilization patterns that each patient encounters, and we know the price of that encounter. And we compare those incremental costs of, in this case, it's the multigene panel versus the single-gene panel. So it's not just the cost of the panel, not just the cost of systemic therapy, but hospitalizations, physician encounters, etc. And then similarly, we look at, in this case, we looked at overall survival - we can also look at progression-free survival - and ask the simple question, you know, what is the incremental cost per life-year gained? And in that way, we get a metric or an understanding of value for money. And how we evaluate that within a deliberative priority setting context is we look at safety and efficacy first. So a regulatory package that you might get from, in our case, Health Canada or the FDA, so we look at that package, and we deliberate on, okay, is it safe and is it effective? How many patients are affected, etc. And then separately, what is the cost-effectiveness? And at what price, if it's not cost-effective, at what price would it be cost-effective? Okay, so for example, we have this metric called the incremental cost-effectiveness ratio, which is incremental cost in the numerator, and in this case, life-years gained in the denominator. And if it is around $50,000 or $100,000 per life-year gained—so if it's in that range, this ratio—then we might say it's cost-effective. If it's above this range, which is common in oncology, especially when we talk about ICIs, etc., then you might want to negotiate a price. And indeed, when we negotiate that price, we use the economic evaluation, that incremental cost-effectiveness ratio, as a way to understand at what price should we negotiate to in order to get value for money for the healthcare system. Dr. Rafeh Naqash:Thank you for explaining those very interesting terminologies. Now, one question I have in the context of what you just mentioned is, you know, like the drug development space, you talked about efficacy and safety, but then on the safety side, we talk about all-grade adverse events or treatment-related adverse events—two different terminologies. From a healthcare utilization perspective, how do you untangle if a patient on a BRAF therapy got admitted for a hypoxic respiratory failure due to COPD, resulting in a hospitalization from the cost, overall cost utilization, or does it not matter? Dr. Dean Regier:We try to do as much digging into those questions as possible. And so, this is real-world data, right? Real-world data is not exactly as clean as you'd get from a well-conducted clinical trial. And so what we do is we look at potential adverse event, whether it's hospitalization, and the types of therapies around that hospitalization to try- and then engage with clinicians to try to understand or tease out the different grades of the adverse event. Whether it's successful or not, I think that is a real question that we grapple with in terms of are we accurate in delineating different levels of adverse events? But we try to take the data around the event to try to understand the context in which it happens. Dr. Rafeh Naqash:Thank you for explaining that, Dean. So, again to the results of this manuscript, could you go into the methodology briefly? Believe you had 147 patients, 147 patients in one arm, 147 in the other. How did you split that cohort, and what were some of the characteristics of this cohort? Dr. Dean Regier:So, the idea, of course, is that we have selection criteria, study inclusion criteria, which included in our case 364 patients. And these were patients who had advanced melanoma within our study time period. So that was 2016 to 2018. And we had one additional year follow. So we had three total years. And what we did is that we linked our data, our healthcare system data. During this time, because the policy change was in 2016, we had patients both go on the multigene panel and on the single-gene BRAF testing. So, the idea was to emulate a pragmatic randomized controlled trial where we looked at contemporaneous patients who had multigene panel testing versus single-gene BRAF testing. And then we did a matching procedure—we call it genetic matching. And that is a type of matching that allows us to balance covariates across the patient groups, across the multigene versus BRAF testing cohorts. The idea again is, as you get in a randomized controlled trial, you have these baseline characteristics that look the same. And then the hope is that you address any source selection or confounding biases that prohibit you to have a clean answer to the question: Is it effective or cost-effective? So you address all those biases that may prohibit you to find a signal if indeed a signal is there. And so, what we did is we created—we did this genetic matching to balance covariates across the two cohorts, and we matched them one-to-one. And so what we were able to do is we were able to find, of those 364 patients in our pool, 147 in the multigene versus 147 in the single-gene BRAF testing that were very, very similar. In fact, we created what's called a directed acyclic graph or a DAG, together with clinicians to say, “Hey, what biases would you expect to have in these two cohorts that might limit our ability to find a signal of effectiveness?” And so we worked with clinicians, with health economists, with epidemiologists to really understand those different biases at play. And the genetic matching was able to match the cohorts on the covariates of interest. Dr. Rafeh Naqash:And then could you speak on some of the highlights from the results? I know you did survival analysis, cost-effectiveness, could you explain that in terms of what you found? Dr. Dean Regier:We did two analyses. The intention-to-treat analysis is meant to emulate the pragmatic randomized controlled trial. And what that does is it answers the question, for all those eligible for multigene or single-gene testing: What is the cost-effectiveness in terms of incremental life-years gained and incremental cost per life-years gained? And the second one was around a protocol analysis, which really answered the question of: For those patients who were actually treated, what was the incremental effectiveness and cost-effectiveness? Now, they're different in two very important ways. For the intention-to-treat, it's around population questions. If we gave single-gene or multigene to the entire population of advanced melanoma patients, what is the cost-effectiveness? The per-protocol is really around that clinical question of those who actually received treatment, what was the incremental cost and effectiveness? So very different questions in terms of population versus clinical cost and effectiveness. So, for the intention-to-treat, what we found is that in terms of life-years gained is around 0.22, which is around 2.5 months of additional life that is afforded to patients who went through the multigene panel testing versus the single-gene testing. That was non-statistically significant from zero at the 5% level. But on average, you would expect this additional 2.5 months of life. The incremental costs were again non-statistically significant, but they're around $20,000. And so when we look at incremental cost-effectiveness, we can also look at the uncertainty around that question, meaning what percentage of incremental cost-effectiveness estimates are likely to be cost-effective at different willingness-to-pay thresholds? Okay? So if you are willing to pay $100,000 to get one gain of life-years, around 52.8% of our estimates, in terms of when we looked at the entire uncertainty, would be cost-effective. So actually that meets the threshold of implementation in our healthcare system. So it's quite uncertain, just over 50%. But what we see is that decision-makers actually have a high tolerance for uncertainty around cost-effectiveness. And so, while it is uncertain, we would say that, well, the cost-effectiveness is finely balanced. Now, when we looked at the population, the per-protocol population, those folks who just got treatment, we actually have a different story. We have all of a sudden around 4.5 or just under 5 months of life gained that is statistically significantly different from zero, meaning that this is a strong signal of benefit in terms of life-years gained. In terms of the changes in costs or the incremental costs, they are larger again, but statistically insignificant. So the question now is, to what extent is it cost-effective? What is the probability of it being cost-effective? And at the $100,000 per life-year gained willingness-to-pay, there was a 73% chance that multigene panel testing versus single-gene testing is cost-effective. Dr. Rafeh Naqash:So one of the questions I have here, this is a clarification both for myself and maybe the listeners also. So protocol treatment is basically if you had gene testing and you have a BRAF in the multigene panel, then the patient went on a BRAF treatment. Is that correct? Dr. Dean Regier:It's still physician choice. And I think that's important to say that. So typically what we saw in both in our pre- and post-matching data is that we saw around 50% of patients, irrespective of BRAF status, get an ICI, which is appropriate, right? And so the idea here is that you get physician-guided care, but if the patient no longer performs on the ICI, then it gives them a little bit more information on what to do next. Even during that time when we thought it wasn't going to be common to do an ICI, but it was actually quite common. Dr. Rafeh Naqash:Now, did you have any patients in this study who had the multigene testing done and had an NRAS or a KIT mutation and then went on to those therapies, which were not captured obviously in the single-gene testing, which would have just tried to look at BRAF? Dr. Dean Regier:So I did look at the data this morning because I thought that might come up in terms of my own questions that I had. I couldn't find it, but what we did see is that some patients went on to clinical trials. So, meaning that this multigene panel testing allowed, as you would hope in a learning healthcare system, patients to move on to clinical trials to have a better chance at more appropriate care if a target therapy was available. Dr. Rafeh Naqash:And the other question in that context, which is not necessarily related to the gene platform, but more on the variant allele frequency, so if you had a multigene panel that captured something that was present at a high VAF, with suspicion that this could be germline, did you have any of those patients? I'm guessing if you did, probably very low number, but I'm just thinking from a cost-effective standpoint, if you identify somebody with germline, their, you know, first-degree relative gets tested, that ends up, you know, prevention, etc. rather than somebody actually developing cancer subsequently. That's a lot of financial gains to the system if you capture something early. So did you look at that or maybe you're planning to look at that? Dr. Dean Regier:We did not look at that, but that is a really important question that typically goes unanswered in economic evaluations. And so, the short answer is yes, that result, if there was a germline finding, would be returned to the patient, and then the family would be able to be eligible for screening in the appropriate context. What we have found in economic evaluations, and we've recently published this research, is that that scope of analysis is rarely incorporated into the economic evaluation. So those downstream costs and those downstream benefits are ignored. And when you- especially also when you think about things like secondary or incidental findings, right? So it could be a germline finding for cancer, but what about all those other findings that we might have if you go with an exome or if you go with a genome, which by the way, we do have in British Columbia—we do whole-genome and transcriptome sequencing through something called the Personalized OncoGenomics program. That scope of evaluation, because it's very hard to get the right types of data, because it requires a decision model over the lifetime of both the patients and potentially their family, it becomes very complicated or complex to model over patients' and families' lifetime. That doesn't mean that we should not do it, however. Dr. Rafeh Naqash:So, in summary Dean, could you summarize some of the known and unknowns of what you learned and what you're planning in subsequent steps to this project? Dr. Dean Regier:Our North Star, if you will, is to really understand the entire system effect of next-generation sequencing panels, exome sequencing, whole genomes, or whole genomes and transcriptome analysis, which we think should be the future of precision oncology. The next steps in our research is to provide a nice base around multigene panels in terms of multigene versus single-gene testing, whether that be colorectal cancer, lung cancer, melanoma, etc., and to map out the entire system implications of implementing next-generation sequencing panels. And then we want to answer the questions around, “Well, what if we do exomes for all patients? What if we do whole genomes and transcriptomes for all patients? What are the comparative outcomes for a true tumor-agnostic precision oncology approach, accounting for, as you say, things like return of results with respect to hereditary cancers?” I think the challenge that's going to be encountered is really around the persistent high costs of something like a whole-genome and transcriptome sequencing approach. Although we do see the technology prices going down—the "$1,000 genome" or “$6,000 genome" on whatever Illumina machine you might have—that bioinformatics is continuing to be expensive. And so, there are pipelines that are automated, of course, and you can create a targeted gene report really rapidly within a reasonable turnaround time. But of course, for secondary or what I call level two analysis, that bioinformatics is going to continue to be expensive. And so, we're just continually asking that question is: In our healthcare system and in other healthcare systems, if you want to take a precision oncology approach, how do you create the pipelines? And what types of technologies really lend themselves to benefits over and above next-generation sequencing or multigene panels, allowing for access to off-label therapies? What does that look like? Does that actually improve patients? I think some of the challenges, of course, is because of heterogeneity, small benefiting populations, finding a signal if a signal is indeed there is really challenging. And so, what we are thinking through is, with respect to real-world evidence methods and emulating randomized controlled trials, what types of evidence methods actually allow us to find those signals if indeed those signals are there in the context of small benefiting populations? Dr. Rafeh Naqash:Thank you so much, Dean. Sounds like a very exciting field, especially in the current day and age where cost-effectiveness, financial toxicity is an important aspect of how we improve upon what is existing in oncology. And then lots more to be explored, as you mentioned. The last minute and a half I want to ask about you as an individual, as a researcher. There's very few people who have expertise in oncology, biomarkers, and health economics. So could you tell us for the sake of our trainees and early career physicians who might be listening, what was your trajectory briefly? How did you end up doing what you're doing? And maybe some advice for people who are interested in the cost of care, the cost of oncology drugs - what would your advice be for them very briefly? Dr. Dean Regier:Sure. So I'm an economist by training, and indeed I knew very little about the healthcare system and how it works. But I was recruited at one point to BC Cancer, to British Columbia, to really try to understand some of those questions around costs, and then I learned also around cost-effectiveness. And so, I did training in Scotland to understand patient preferences and patient values around quality of care, not just quantity of life, but also their quality of life and how that care was provided to them. And then after that, I was at Oxford University at the Nuffield Department of Population Health to understand how that can be incorporated into randomized control trials in children. And so, I did a little bit of learning about RCTs. Of course, during the way I picked up some epidemiology with deep understanding of what I call econometrics, what others might call biostatistics or just statistics. And from there, it was about working with clinicians, working with epidemiologists, working with clinical trialists, working with economists to understand the different approaches or ways of thinking of how to estimate efficacy, effectiveness, safety, and cost-effectiveness. I think this is really important to think through is that we have clinical trialists, we have people with deep understanding of biostatistics, we have genome scientists, we have clinicians, and then you add economists into the mix. What I've really benefited from is that interdisciplinary experience, meaning that when I talk to some of the world's leading genome scientists, I understand where they're coming from, what their hope and vision is. And they start to understand where I'm coming from and some of the tools that I use to understand comparative effectiveness and cost-effectiveness. And then we work together to actually change our methods in order to answer those questions that we're passionate about and curious about better for the benefit of patients. So, the short answer is it's been actually quite a trajectory between Canada, the UK. I spent some time at the University of Washington looking at the Fred Hutch Cancer Research Center, looking at precision oncology. And along the way, it's been an experience about interdisciplinary research approaches to evaluating comparative outcomes. And also really thinking through not just at one point in time on-off decisions—is this effective? Is it safe? Is it cost-effective?—not those on-off decisions, but those decisions across the lifecycle of a health product. What do those look like at each point in time? Because we gain new evidence, new information at each point in time as patients have more and more experience around it. And so what really is kind of driving our research is really thinking about interdisciplinary approaches to lifecycle evaluation of promising new drugs with the goal of having these promising technologies to patients sooner in a way that is sustainable for the healthcare system. Dr. Rafeh Naqash:Awesome. Thank you so much for those insights and also giving us a sneak peek of your very successful career. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast. Thank you. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Host Dr. Nate Pennell and his guest, Dr. Chloe Atreya, discuss the ASCO Educational Book article, “Integrative Oncology: Incorporating Evidence-Based Approaches to Patients With GI Cancers,” highlighting the use of mind-body approaches, exercise, nutrition, acupuncture/acupressure, and natural products. Transcript Dr. Nate Pennell: Welcome to ASCO Education: By the Book, our new monthly podcast series that will feature engaging discussions between editors and authors from the ASCO Educational Book. We'll be bringing you compelling insights on key topics featured in Education Sessions at ASCO meetings and some deep dives on the approaches shaping modern oncology.  I'm Dr. Nate Pennell, director of the Cleveland Clinic Lung Cancer Medical Oncology Program as well as vice chair of clinical research for the Taussig Cancer Institute. Today, I'm delighted to welcome Dr. Chloe Atreya, a professor of Medicine in the GI Oncology Group at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, and the UCSF Osher Center for Integrative Health, to discuss her article titled, “Integrative Oncology Incorporating Evidence-Based Approaches to Patients With GI Cancers”, which was recently published in the ASCO Educational Book. Our full disclosures are available in the transcript of this episode.  Dr. Atreya, it's great to have you on the podcast today. Thanks for joining me. Dr. Chloe Atreya: Thanks Dr. Pennell. It's a pleasure to be here. Dr. Nate Pennell: Dr. Atreya, you co-direct the UCSF Integrative Oncology Program with a goal to really help patients with cancer live as well as possible. And before we dive into the review article and guidelines, I'd love to just know a little bit about what inspired you to go into this field? Dr. Chloe Atreya: Yeah, thank you for asking. I've had a long-standing interest in different approaches to medicine from global traditions and I have a degree in pharmacology, and I continue to work on new drug therapies for patients with colorectal cancer. And one thing that I found is that developing new drugs is a long-term process and often we're not able to get the drugs to the patients in front of us. And so early on as a new faculty member at UCSF, I was trying to figure out what I could do for the patient in front of me if those new drug therapies may not be available in their lifetime. And one thing I recognized was that in some conversations the patient and their family members, even if the patient had metastatic disease, they were able to stay very present and to live well without being sidelined by what might happen in the future. And then in other encounters, people were so afraid of what might be happening in the future, or they may have regrets maybe about not getting that colonoscopy and that was eroding their ability to live well in the present.  So, I started asking the patients and family members who were able to stay present, “What's your secret? How do you do this?” And people would tell me, “It's my meditation practice,” or “It's my yoga practice.” And so, I became interested in this. And an entry point for me, and an entry point to the Osher Center at UCSF was that I took the Mindfulness-Based Stress Reduction Program to try to understand experientially the evidence for this and became very interested in it. I never thought I would be facilitating meditation for patients, but it became a growing interest. And as people are living longer with cancer and are being diagnosed at younger ages, often with young families, how one lives with cancer is becoming increasingly important.   Dr. Nate Pennell: I've always been very aware that it seemed like the patients that I treated who had the best quality of life during their life with cancer, however that ended up going, were those who were able to sort of compartmentalize it, where, when it was time to focus on discussing treatment or their scans, they were, you know, of course, had anxiety and other things that went along with that. But when they weren't in that, they were able to go back to their lives and kind of not think about cancer all the time. Whereas other people sort of adopt that as their identity almost is that they are living with cancer and that kind of consumes all of their time in between visits and really impacts how they're able to enjoy the rest of their lives. And so, I was really interested when I was reading your paper about how mindfulness seemed to be sort of like a formal way to help patients achieve that split. I'm really happy that we're able to talk about that. Dr. Chloe Atreya: Yeah, I think that's absolutely right. So, each of our patients is more than their cancer diagnosis. And the other thing I would say is that sometimes patients can use the cancer diagnosis to get to, “What is it that I really care about in life?” And that can actually heighten an experience of appreciation for the small things in life, appreciation for the people that they love, and that can have an impact beyond their lifetime. Dr. Nate Pennell: Just in general, I feel like integrative medicine has come a long way, especially over the last decade or so. So, there's now mature data supporting the incorporation of elements of integrative oncology into comprehensive cancer care. We've got collaborations with ASCO. They've published clinical practice guidelines around diet, around exercise, and around the use of cannabinoids. ASCO has worked with the Society for Integrative Oncology to address management of pain, anxiety, depression, fatigue – lots of different evidence bases now to try to help guide people, because this is certainly something our patients are incredibly interested in learning about. Can you get our listeners up to speed a little bit on the updated guidelines and resources supporting integrative oncology? Dr. Chloe Atreya: Sure. I can give a summary of some of the key findings. And these are rigorous guidelines that came together by consensus from expert panels. I had the honor of serving on the anxiety and depression panel. So, these panels will rate the quality of the evidence available to come up with a strength of recommendation. I think that people are at least superficially aware of the importance of diet and physical activity and that cannabis and cannabinoids have evidence of benefit for nausea and vomiting. They may not be aware of some of the evidence supporting these other modalities. So, for anxiety and depression, mindfulness-based interventions, which include meditation and meditative movement, have the strongest level of evidence. And the clinical practice guidelines indicate that they should be offered to any adult patient during or after treatment who is experiencing symptoms of anxiety or depression. Other modalities that can help with anxiety and depression include yoga and Tai Chi or Qigong. And with the fatigue guidelines, mindfulness-based interventions are also strongly recommended, along with exercise and cognitive behavioral therapy, Tai Chi and Qigong during treatment, yoga after treatment.  And some of these recommendations also will depend on where the evidence is. So, yoga is an example of an intervention that I think can be helpful during treatment, but most of our evidence is on patients who are post-treatment. So, most of our guidelines separate out during treatment and the post-treatment phase because the quality of evidence may be different for these different phases of treatment.  With the pain guidelines, the strongest recommendation is for acupuncture, specifically for people with breast cancer who may be experiencing joint pain related to aromatase inhibitors. However, acupuncture and other therapies, including massage, can be helpful with pain as well. So those are a few of the highlights. Dr. Nate Pennell: Yeah, I was surprised at the really good level of evidence for the mindfulness-based practices because I don't think that's the first thing that jumps to mind when I think about integrative oncology. I tend to think more about physical interventions like acupuncture or supplements or whatnot. So, I think this is really fantastic that we're highlighting this.  And a lot of these interventions like the Qigong, Tai Chi, yoga, is it the physical practice of those that benefits them or is it that it gives them something to focus on, to be mindful of? Is that the most important intervention? It doesn't really matter what you're doing as long as you have something that kind of takes you out of your experience and allows you to focus on the moment. Dr. Chloe Atreya: I do think it is a mind, body and spirit integration, so that all aspects are important. We also say that the best practice is the one that you actually practice. So, part of the reason that it's important to have these different modalities is that not everybody is going to take up meditation. And there may be people for whom stationary meditation, sitting and meditating, works well, and other people for whom meditative movement practices may be what they gravitate to. And so, I think that it's important to have a variety of options. And one thing that's distinct from some of our pharmacologic therapies is that the safety of these is, you know, quite good. So, it becomes less important to say, “Overall, is Tai Chi better or is yoga better?” for instance. It really depends on what it is that someone is going to take up. Dr. Nate Pennell: And of course, something that's been really nice evidence-based for a long time, even back when I was in my training in the 2000s with Jennifer Temel at Massachusetts General Hospital, was the impact of physical activity and exercise on patients with cancer. It seems like that is pretty much a universally good recommendation for patients. Dr. Chloe Atreya: Yes, that's absolutely right. Physical activity has been associated with improved survival after a cancer diagnosis. And that's both cancer specific survival and overall survival.  The other thing I'll say about physical activity, especially the mindful movement practices like Tai Chi and Qigong and yoga, is that they induce physiologic shifts in the body that can promote relaxation, so they can dampen that stress response in a physiologic way. And these movement practices are also the best way to reduce cancer-associated fatigue. Dr. Nate Pennell: One of the things that patients are always very curious about when they talk to me, and I never really feel like I'm as well qualified as I'd like to be to advise them around dietary changes in nutrition. And can you take me a little bit through some of the evidence base for what works and what doesn't work? Dr. Chloe Atreya: Sure. I do think that it needs to be tailored to the patient's needs. Overall, a diet that is plant-based and includes whole grains is really important. And I often tell patients to eat the rainbow because all of those different phytochemicals that cause the different colors in our fruits and vegetables are supporting different gut microbiota. So that is a basis for a healthy gut microbiome. That said, you know, if someone is experiencing symptoms related to cancer or cancer therapy, it is important to tailor dietary approaches. This is where some of the mindful eating practices can help. So, sometimes actually not just focusing on what we eat, but how we eat can help with symptoms that are associated with eating. So, some of our patients have loss of appetite, and shifting one's relationship to food can help with nutrition. Sometimes ‘slow it down' practices can help both with appetite and with digestion. Dr. Nate Pennell: One of the things that you said both in the paper and just now on our podcast, talking about how individualized and personalized this is. And I really liked the emphasis that you had on flexibility and self-compassion over rigid discipline and prescriptive recommendations here. And this is perhaps one of the real benefits of having an integrative oncology team that can work with patients as opposed to them just trying to find things online. Dr. Chloe Atreya: Yes, particularly during treatment, I think that's really important. And that was borne out by our early studies we called “Being Present.” So, after I was observing the benefits anecdotally among my patients of the ability to be present, we designed these pilot studies to teach meditation and meditative practices to patients. And in these pilot studies, the original ones were pretty prescriptive in a way that mindfulness-based stress reduction is fairly prescriptive in terms of like, “This is what we're asking you to do. Just stick with the program.” And there can be benefits if you can stick with the program. It's really hard though if someone is going through treatment and with GI cancers, it may be that they're getting chemotherapy every two weeks and they have one week where they're feeling really crummy and another week where they're trying to get things done. And we realized that sometimes people were getting overwhelmed and feeling like the mindfulness practice was another thing on their to-do list and that they were failing if they didn't do this thing that was important for them. And so, we've really kind of changed our emphasis. And part of our emphasis now is on incorporating mindfulness practices into daily life. Any activity that doesn't require a lot of executive function can be done mindfully, meaning with full attention. And so, especially for some of our very busy patients, that can be a way of, again, shifting how I'm doing things rather than adding a new thing to do. Dr. Nate Pennell: And then another part I know that patients are always very curious about that I'm really happy to see that we're starting to build an evidence base for is the use of supplements and natural products. So, can you take us a little bit through where we stand in terms of evidence behind, say, cannabis and some of the other available products out there? Dr. Chloe Atreya: Yeah, I would say that is an area that requires a lot more study. It's pretty complicated because unlike mindfulness practices where there are few interactions with other treatments, there is the potential for interactions, particularly with the supplements. And the quality of the supplements matters. And then there tends to be a lot of heterogeneity among the studies both in the patients and what other treatments they may be receiving, as well as the doses of the supplements that they're receiving.  One of my earliest mentors at Yale is someone named Dr. Tommy Chang, who has applied the same rigor that that we apply to testing of biomedical compounds to traditional Chinese medicine formulas. And so, ensuring that the formulation is stable and then formally testing these formulations along with chemotherapy. And we need more funding for that type of research in order to really elevate our knowledge of these natural products. We often will direct patients to the Memorial Sloan Kettering ‘About Herbs, Botanicals, and Other Products' database as one accessible source to learn more about the supplements. We also work with our pharmacists who can provide the data that exists, but we do need to take it with a grain of salt because of the heterogeneity in the data. And then it's really important if people are going to take supplements, for them to take supplements that are of high quality. And that's something in the article that we list all of the things that one should look for on the label of a supplement to ensure that it is what it's billed to be. Dr. Nate Pennell: So, most of what we've been talking about so far has really been applying to all patients with cancer, but you of course are a GI medical oncologist, and this is a publication in the Educational Book from the ASCO GI Symposium. GI cancers obviously have an incredibly high and rising incidence rate among people under 50, representing a quarter of all cancer incidence worldwide, a third of cancer related deaths worldwide. Is there something specific that GI oncologists and patients with GI cancers can take home from your paper or is this applicable to pretty much everyone? Dr. Chloe Atreya: Yeah, so the evidence that we review is specifically for GI cancers. So, it shows both its strengths and also some of the limitations. So many of the studies have focused on other cancers, especially breast cancer. In the integrative oncology field, there are definitely gaps in studying GI cancers. At the same time, I would say that GI cancers are very much linked to lifestyle in ways that are complicated, and we don't fully understand. However, the best ways that we can protect against development of GI cancers, acknowledging that no one is to blame for developing a GI cancer and no one is fully protected, but the best things that we can do for overall health and to prevent GI cancers are a diet that is plant-based, has whole grains. There's some data about fish that especially the deep-water fish, may be protective and then engaging in physical activity.  One thing I would like for people to take away is that these things that we know that are preventative against developing cancer are also important after development of a GI cancer. Most of the data comes from studies of patients with colorectal cancer and that again, both cancer specific and overall mortality is improved with better diet and with physical activity. So, this is even after a cancer diagnosis. And I also think that, and this is hard to really prove, but we're in a pretty inflammatory environment right now. So, the things that we can do to decrease stress, improve sleep, decrease inflammation in the body, and we do know that inflammation is a risk factor for developing GI cancers. So, I think that all of the integrative modalities are important both for prevention and after diagnosis. Dr. Nate Pennell: And one of the things you just mentioned is that most of the studies looking at integrative oncology and GI cancers have focused on colorectal cancer, which of course, is the most common GI cancer. But you also have pointed out that there are gaps in research and what's going on and what needs to be done in order to broaden some of this experience to other GI cancers. Dr. Chloe Atreya: Yeah, and I will say that there are gaps even for colorectal cancer. So right now, some of the authors on the article are collaborating on a textbook chapter for the Society for Integrative Oncology. And so, we're again examining the evidence specifically for colorectal cancer and are in agreement that the level of evidence specific to colorectal cancer is not as high as it is for all patients with adult cancers. And so even colorectal cancer we need to study more.  Just as there are different phases of cancer where treatments may need to be tailored, we also may need to tailor our treatments for different cancer types. And that includes what symptoms the patients are commonly experiencing and how intense the treatment is, and also the duration of treatment. Those are factors that can influence which modalities may be most important or most applicable to a given individual. Dr. Nate Pennell: So, a lot of this sounds fantastic. It sounds like things that a lot of patients would really appreciate working into their care. Your article focused a little bit on some of the logistics of providing this type of care, including group medical visits, multidisciplinary clinics staffed by multiple types of clinicians, including APPs and psychologists, and talked about the sustainability of this in terms of increasing the uptake of guideline-based integrative oncology. Talk a little bit more about both at your institution, I guess, and the overall health system and how this might be both sustainable and perhaps how we broaden this out to patients outside of places like UCSF. Dr. Chloe Atreya: Yes, that's a major focus of our research effort. A lot of comprehensive cancer centers and other places where patients are receiving care, people may have access to dietitians, which is really important and nutritionists. In the article we also provide resources for working with exercise therapists and those are people who may be working remotely and can help people, for instance, who may be in, in rural areas. And then our focus with the mind-body practices in particular has been on group medical visits. And this grew out of, again, my ‘being present' pilot studies where we were showing some benefit. But then when the grant ends, there isn't a way to continue to deliver this care. And so, we were asking ourselves, you know, is there a way to make this sustainable? And group medical visits have been used in other settings, and they've been working really well at our institution and other institutions are now taking them up as well. And this is a way that in this case it's me and many of my colleagues who are delivering these, where I can see eight or ten patients at once. In my case, it's a series of four two-hour sessions delivered by telehealth. So, we're able to focus on the integrative practices in a way that's experiential. So, in the clinic I may be able to mention, you know, after we go over the CT scans, after we go over the labs and the molecular profiling, you know, may be able to say, “Hey, you know, meditation may be helpful for your anxiety,” but in the group medical visits we can actually practice meditation, we can practice chair yoga. And that's where people have that experience in their bodies of these different modalities. And the feedback that we're receiving is that that sticks much more to experience it then you have resources to continue it. And then the group is helpful both in terms of delivery, so timely and efficient care for patients. It's also building community and reducing the social isolation that many of our patients undergoing treatment for cancer experience. Dr. Nate Pennell: I think that makes perfect sense, and I'm glad you brought up telehealth as an option. I don't know how many trained integrative oncologists there are out there, but I'm going to guess this is not a huge number out there. And much like other specialties that really can improve patients' quality of life, like palliative medicine, for example, not everyone has access to a trained expert in their cancer center, and things like telemedicine and telehealth can really potentially broaden that. How do you think telehealth could help broaden the exposure of cancer patients and even practitioners of oncology to integrative medicine? Dr. Chloe Atreya: Yes, I think that telehealth is crucial for all patients with cancer to be able to receive comprehensive cancer care, no matter where they're receiving their chemotherapy or other cancer-directed treatments. So, we will routinely be including patients who live outside of San Francisco. Most of our patients live outside of San Francisco. There's no way that they could participate if they had to drive into the city again to access this. And in the group setting, it's not even safe for people who are receiving chemotherapy to meet in a group most times. And with symptoms, often people aren't feeling so well and they're able to join us on Zoom in a way that they wouldn't be able to make the visit if it was in person. And so, this has really allowed us to expand our catchment area and to include patients, in our case, in all of California. You also mentioned training, and that's also important. So, as someone who's involved in the [UCSF] Osher Collaborative, there are faculty scholars who are at universities all over the US, so I've been able to start training some of those physicians to deliver group medical visits at their sites as well via telehealth. Dr. Nate Pennell: I'm glad we were able to make a plug for that. We need our political leadership to continue to support reimbursement for telehealth because it really does bring access to so many important elements of health care to patients who really struggle to travel to tertiary care centers. And their local cancer center can be quite a distance away.  So, sticking to the theme of training, clinician education and resources are really crucial to continue to support the uptake of integrative oncology in comprehensive cancer care. Where do you think things stand today in terms of clinician education and professional development in integrative oncology. Dr. Chloe Atreya: It's growing. Our medical students now are receiving training in integrative medicine, and making a plug for the Educational Book, I was really happy that ASCO let us have a table that's full of hyperlinks. So that's not typical for an article. Usually, you have to go to the reference list, but I really wanted to make it practical and accessible to people, both the resources that can be shared with patients that are curated and selected that we thought were of high-quality examples for patients. At the bottom of that table also are training resources for clinicians, and some of those include: The Center for Mind-Body Medicine, where people can receive training in how to teach these mind-body practices; The Integrated Center for Group Medical Visits, where people can learn how to develop their own group medical visits; of course, there's the Society for Integrative Oncology; and then I had just mentioned the Osher Collaborative Faculty Fellowship. Dr. Nate Pennell: Oh, that is fantastic. And just looking through, I mean, this article is really a fantastic resource both of the evidence base behind all of the elements that we've discussed today. Actually, the table that you mentioned with all of the direct hyperlinks to the resources is fantastic. Even recommendations for specific dietary changes after GI cancer diagnosis. So, I highly recommend everyone read the full paper after they have listened to the podcast today.  Before we wrap up, is there anything that we didn't get a chance to discuss that you wanted to make sure our listeners are aware of? Dr. Chloe Atreya: One thing that I did want to bring up is the disparities that exist in access to high quality symptom management care. So, patients who are racial and ethnic minorities, particularly our black and Latinx patients, the evidence shows that they aren't receiving the same degree of symptom management care as non-Hispanic White patients. And that is part of what may be leading to some of the disparities in cancer outcomes. So, if symptoms are poorly managed, it's harder for patients to stay with the treatment, and integrative oncology is one way to try to, especially with telehealth, this is a way to try to improve symptom management for all of our patients to help improve both their quality of life and their cancer outcomes. Dr. Nate Pennell: Well, Dr. Atreya, it's been great speaking with you today and thank you for joining me on the ASCO Education: By the Book Podcast and thank you for all of your work in advancing integrative oncology for GI cancers and beyond. Dr. Chloe Atreya: Thank you, Dr. Pennell. It's been a pleasure speaking with you. Dr. Nate Pennell: And thank you to all of our listeners who joined us today. You'll find a link to the article discussed today in the transcript of the episode. We hope you'll join us again for more insightful views on topics you'll be hearing at the Education Sessions from ASCO meetings throughout the year and our deep dives on approaches that are shaping modern oncology. Disclaimer: The purpose of this podcast is to educate, educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers:    Dr. Nathan Pennell   @n8pennell  @n8pennell.bsky.social  Dr. Chloe Atreya  Follow ASCO on social media:    @ASCO on X (formerly Twitter)    ASCO on Bluesky   ASCO on Facebook    ASCO on LinkedIn    Disclosures:   Dr. Nate Pennell:       Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron      Research Funding (Institution): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi   Dr. Chloe Atreya: Consulting or Advisory Role: Roche Genentech, Agenus Research Funding (Institution): Novartis, Merck, Bristol-Myers Squibb, Guardant Health, Gossamer Bio, Erasca, Inc.

Dr. John Sweetenham, Dr. Larry Shulman, and Dr. Rebecca Maniago discuss the integration of clinical pathways and decision support tools into the cancer center workflow, challenges to implementation at the point of care, and the promise of AI to further unlock these tools for clinicians. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. Over the last decade or so, there has been a great deal of work and a lot of discussion about the implementation of oncology clinical care pathways at the point of care, which are designed to reduce variability in care, reduce costs, and improve the quality of care and outcomes. Although clinical pathways aim to guide treatment decisions, current data suggests that the utilization of these pathways at the point of care is very low. There are many reasons for this, which we will get into on the episode today.   My guests today are Dr. Larry Shulman and Rebecca Maniago. Dr. Shulman is a professor of medicine at the University of Pennsylvania Abramson Cancer Center. He's also the immediate past chair of the Commission on Cancer and serves on the National Cancer Policy Forum of the National Academies of Sciences, Engineering and Medicine. Rebecca Maniago is the director of clinical oncology at Flatiron Health, a technology platform that collects and analyzes real-world clinical data from electronic health records to facilitate decision making and research.  Our full disclosures are available in the transcript of this episode. Larry and Rebecca, welcome to the ASCO Daily News Podcast and many thanks for being here.  Dr. Larry Shulman: Thank you, John.  Rebecca Maniago: Thank you for having me.  Dr. John Sweetenham: Larry, I'm going to start out, if I may, with a question for you. You and I, in a previous podcast, have discussed some of these issues regarding pathway implementation before. But to start out with, it's certainly, I think, helpful for the listeners to remind us all of what are the benefits of oncology clinical pathways and why are we still talking about this 10 years or more on.  Dr. Larry Shulman: Yeah, and that's a great question, John. I think the good news is, and all of us who live in the oncology sphere know this, that there's been tremendous progress in cancer therapies over the last decade. But what that has entailed is the introduction of many new therapies. Their complexity is becoming really very tough for people to manage.  And so what we have are oncologists who are really trying to do their best to deliver care to patients that will give them the best chance for survival and quality of life. But it's really, really hard to keep up with everything that's happening in oncology in the context of what we all know is a very busy clinic schedule. Lots of patients coming through and decisions need to be made quickly. Pathways really could help us to guide us into recommending and delivering the best therapies for our patients for a particular disease. You know, cancer is complicated. There are many different types and there are many different therapies. It's just a lot to deal with without some assistance from pathways or pathway tools.  Dr. John Sweetenham: Thanks, Larry. So, knowing that's the case and knowing that these tools reduce variability, improve costs, improve quality of care as well. Starting with you again, Larry, if I may, why do you think it's been so difficult for so many oncologists to use these pathways effectively at the point of care?  Dr. Larry Shulman: So, I just wanted to step back a little bit. There are very extensive guidelines that tell us what the best therapies are for really all of the cancers. These guidelines come from the National Comprehensive Cancer Network or NCCN and the American Society of Clinical Oncology or ASCO and other professional organizations. And they're there. They're there, in free information off their websites.  But the problem is how to translate those pretty dense documents into something that will work in the clinic for a patient, for the physician who's working in the electronic health record. And the tools that are available, and there are a number of tools that can integrate with electronic health records, are expensive. You need to purchase them from the vendor and there are yearly fees.  And they're also difficult to implement. You need to work with the vendor to integrate them into your own rendition of your electronic health record. And there's a lot of customization that needs to be done. So, it's a financial challenge and it's also a time challenge for people to integrate these tools into their workflow, into their electronic health records.  Dr. John Sweetenham: Thanks, Larry. So speaking from my own past experience of pathway implementation, it certainly has been a major challenge for the reasons that you mentioned and also because of the, I think resistance may or may not be too strong a word, of many of the clinicians to use these for a number of reasons, part of which are the time it takes, part of which many of them feel that the pathways aren't really changing decisions that they might make anyway. So, you know, the uptake of pathway utilization, even in those centers which have been successful in getting something installed and plugged into their EHR, on the whole, hasn't been as good as it could have been. So maybe I'll turn to you, Rebecca, because I know that this is something that you've worked on a lot.  And it's a kind of double-barreled question. I think the first part of it is, you know, what do you think are the major roadblocks to high physician uptake in the use of these pathways platforms? And maybe you could talk a little bit about what the various software platforms do to make them more physician-friendly and to enhance utilization right on the front line.  Dr. Rebecca Maniago: Yeah, that's a great question. And so, you know, I've worked with a number of customers and physicians over the past five and a half years on implementing these pathways. And the number one pushback is really about the time it takes in the workflow. So, if I had a dollar for every time I heard “every click counts,” I'd be a rich person and it does come down to clicks. And so, you know, as a software vendor, we really have to focus on how do we reduce that friction?  How do we make sure that the clicks we are asking for are the ones that actually matter? And how do we continue to streamline that process? And so, you know, while there is a fine balance, because as part of a Pathways platform, at the end of the day, we do need to understand some data about that patient. You need to understand the clinical scenario so you can surface the right treatment recommendation, which means there is some amount of data capture that has to happen. In some circumstances, you know, we can pull some of that data in from the EHR.  But unfortunately, the reality is that a lot of that data is messy and it's sort of stuck in documents and unstructured places. And so it doesn't easily flow in, which means we rely on the provider to give us that information. And oftentimes they've already entered it other places. So what's more frustrating than entering data twice? But, you know, I do see a great opportunity here. And this is certainly where software companies are focused is with AI.  So, know, for, especially for this data aggregation, a lot of these AI tools can actually scan through the chart instead of relying on the physician to sort of manually skim through and aggregate and find all that pertinent information. That's what AI is really good at. And almost instantaneously, it can find the messy data that lives in those unstructured documents. And wouldn't it be nice if that was automatically populated within these applications so that really all we're asking of the clinician is to validate that that information is accurate. And then choose the treatment that cuts down on the number of clicks, it cuts down on frustration. You know, again, the physician will be the one that needs to make that decision. AI is not there to replace that, but it certainly has a great opportunity to reduce some of this manual documentation and the things that physicians find the most frustrating, especially as it relates to using these pathways tools.  Dr. John Sweetenham: One of the pretty common pushbacks that I heard during my time in a couple of institutions was, “Well, you know, I'm sitting here at the point of care with my patients and I already know what I want to do and how I'm going to treat that patient if it's not in the context of a clinical trial. So I don't need to go through, you know, X number of clicks to get me to where I know I'm going to be anyway.”  Does either of you have any thoughts about that? I think you've sort of partially answered it, but what do you think, Rebecca? Do you think that this is something that is more easily overcome-able, if that's even a word, than it was a few years back?  Rebecca Maniago: Yeah, I do. And I think this is where the customization comes into play. So while they may know what an appropriate treatment for their patient is, there are more options now than ever, which means at a local level, there may be multiple options that are clinically equivalent. And so when you think about things like payer pathways or drug margins as an organization, they have to drive some of that from within. But having the capability to do so can then start to sort of sell the value to the provider that, yes, you may know what you want to order for your patient, but would you consider something else if it was clinically equivalent, but it had other benefits to either the patient or the organization?  Dr. Larry Shulman: The other thing I would add to that, John, if I can jump in here is that the data is the data and the data shows us that guideline concordant care is not always prescribed to the US. And in fact, in some circumstances, the gaps between what should be prescribed and what is being prescribed are quite wide. So, you know, people feel like they're always doing the best job and making the best recommendations. And I think, you know, I think I am. But, you know, like many of my colleagues at academic cancer centers, I'm highly specialized. I only see patients with breast cancer. But many oncologists throughout the country are more generalists. They're seeing patients with multiple diseases. And it's harder for them to be completely on top of what the current recommendations are in any particular circumstance. Our diseases are complicated. They're getting more complicated all the time with molecular and genomic testing and subcategorizations of different cancers. So, I don't think that we can be too cocky about it, quite frankly. I think we ought to use technology that Rebecca describes for the tools and for AI to really help us. I think if we turn our backs on that, I think we're making a big mistake. You just got to look at the data. The data is pretty convincing.  Dr. John Sweetenham: You know ever since we started looking seriously at decision support through pathways a number of years ago, the word has always been around the payers role in this and the day will come where we are going to get reimbursed based on pathway and concordance and I'm not sure that that day has arrived. So I have a question for both of you in this regard actually. And the first of those is maybe I'll start with you for this part of it, Larry. Where do you think we are in that regard? And are you hearing more and more of payers starting to look at pathway compliance? And then on the other end of that, and maybe I'll ask Rebecca about this, is one of the other pushback issues that I used to experience from physicians I worked with was they may go through the pathways platform and come up with a treatment recommendation. The best example of this I can think might be that the recommendation might be a biosimilar. Let's just use that as an example. But the next stage in the process would be to find out whether the patient's insurance would actually cover that particular biosimilar, which opened up a whole new can of worms. So there are two kinds of payer aspects of that. Maybe Larry, I'll ask you to start off by talking about that kind of coverage issue. And then I'll ask Rebecca, if you have any thoughts about the flow the other way in terms of getting drugs approved and what we can do to help from an insurance perspective.  Dr. Larry Shulman: Sure, that's really an important point, John. Our current state of affairs with the payers and their attempt to be sure that we're providing responsible, guideline concordant care is the use of prior authorization processes, which are incredibly costly, both for the oncology practices and for the payers.  They have an army of nurses sitting at the phone talking to us in the oncology practices to decide whether they're going to pay for something. And frankly, generally, the payers will pay for things that are part of either the NCCN or ASCO or other professional organizations' guidelines. But you need to prove to them over the phone that in fact the patient qualifies for that.  We have actually had some experiments with some of the payers to prove that to them in different ways by auto transmission of data. And this would be a big savings for them and for us, it would take away some of the delays in therapy while we're waiting for prior authorizations to go through. And we shouldn't have to do this by phone.   The EHR and the pathway tools should aggregate the data, aggregate the potential treatment and be able to transmit those data to the payer. And if in fact it meets the appropriate criteria for guideline concordant care would be approved. Right now, it's a terrible, costly, timely manual process that they should be able to fix.  Dr. John Sweetenham: Thanks, Larry. And have you, you know, from a broader perspective, so not thinking necessarily about individual patients and specific issues around prior authorization, have you seen any movement among the payers to kind of get more aggressive about this and say, okay, you know, we are going to want to see your numbers, we want to know how many of your physicians are now using their pathways platform and so on. Are you seeing any word that that might be happening? Because certainly a few years back, that was the word on the street, as it were, that this day was coming.  Dr. Lawrence Shulman: And that's the proposal that we've made to several of our payers. Let us give you the aggregate data. If our guideline concordance is above a certain level, give us a gold card, give us a pass, and we won't need to do pre-authorizations. We've actually done that at my institution in radiology. Aggregate data gives individual physicians that pass if their guideline concordance was appropriate. I got to pass. So I don't need to go through those radiology pre-authorizations for my patients. And I think we can do the same thing with therapeutics. It's been a little bit more cumbersome to do it, and there's some detailed reasons why that is. But that's really what they want to know. And the payers want to know that patients are getting guideline concordant care, but they also realize it's not going be 100%. There are always a few outlier patients who require some variation from the guidelines. But if we get above 80% guideline concordant care, I think many of the payers would be happy to accept that as long as we continue to feed them the data. And that's the case in our radiology process with one of the payers is, you know, I get a gold card, but they continue to look at my data. And if I don't continue to perform well, they'll take that away.  Dr. John Sweetenham: Thanks, Larry. And Rebecca, just returning to you, this issue of prior authorization and facilitating life for the physician at the point of care in terms of knowing, you know, which specific treatment might be covered for a patient. Do you have any thoughts or maybe you could give us some insights on what software vendors are doing to facilitate that part of the process, the communication back to the payers to take some of that burden off the physician and the physician staff?  Rebecca Maniago: Yeah, absolutely. And this is a problem we've been trying to tackle for years. And it's not easy. We've tackled it in a couple ways. So first, we try to sort of link up to the payer portal where the information that was being attested to within the application could then be automatically sent. Because at the end of the day, the data points that are being collected to surface treatment recommendations ultimately are the same data points that the payer wants.  Unfortunately, there are a lot of data interoperability challenges within that space. So that was not something that was going to be sustainable. However, in current state, because as I mentioned, the customization is key for these products, focusing more on how can we allow practices to embed payer pathways within the application. So again, you kind of start with the backbone of your standard guidelines but then having the capability of adding in a payer pathway that will only show up as that preferred option for a patient who has that insurance, at least at the point of care, the provider sees what the insurer would then approve. So while it's not automatically assuring authorization, we are at least steering the decision in a direction where we think most likely this is going to be approved based upon the pathway that they have access to. So that sort of current state, I agree. We've been talking about this idea of gold carding for years.  Presumably the data is there today, right? Like we are able to capture structured data with every order placed to recognize concordance to Larry's point. All those reports are available to provide to payers. I just haven't seen a lot of practices have a lot of success when they tackle it on their own from that direction.  Dr. John Sweetenham: Right, thanks. Larry, you and I were at the NCCN annual meeting recently and I know that you've been quite heavily involved in the policy program and in the policy forums and so on at NCCN. Are you able to share anything from this year's meeting in terms of care pathways implementation and what you think might happen next in that regard?  Dr. Larry Shulman: NCCN, in my own opinion, has really led the way in defining what guideline concordant care is through their guidelines, which are very extensive, covering basically every cancer and every situation with every cancer. And it's really an astounding amount of amazing work that all of us use and the payers largely use as well. But they've increasingly understood that there's a gap between their guidelines and the implementation of their guidelines. And they are working on some things. They are working on the digitalization of their guidelines to make them more accessible, but also thinking about ways that they may, in fact, fit into the work processes that all of us have when we go to clinic.  They're acutely aware that the country is not where it needs to be in regard to a translation, if you will, of their guidelines in the practice. And I think we're all thinking really hard about whether there are things that we can team up to do, if you will, to try to close those gaps.  Dr. John Sweetenham: Great, thank you. Just switching gears a little bit back to you, if I can, Rebecca. I think you've said a little bit about this already. What do you think are the next steps that we need to take to more effectively implement these tools in the clinic? I think we've discussed a little bit some of the roadblocks to that. But where do you think we need to go next in terms of getting better use of these pathways?  Rebecca Maniago: Yeah, I will say one thing that we haven't really touched on is the pharmacy team. So the biggest blocker that I see is actually the pre-implementation. So there's a lot of focus on how do we get physicians to use this? How do we increase adoption? But often the first barrier is the regimen library. So no matter what the pathways platform is, the backbone of it will be those regimens. And so, really helping organizations and we partner with pharmacies, they're doing all the backend configuration. And so how can we make that piece of the technology easier for them to implement because that's really the lead up and there's a ton of cleanup and maintenance. You know, as a pharmacist, I empathize, but really that's where it all begins. And so I think, you know, continuing to focus on not only the front end user and the physician, but everybody that's going to be involved in order to make a pathway program successful needs to be, you know, at the table in the beginning, helping set up those processes and, and buying into the why this is important.  Dr. John Sweetenham: That's a great point.  Dr. Larry Shulman: So could I just jump in one quickly here, John? So pathways, as we've discussed, the tools are expensive. There is a person cost, as Rebecca is just describing, about customization and implementation. But there are very good data in the literature to show that when you follow pathways, care is less costly. Survival is better, which is obviously our primary goal, but also cost is less. And the payers can benefit from that. And the question is, can they figure out ways to use that to help to fund the purchase and maintenance of pathway products that will give their patients better care, but also less costly care? And so I think that is a potential solution. I've had that conversation with some payers as well. And it would be great to see that happen. I think that would be a huge step.  Rebecca Maniago: Yeah, we have some, if they're able to set it up in the right way and really optimize, you know, from the pharmacy perspective, we have practices who the application is more than, you know, paying for itself just by way of using it to the fullest potential that it has.  Dr. John Sweetenham: Yeah, that's a really great point. A couple of other more general questions. I'm going to start with you, Rebecca, and Larry ask you to respond as well. Are you hearing anything from patients around this issue? Are they aware or becoming more aware that pathways are being used in the clinic when they're seen by their physicians? And do they have a say, are there patient advocates involved in this part of the process? Rebecca, maybe you could start.  Rebecca Maniago: I haven't had as much exposure to that side of it. So, you know, I would love to hear what Larry thinks because most of my exposure is at the physician level, which of course they are the ones who are making the decision with the patient. So my assumption is that there is at least some level of understanding that there are options and that, you know, together let's decide on the best one for you. But again, I would love to hear what Larry has to say.  Dr. Larry Shulman: Yeah, so that's a really interesting question. I actually was discussing that at the cancer center last week, particularly around the utilization of AI in this process. And, you know, right now, as you know, if you submit a journal article or, you know, many other things, ask you whether you used AI to generate it. If in fact we use tools that include AI, we're not.  Are we obligated to tell the patient that you're making this recommendation together with computer assist, if you will, that helps you to make the recommendation you are making to them? Ultimately, I think it's the physician who's responsible for the choice, but should we disclose it? I have to tell you personally, I haven't thought about doing that. But I think it's a really, really good question is whether we should upfront tell the patients that we've had assistance in making the recommendations that we have.  Dr. John Sweetenham: Right, very interesting point. To close it out, one more question for both of you and again, it's the same one. Rebecca, to start with, we've all been, as I said right up front, talking and, you know, working on this issue for more than 10 years now. In 10 years from now, how would you like it to look and how do you think it might look?  Rebecca Maniago: Great question. I think we may get to where I would like to see it quicker than 10 years. I think AI provides a lot of opportunity and excitement. I'd love to turn a corner where physicians no longer see tools like this as a hindrance, rather they rely on them, they trust them, they help them get through their day. They continue to improve quality of care and reduce costs and patient burden. Obviously, that's the pipe dream, but I think we may get there before 10 years, given what I think AI is going to enable.  Dr. Larry Shulman: Yeah, I want to add to Rebecca's comments. One of the things that I worry about, and ASCO worries about a lot, is the oncology workforce, which is progressively strained in their attempts to care for all the cancer patients in the US. And for all of us who practice oncology, for many reasons, it's become more and more inefficient, whether it's use of the EHR, pre-authorization work, and so on.  And we really need to turn that around. We need to make practice not only better, which I think these tools can do, including AI, as Rebecca says, but make it much more efficient because that's going to allow us to both deliver more high-quality care to our patients, but also to care for more patients and have them benefit from our expertise and what we have to offer. So I think this is really an obligation on our part. I think it's an imperative that we move in this direction for both quality reasons and efficiency reasons.  Dr. John Sweetenham: Thanks, Larry. Well, I've really enjoyed the conversation today and I think, you know, it's been great to think about some of the challenges that we still have in this regard. But it's also great to hear what I'm sensing is quite a lot of optimism about how things may play out over the next few years. And it does sound as if there's a lot of hard work going on to bring us to a point where the clinical decision support tools are going to truly support what our oncologists are doing and no longer be seen as an obstruction. So, I want to thank you both for sharing your insights with us today on the ASCO Daily News Podcast.  Dr. Larry Shulman: Thank you so much, John.  Rebecca Maniago: Thank you so much.  Dr. John Sweetenham: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.  Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers:  Dr. John Sweetenham  Dr. Lawrence Shulman  Rebecca Maniago  Follow ASCO on social media:  @ASCO on Twitter  @ASCO on Bluesky  ASCO on Facebook  ASCO on LinkedIn        Disclosures:  Dr. John Sweetenham:  No relationships to disclose    Dr. Lawrence Shulman:  Consulting or Advisory Role: Genetech     Rebecca Maniago:   No relationships to disclose.     

JCO PO author Dr. Timothy Showalter at Artera and University of Virginia shares insights into his JCO PO article, “Digital Pathology–Based Multimodal Artificial Intelligence Scores and Outcomes in a Randomized Phase III Trial in Men With Nonmetastatic Castration-Resistant Prostate Cancer” . Host Dr. Rafeh Naqash and Dr. Showalter discuss how multimodal AI as a prognostic marker in nonmetastatic castration-resistant prostate cancer may serve as a predictive biomarker with high-risk patients deriving the greatest benefit from treatment with apalutamide. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we'll bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast Editor for JCO Precision Oncology and assistant professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, we are excited to be joined by Dr. Timothy Showalter, Chief Medical Officer at Artera and professor of Radiation Oncology at the University of Virginia and author of the JCO Precision Oncology article entitled, “Digital Pathology Based Multimodal Artificial Intelligence Scores and Outcomes in a Randomized Phase 3 Trial in Men with Non-Metastatic Castration Resistant Prostate Cancer.” At the time of this recording, our guest's disclosures will be linked in the transcript. Dr. Showalter, it's a pleasure to have you here today. Dr. Timothy Showalter: It's a pleasure to be here. Thanks for having me. Dr. Rafeh Naqash: I think this is going to be a very interesting discussion, not just from a biomarker perspective, but also in terms of how technologies have evolved and how we are trying to stratify patients, trying to escalate or deescalate treatments based on biomarkers. And this article is a good example of that. One of the things I do want to highlight as part of this article is that Dr. Felix Feng is the first author for this article. Unfortunately, Dr. Felix Feng passed away in December of 2024. He was a luminary in this field of prostate cancer research. He was also the Chair of the NRG GU Committee as well as Board of Directors for RTOG Foundation and has mentored a lot of individuals from what I have heard. I didn't know Dr. Feng but heard a lot about him from my GU colleagues. It's a huge loss for the community, but it was an interesting surprise for me when I saw his name on this article as I was reviewing it. Could you briefly talk about Dr. Feng for a minute and how you knew him and how he's been an asset to the field? Dr. Timothy Showalter: Yeah. I'm always happy to talk about Felix whenever there's an opportunity. You know, I was fortunate to know Felix Feng for about 20 years as we met during our residency programs through a career development workshop that we both attended and stayed close ever since. And you know, he's someone who made an impact on hundreds of lives of cancer researchers and other radiation oncologists and physicians in addition to the cancer patients he helped, either through direct clinical care or through his innovation. For this project in particular, I first became involved soon after Felix had co-founded Artera, which is, you know the company that developed this. And because Felix was such a prolific researcher, he was actually involved in this and this research project from all different angles, both from the multimodal digital pathology tool to the trial itself and being part of moving the field forward in that way. It's really great to be able to sort of celebrate a great example of Felix's legacy, which is team science, and really moving the field forward in terms of translational projects based on clinical trials. So, it's a great opportunity to highlight some of his work and I'm really happy to talk about it with you. Dr. Rafeh Naqash: Thanks, Tim. Definitely a huge loss for the scientific community. And I did see a while back that there was an international symposium organized, showcasing his work for him to talk about his journey last year where more than 200, 250 people from around the globe actually attended that. That speaks volumes to the kind of impact he's had as an individual and impact he's had on the scientific side of things as well. Dr. Timothy Showalter: Yes. And we just had the second annual Feng Symposium the day before ASCO GU this year with, again, a great turnout and some great science highlighted, as well as a real focus on mentorship and team science and collaboration. Dr. Rafeh Naqash: Thank you so much for telling us all about that. Now going to what you guys published in JCO Precision Oncology, which is this article on using a biomarker approach to stratify non-metastatic prostate cancer using this artificial intelligence based H&E score. Could you tell us the background for what started off this project? And I see there is a clinical trial data set that you guys have used, but there's probably some background to how this score or how this technology came into being. So, could you superficially give us an idea of how that started? Dr. Timothy Showalter: Sure. So, the multimodal AI score was first published in a peer reviewed journal back in 2022 and the test was originally developed through a collaboration with the Radiation Therapy Oncology Group or Energy Oncology Prostate Cancer Research Team. The original publication describes development and validation of a risk stratification tool designed to predict distant metastasis and prostate cancer specific mortality for men with localized prostate cancer. And the first validation was in men who were treated with definitive radiation therapy. There have been subsequent publications in that context and there's a set of algorithms that have been validated in localized prostate cancer and there's a test that's listed on NCCN guidelines based on that technology. The genesis for this paper was really looking at extending that risk stratification tool that was developed in localized prostate cancer to see if it could one, validate in a non-metastatic castrate refractory prostate cancer population for patients enrolled on the SPARTAN trial. And two, whether there was a potential role for the test output in terms of predicting benefit from apalutamide for patients with non-metastatic prostate cancer. For patients who are enrolled on the SPARTAN study, almost 40% of them had H&E stain biopsy slide material available and were eligible to be included in this study. Dr. Rafeh Naqash: Going a step back to how prostate cancer, perhaps on the diagnostic side using the pathology images is different as you guys have Gleason scoring, which to the best of my knowledge is not necessarily something that most other tumor types use. Maybe Ki-67 is somewhat of a comparison in some of the neuroendocrine cancers where high Ki-67 correlates with aggressive biology for prognosis. And similarly high Gleason scores, as we know for some of the trainees, correlates with poor prognosis. So, was the idea behind this based on trying to stratify or sub-stratify Gleason scoring further, where you may not necessarily know what to do with the intermediate high Gleason score individual tumor tissues? Dr. Timothy Showalter: Well, yeah. I mean, Gleason score is a really powerful risk stratification tool. As you know, our clinical risk groupings are really anchored to Gleason scores as an important driver for that. And while that's a powerful tool, I think, you know, some of the original recognition for applying computer vision AI into this context is that there are likely many other features located in the morphology that can be used to build a prognostic model. Going back to the genesis of the discovery project for the multimodal AI model, I think Felix Feng would have described it as doing with digital pathology and computer vision AI what can otherwise be done with gene expression testing. You know, he would have approached it from a genomic perspective. That's what the idea was. So, it's along the line of what you're saying, which is to think about assigning a stronger Gleason score. But I think really more broadly, the motivation was to come up with an advanced complementary risk stratification tool that can be used in conjunction with clinical risk factors to help make better therapy recommendations potentially. So that was the motivation behind it. Dr. Rafeh Naqash: Sure. And one of the, I think, other important teaching points we try to think about, trainees of course, who are listening to this podcast, is trying to differentiate between prognostic and predictive scores. So, highlighting the results that you guys show in relation to the MMAI score, the digital pathology score, and outcomes as far as survival as well as outcomes in general, could you try to help the listeners understand the difference between the prognostic aspect of this test and the predictive aspect of this test? Dr. Timothy Showalter: So let me recap for the listeners what we found in the study and how it kind of fits into the prognostic and the predictive insights. So, one, you know, as I mentioned before, this is ultimately a model that was developed and validated for localized prostate cancer for risk stratification. So, first, the team looked at whether that same tool developed in localized prostate cancer serves as a prognostic tool in non-metastatic castrate-refractory prostate cancer. So, we applied the tool as it was previously developed and identified that about 2/3 of patients on the SPARTAN trial that had specimens available for analysis qualified as high risk and 1/3 of patients as either intermediate or low risk, which we called in the paper ‘non-high risk'. And we're able to show that the multimodal AI score, which ranges from 0 to 1, and risk group, was associated with metastasis free survival time to second progression or PFS 2 and overall survival. And so that shows that it performs as a prognostic tool in this setting. And this paper was the first validation of this tool in non-metastatic castrate-refractory prostate cancer. So, what that means to trainees is basically it helps you understand how aggressive that cancer is or better stratify the risk of progression over time. So that's the prognostic performance. Dr. Rafeh Naqash: Thank you for trying to explain that. It's always useful to get an example and understand the difference between prognostic and predictive. Now again, going back to the technology, which obviously is way more complicated than the four letter word MMAI, I per se haven't necessarily done research in this space, but I've collaborated with some individuals who've done digital pathology assessments, and one of the projects we worked on was TIL estimation and immune checkpoint related adverse events using some correlation and something that one of my collaborators had sent to me when we were working on this project as part of this H&E slide digitalization, you need color deconvolution, you need segmentation cell profiling. Superficially, is that something that was done as part of development of this MMAI score as well? Dr. Timothy Showalter You need a ground truth, right? So, you need to train your model to predict whatever the outcome is. You know, if you're designing an AI algorithm for Ki-67 or something I think you mentioned before, you would need to have a set of Ki-67 scores and train your models to create those scores. In this case, the clinical annotation for how we develop the multimodal AI algorithm is the clinical endpoints. So going back to how this tool was developed, the computer vision AI model is interpreting a set of features on the scan and what it's trying to do is identify high risk features and make a map that would ultimately predict clinical outcomes. So, it's a little bit different than the many digital pathology algorithms where the AI is being trained to predict a particular morphological finding. In this case, the ground truth that the model is trained to predict is the clinical outcome. Dr. Rafeh Naqash: Sure. And from what you explained earlier, obviously, tumors that had a high MMAI score were the ones that were benefiting the most from the ADT plus the applausive. Is this specific for this androgen receptor inhibitor or is it interchangeable with other inhibitors that are currently approved? Dr. Timothy Showalter: That's a great question and we don't know yet. So, as you're alluding to, we did find that the MMAI risk score was predictive for benefit from apalutamide and so it met the statistical definition of having a significant interaction p value so we can call it a predictive performance. And so far, we've only looked in this population for apalutamide. I think you're raising a really interesting point, which is the next question is, is this generalizable to other androgen receptor inhibitors? There will be future research looking at that, but I think it's too early to say. Just for summary, I think I mentioned before, there are about 40% of patients enrolled on the SPARTAN study had specimens available for inclusion in this analysis. So, the SPARTAN study did show in the entire clinical trial set that patients with non-metastatic castrate-refractory prostate cancer benefited from apalutamide. The current study did show that there seems to be a larger magnitude of benefit for those patients who are multimodal AI high risk scores. And I think that's very interesting research and suggests that there's some interaction there. But I certainly would want to emphasize that we have not shown that patients with intermediate or low risk don't benefit from apalutamide. I think we can say that the original study showed that that trial showed a benefit and that we've got this interesting story with multimodal AI as well. Dr. Rafeh Naqash: Sure. And I think from a similar comparison, ctDNA where ctDNA shows prognostic aspects, I treat people with lung cancer especially, and if you're ctDNA positive at a 3 to 4-month period, likely chances of you having a shorter disease-free interval is higher. Same thing I think for colorectal cancers. And now there are studies that are using ctDNA as an integral biomarker to stratify patients positive/negative and then decide on escalation/de-escalation of treatment. So, using a similar approach, is there something that is being done in the context of the H&E based stratification to de-intensify or intensify treatments based on this approach? Dr. Timothy Showalter: You're hitting right on the point in the most promising direction. You know, as we pointed out in the manuscript, one of the most exciting areas as a next step for this is to use a tool like this for stratification for prospective trials. The multimodal AI test is not being used currently in clinical trials of non-metastatic castrate-refractory prostate cancer, which is a disease setting for this paper. There are other trials that are in development or currently accruing where multimodal AI stratification approach is being taken, where you see among the high-risk scores, at least in the postoperative setting for a clinical trial that's open right now, high risk score patients are being randomized to basically a treatment intensification question. And then the multimodal AI low risk patients are being randomized to a de-intensification experimental arm where less androgen deprivation therapy is being given. So, I think it's a really promising area to see, and I think what has been shown is that this tool has been validated really across the disease continuum. And so, I think there are opportunities to do that in multiple clinical scenarios. Dr. Rafeh Naqash: Then moving on to the technological advancements, very fascinating how we've kind of evolved over the last 10 years perhaps, from DNA based biomarkers to RNA expression and now H&E. And when you look at cost savings, if you were to think of H&E as a simpler, easier methodology, perhaps, with the limitations that centers need to digitalize their slides, probably will have more cost savings. But in your experience, as you've tried to navigate this H&E aspect of trying to either develop the model or validate the model, what are some of the logistics that you've experienced can be a challenge? As we evolve in this biomarker space, how can centers try to tackle those challenges early on in terms of digitalizing data, whether it's simple data or slides for that matter? Dr. Timothy Showalter: I think there's two main areas to cover. One, I think that the push towards digitalization is going to be, I think, really driven by increasing availability and access to augmentative technologies like this multimodal AI technology where it's really adding some sort of a clinical insight beyond what is going to be generated through routine human diagnostic pathology. I think that when you can get these sorts of algorithms for patient care and have them so readily accessible with a fast turnaround time, I think that's really going to drive the field forward. Right now, in the United States, the latest data I've seen is that less than 10% of pathology labs have gone digital. So, we're still at an early stage in that. I hope that this test and similar ones are part of that push to go more digital. The other, I think, more interesting challenge that's a technical challenge but isn't about necessarily how you collect the data, but it certainly creates data volume challenges, is how do you deal with image robustness and sort of translating these tools into routine real-world settings. And as you can imagine, there's a lot of variation for staining protocols, intensity scanner variations, all these things that can affect the reliability of your test. And at least for this research group that I'm a part of that has developed this multimodal AI tool can tell you that the development is sophisticated, but very data and energy intensive in terms of how to deal with making a tool that can be consistent across a whole range of image parameters. And so that presents its own challenges for dealing with a large amount of compute time and AI cycles to make robust algorithms like that. And practically speaking, I think moving into other diseases and making this widely available, the size of data required and the amount of cloud compute time will be a real challenge. Dr. Rafeh Naqash: Thank you for summarizing. I can say that definitely, you know, this is maybe a small step in prostate cancer biomarker research, but perhaps a big step in the overall landscape of biomarker research in general. So definitely very interesting. Now, moving on to the next part of the discussion is more about you as a researcher, as an individual, your career path, if you can summarize that for us. And more interestingly, this intersection between being part of industry as well as academia for perhaps some of the listeners, trainees who might be thinking about what path they want to choose. Dr. Timothy Showalter: Sure. So, as you may know, I'm a professor at the University of Virginia and I climbed the academic ladder and had a full research grant program and thought I'd be in academia forever. And my story is that along the way, I kind of by accident ended up founding a medical device company that was called Advaray and that was related to NCI SBIR funding. And I found myself as a company founder and ultimately in that process, I started to learn about the opportunity to make an impact by being an innovator within the industry space. And that was really the starting point for me. About four years ago, soon after Felix Feng co-founded Artera, he called me and told me that he needed me to join the company. For those who were lucky to know Felix well, at that very moment, it was inevitable that I was going to join Artera and be a part of this. He was just so persuasive. So, I will say, you know, from my experience of being sort of in between the academic and industry area, it's been a really great opportunity for me to enter a space where there's another way of making an impact within cancer care. I've gotten to work with top notch collaborators, work on great science, and be part of a team that's growing a company that can make technology like this available. Dr. Rafeh Naqash: Thank you so much, Tim, for sharing some of those thoughts and insights. We really appreciate you discussing this very interesting work with us and also appreciate you submitting this to JCO Precision Oncology and hopefully we'll see more of this as this space evolves and maybe perhaps bigger more better validation studies in the context of this test. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

On the inaugural episode of ASCO Education: By the Book, Dr. Nathan Pennell and Dr. Don Dizon share reflections on the evolution of the ASCO Educational Book, its global reach, and the role of its new companion podcast to further shine a spotlight on the issues shaping the future of modern oncology. TRANSCRIPT Dr. Nathan Pennell: Hello, I'm Dr. Nate Pennell, welcoming you to the first episode of our new podcast, ASCO Education: By the Book. The podcast will feature engaging discussions between editors and authors from the ASCO Educational Book. Each month, you'll hear nuanced views on key topics in oncology featured in Education Sessions at ASCO meetings, as well as some deep dives on the advances shaping modern oncology. Although I am honored to serve as the editor-in-chief (EIC) of the ASCO Educational Book, in my day job, I am the co-director of the Cleveland Clinic Lung Cancer Program and vice chair for clinical research for the Taussig Cancer Center here in Cleveland. I'm delighted to kick off our new podcast with a discussion featuring the Ed Book's previous editor-in-chief. Dr. Don Dizon is a professor of medicine and surgery at Brown University and works as a medical oncologist specializing in breast and pelvic malignancies at Lifespan Cancer Institute in Rhode Island. Dr. Dizon also serves as the vice chair for membership and accrual at the SWOG Cancer Research Network. Don, it's great to have you here for our first episode of ASCO Education: By the Book. Dr. Don Dizon: Really nice to be here and to see you again, my friend. Dr. Nathan Pennell: This was the first thing I thought of when we were kicking off a podcast that I thought we would set the stage for our hopefully many, many listeners to learn a little bit about what the Ed Book used to be like, how it has evolved over the last 14 years or so since we both started here and where it's going. You started as editor-in-chief in 2012, is that right? Dr. Don Dizon: Oh, boy. I believe that is correct, yes. I did two 5-year stints as EIC of the Educational Book, so that sounds about right. Although you're aging me very clearly on this podcast. Dr. Nathan Pennell: I had to go back in my emails to see if I could figure out when we started on this because we've been working on it for some time. Start out a little bit by telling me what do you remember about the Ed Book from back in the day when you were applying to be editor-in-chief and thinking about the Ed Book. What was it like at that time? Dr. Don Dizon: You know, it's so interesting to think about it.  Ten years ago, we were both in a very different place in our careers, and I remember when the Ed Book position came up, I had been writing a column for ASCO. I had done some editorial activities with other journals for sure, but what always struck me was it was very unclear how one was chosen to be a part of the education program at ASCO. And then it was very unclear how those faculty were then selected to write a paper for the Educational Book. And it was back in the day when the Educational Book was completely printed. So, there was this book that was cherished among American fellows in oncology. And it was one that, when I was newly attending, and certainly two or three years before the editor's position came up, it was one that I referenced all the time. So, it was a known commodity for many of us. And there was a certain sense of selectivity about who was invited to write in it. And it wasn't terribly transparent either. So, when the opportunity to apply for editor-in-chief of the Educational Book came up, I had already been doing so much work for ASCO. I had been on the planning committees and served in many roles across the organization, and editing was something I found I enjoyed in other work. So, I decided to put my name in the ring with the intention of sort of bringing the book forward, getting it indexed, for example, so that there was this credit that was more than just societal credit at ASCO. This ended up being something that was referenced and acknowledged as an important paper through PubMed indexing. And then also to provide it as a space where we could be more transparent about who was being invited and broadening the tent as to who could participate as an author in the Ed Book. Dr. Nathan Pennell: It's going to be surprising to many of our younger listeners to learn that the Educational Book used to be just this giant, almost like a brick. I mean, it was this huge tome of articles from the Education Sessions that you got when you got your meeting abstracts book at the annual meeting. And you can always see people on the plane on the way out of Chicago with their giant books. Dr. Don Dizon: Yes. Dr. Nathan Pennell: That added lots of additional weight to the plane, I'm sure, on the way out. Dr. Don Dizon: And it was not uncommon for us to be sitting at an airport, and people would be reading those books with highlighters. Dr. Nathan Pennell: I fondly remember being a fellow and coming up and the Ed Book was always really important to me, so I was excited. We'll also let the listeners in on that. I also applied to be the original editor-in-chief of the Ed Book back in 2012, although I was very junior and did not have any real editorial experience. I think I may have been section editor for The Oncologist at that point. And I had spoken to Dr. Ramaswamy Govindan at WashU who had been the previous editor-in-chief about applying and he was like, “Oh yeah. You should absolutely try that out.” And then when Dr. Dizon was chosen, I was like, “Oh, well. I guess I didn't get it.” And then out of the blue I got a call asking me to join as the associate editor, which I was really always very thankful for that opportunity. Dr. Don Dizon: Well, it was a highly fruitful collaboration, I think, between you and I when we first started. I do remember taking on the reins and sort of saying, “You know, this is our vision of what we want to do.” But then just working with the authors, which we did, about how to construct their papers and what we were looking for, all of that is something I look back really fondly on. Dr. Nathan Pennell: I think it was interesting too because neither one of us had really a lot of transparency into how things worked when we started. We kind of made it up a little bit as we went along. We wanted to get all of the faculty, or at least as many of them as possible contributing to these. And we would go to the ASCO Education Committee meeting and kind of talk about the Ed Book, and we were thinking about, you know, how could we get people to submit. So, at the time it wasn't PubMed indexed. Most people, I think, submitted individual manuscripts just from their talk, which could be anywhere from full length review articles to very brief manuscripts. Dr. Don Dizon: Sometimes it was their slides with like a couple of comments on it. Dr. Nathan Pennell: And some of them were almost like a summary of the talk. Yeah, exactly. And so sort of making that a little more uniform. There was originally an honorarium attached, which went away, but I think PubMed indexing was probably the biggest incentive for people to join. I remember that was one of the first things you really wanted to get. Dr. Don Dizon Yeah. And, you know, it was fortuitous. I'd like to take all the credit for it, but ASCO was very forward thinking with Dr. Ramaswamy and the conversations about going to PubMed with this had preceded my coming in. We knew what we needed to do to get this acknowledged, which was really strengthening the peer review so that these papers could meet the bar to get on PubMed. But you know, within the first, what, two or three years, Nate, of us doing this, we were able to get this accepted. And now it is. If you look at what PubMed did for us, it not only increased the potential of who was going to access it, but for, I think the oncology community, it allowed people access to papers by key opinion leaders that was not blocked by a paywall. And I thought that was just super important at the time. Social media was something, but it wasn't what it is now. But anybody could access these manuscripts and it's still the case today. Dr. Nathan Pennell: I think it's hard to overstate how important that was. People don't realize this, but the Ed Book is really widely accessed, especially outside the US as well. And a lot of people who can't attend the meeting to get the print, well, the once print, book could actually get access to essentially the education session from the annual meeting without having to fly all the way to the US to attend. Now, you know, we have much better virtual meeting offerings now and whatnot. But at the time it was pretty revolutionary to be able to do that. Dr. Don Dizon: Yeah, and you know, it's so interesting when I think back to, you know, this sort of evolution to a fully online publication of the Ed Book. It was really some requests from international participants of the annual meeting who really wanted to continue to see this in print. At that time, it was important to recognize that access to information was not uniform across the world. And people really wanted that print edition, maybe not for themselves, but so that access in more rural areas or where access in the broadband networks were not established that they still could access the book. I think things have changed now. We were able, I think, in your tenure, to see it fully go online. But even I just remember that being a concern as we went forward. Dr. Nathan Pennell: Yeah, we continued with the print book that was available if people asked for it, but apparently few enough people asked for it that it moved fully online. One of the major advantages of being fully online now is of course, it does allow us to publish kind of in real time as the manuscripts come out in the months leading up to the meeting, which has been, I think, a huge boon because it can build momentum for the Education Sessions coming in. People, you know, really look forward to it. Dr. Don Dizon: Yeah, that was actually a concern, you know, when we were phasing out Ed Book and going to this continuous publication model where authors actually had the ability to sort of revise their manuscript and that would be automatically uploaded. You had a static manuscript that was fully printed, and it was no longer an accurate one. And we did have the ability to fix it. And it just goes to show exactly what you're saying. This idea that these are living papers was really an important thing that ASCO embraced quite early, I think. Dr. Nathan Pennell: And with the onset of PubMed indexing, the participation from faculty skyrocketed and almost within a couple of years was up to the vast majority of sessions and faculty participating. Now I think people really understand that this is part of the whole process. But at the time I remember writing out on my slides in all caps, “THIS IS AN EXPECTATION.” And that's about the best word I could give because I asked if we could make people do it, and they were like, no, you can't make people do it. Dr. Don Dizon: So right.  Actually, I don't think people are aware of the work on the back end every year when I was on as EIC, Nate and myself, and then subsequently Dr. Hope Rugo would have these informational sessions with the education faculty and we would tout the Ed Book, tout the expectation, tout it was PubMed indexed and tout multidisciplinary participation. So, we were not seeing four manuscripts reflecting one session. You know, this encouragement to really embrace multidisciplinary care was something that very early on we introduced and really encouraged people not to submit perspective manuscripts, but to really get them in and then harmonize the paper so that it felt like it was, you know, one voice. Dr. Nathan Pennell: I consider that after PubMed indexing, the next major change to the Ed Book, that really made it a better product and that was moving from, you know, just these short individual single author manuscripts to single session combined manuscript that had multiple perspectives and topics, really much more comprehensive review articles. And I don't even remember what the impetus was for that, but it was really a success. Dr. Don Dizon: Yeah, I mean, I think in the beginning it was more of a challenge, I think, because people were really not given guidance on what these papers were supposed to look like. So, we were seeing individual manuscripts come forward. Looking back, it really foreshadowed the importance of multidisciplinary management. But at the time, it was really more about ensuring that people were leaving the session with a singular message of what to do when you're in clinic again. And the goal was to have the manuscripts reflect that sort of consensus view of a topic that was coming in. There were certain things that people still argued would not fit in a multidisciplinary manuscript. You know, if you have someone who's writing and whose entire talk was on the pathology of thyroid cancer. Another topic was on survivorship after thyroid cancer. It was hard to sort of get those two to interact and cover what was being covered. So, we were still getting that. But you're right, at the end of my tenure and into yours, there were far fewer of those individual manuscripts. Dr. Nathan Pennell: And I think it's even made it easier to write because now, you know, you just have to write a section of a manuscript and not put together an entire review. So, it has helped with getting people on board. Dr. Don Dizon: Well, the other thing I thought was really interesting about the process is when you're invited to do an Education Session at ASCO, you're either invited as a faculty speaker or as the chair of the session. And the responsibility of the chair is to ensure that it flows well and that the talks are succinct based on what the agenda or the objectives were as defined by the education committee for that specific group. But that was it. So really being named “Chair” was sort of an honor, an honorific. It really didn't come with responsibility. So, we use the Ed Book as a way to say, “As chair of the session, it is your responsibility to ensure A, a manuscript comes to me, but B, that the content of that paper harmonizes and is accurate.” And it was very rare, but Nate, I think we got dragged into a couple of times where the accuracy of the manuscript was really called into question by the chair. And those were always very, very tricky discussions because everyone that gets invited to ASCO is a recognized leader in their field. Some of us, especially, I would probably say, dating back 10 years from today, the data behind Standards of Care were not necessarily evidence-based. So, there were a lot of opinion-based therapies. You know, maybe not so much in the medical side, but certainly some of it. But when you went to, you know, surgical treatments and maybe even radiotherapy treatments, it was really based on, “My experience at my center is this and this is why I do what I do.” But those kinds of things ended up being some of the more challenging things to handle as an editor. Dr. Nathan Pennell: And those are the– I'll use “fun” in a broad sense. You know, every once in a while, you get an article where it really does take a lot of hands-on work from the editor to work with the author to try to revise it and make it a suitable academic manuscript. But you know what? I can't think, at least in recent years, of any manuscripts that we turned down. They just sometimes needed a little TLC. Dr. Don Dizon: Yeah. And I think the other important thing it reminds me of is how great it was that I wasn't doing this by myself. Because it was so great to be able to reach out to you and say, “Can you give me your take on this paper?” Or, “Can you help me just join a conference call with the authors to make sure that we're on the same page?” And then on the rare example where we were going to reject a paper, it was really important that we, as the editorial team, and I include our ASCO shepherder, through the whole process. We had to all agree that this was not salvageable. Fortunately, it happened very rarely. But I've got to say, not doing this job alone was one of the more important facets of being the EIC of ASCO's Educational Book. Dr. Nathan Pennell: Well, it's nice to hear you say that. I definitely felt that this was a partnership, you know, it was a labor of love. So, I want to go to what I consider sort of the third major pillar of the changes to the Ed Book during your tenure, and that was the introduction of a whole new kind of manuscript. So up to, I don't know, maybe seven or eight years ago, all the articles were authored just by people who were presenting at the Annual Meeting. And then you had an idea to introduce invited manuscripts. So take me through that. Dr. Don Dizon: Yeah, well, you know, again, it went to this sort of, what can people who are being asked to sort of lead ASCO for that year, what can they demonstrate as sort of a more tangible contribution to the Society and to oncology in general? And I think that was the impetus to use the Ed Book for everyone who was in a leadership position to make their mark. That said, I was here, and I was either president of the society or I was Education Program Chair or Scientific Program Chair, and they got to select an article type that was not being covered in the annual meeting and suggest the authors and work with those authors to construct a manuscript. Never did any one of those folks suggest themselves, which I thought was fascinating. They didn't say, “I want to be the one to write this piece,” because this was never meant to be a presidential speech or a commemorative speech or opportunity for them as leaders. But we wanted to ensure that whatever passion they had within oncology was represented in the book. And again, it was this sort of sense of, I want everyone to look at the Ed Book and see themselves in it and see what they contributed. And that was really important for those who were really shepherding each Annual Meeting each year for ASCO that they had the opportunity to do that. And I was really pleased that leadership really took to that idea and were very excited about bringing ideas and also author groups into the Educational Book who would not have had the opportunity otherwise. I thought that was just really nice. It was about inclusiveness and just making sure that people had the opportunity to say, “If you want to participate, we want you to participate.” Dr. Nathan Pennell: Yeah, I agree. I think the ASCO leadership jumped on this and continues to still really appreciate the opportunity to be able to kind of invite someone on a topic that's meaningful to them. I think we've tried to work in things that incorporate the presidential theme each year in our invited manuscript, so it really allows them to put kind of a stamp on the flavor of each edition. And the numbers reflect that these tend to be among our more highly read articles as well. Dr. Don Dizon: You know, looking back on what we did together, that was something I'm really, really quite proud of, that we were able to sort of help the Educational Book evolve that way. Dr. Nathan Pennell: I agree. You brought up briefly a few minutes ago about social media and its role over time. I think when we started in 2012, I had just joined Twitter now X in 2011, and I think we were both sort of early adopters in the social media. Do you feel like social media has had a role in the growth of the Ed Book or is this something that you think we can develop further? Dr. Don Dizon: When we were doing Ed Book together, professional social media was actually a quite identified space. You know, we were all on the same platform. We analyzed what the outcomes were on that platform and our communities gathered on that platform. So, it was a really good place to highlight what we were publishing, especially as we went to continuous publishing.  I don't remember if it was you or me, but we even started asking our authors for a tweet and those tweets needed work. It was you. It was you or I would actually lay in these tweets to say, “Yeah, we need to just, you know, work on this.” But I think it's harder today. There's no one preferred platform. Alternate platforms are still evolving. So, I think there are opportunities there. The question is: Is that opportunity meaningful enough for the Ed Book to demonstrate its return on an investment, for example? What I always thought about social media, and it's still true today, is that it will get eyes on whatever you're looking at far beyond who you intended to see it. So, you know, your tweets regarding a phase 3 clinical trial in lung cancer, which were so informative, were reaching me, who was not a lung oncologist who doesn't even see lung cancer and getting me more interested in finding that article and more and more pointing to the Educational Book content that speaks to that piece, you know. And I think coupling an impression of the data, associating that with something that is freely accessed is, I think, a golden opportunity not only for our colleagues, but also for anyone who's interested in a topic. Whether you are diagnosed with that cancer or you are taking care of someone with that cancer, or you heard about that cancer, there are people who would like to see information that is relevant and embedded and delivered by people who know what they're talking about. And I think our voices on social media are important because of it. And I think that's where the contribution is. So, if we had to see what the metric was for any social media efforts, it has to be more of the click rates, not just by ASCO members, but the click rates across societies and across countries. Dr. Nathan Pennell: Yeah, social media is, I mean, obviously evolving quite a bit in the last couple of years. But I do know that in terms the alt metrics for the track access through social media and online, the ones that are shared online by the authors, by the Ed Book team, do seem to get more attention. I think a lot of people don't like to just sit with a print journal anymore or an email table of contents for specific journals. People find these articles that are meaningful to them through their network and oftentimes that is online on social media. Dr. Don Dizon: Yes, 100%. And you know what I think we should encourage people to do is look at the source. And if the Ed Book becomes a source of information, I think that will be a plus to the conversations in our world. We're still dealing with a place where, depending on who sponsored the trial, whether it was an industry-sponsored trial, whether it was NCI sponsored or sponsored by the National Institutes of Health, for example, access to the primary data sets may or may not be available across the world, but the Ed Book is. And if the Ed Book can summarize that data and use terms and words that are accessible no matter what your grade level of education is. If we can explain the graphs and the figures in a way that people can actually easily more understand it. If there's a way that we structure our conversations in the Ed Book so that the plethora of inclusion/exclusion criteria are summarized and simplified, then I think we can achieve a place where good information becomes more accessible, and we can point to a summary of the source data in places where the source is not available. Dr. Nathan Pennell: One of the other things that I continue to be surprised at how popular these podcasts are. And that gives you an opportunity pretty much the opposite. Instead of sort of a nugget that directs you to the source material, you've got a more in-depth discussion of the manuscript. And so, I'm delighted that we have our own podcast. For many years, the Ed Book would sort of do a sort of a “Weird Al takeover” of the ASCO Daily News Podcast for a couple of episodes around the Annual Meeting, and I think those were always really popular enough that we were able to argue that we deserved our own podcast. And I'm really looking forward to having these in-depth discussions with authors. Dr. Don Dizon: It's an amazing evolution of where the Ed Book has gone, right? We took it from print only, societally only, to something that is now accessed worldwide via PubMed. We took it from book to fully online print. And now I think making the content live is a natural next step. So, I applaud you for doing the podcast and giving people an opportunity actually to discuss what their article discusses. And if there's a controversial point, giving them the freedom and the opportunity to sort of give more nuanced views on what may not be something that there's 100% consensus over. Dr. Nathan Pennell: Yes. Well, I hope other people enjoy these as well. Just want to highlight a few of the things that have happened just in the couple years since you stepped down as editor-in-chief. One of them, and I don't know if you noticed, but last year we started adding manuscripts from the ASCO thematic meetings, so ASCO GI and ASCO GU, something we had certainly talked about in the past, but had lacked bandwidth to really do. And they seem to be pretty widely accessed. Dr. Don Dizon: That's fantastic. Yes, I do remember talking about the coverage of the thematic meetings and you're right, this takes a long time to sort of concentrate on the Annual Meeting. It may seem like everything happens in the span of like eight weeks. Dr. Nathan Pennell: It does feel like that sometimes. Dr. Don Dizon: Right? But this is actually something that starts a year before, once the education program is set. We're in the room when they set it. But then it's really chasing down manuscripts and then making sure that they're peer reviewed because the peer review is still really important, and then making sure that any revisions are made before it's finalized and goes to press. That is a many months process. So, when we're trying to introduce, “Oh, we should also do ASCO GU or-,” the question was, how do you want to do that given this very, very involved process going forward? So, I'm glad you were able to figure it out. Dr. Nathan Pennell: Well, it's challenging. I don't think people realize quite the compressed timeline for these. You know, the Education Session and authors and invited faculty are picked in the fall, and then basically you have to start turning in your manuscripts in February, March of the following year. And so, it's a really tight turnaround for this. When we talk about the ASCO thematic meetings, it's an even tighter window. Dr. Don Dizon: Right, exactly. Dr. Nathan Pennell: And so, it's challenging to get that moving, but I was really, really proud that we were able to pull that off. Dr. Don Dizon: Well, congratulations again. And I think that is a necessary step, because so much of what's going on in the various disease management sites is only covered cursorily through the Annual Meeting itself. I mean, there's just so much science breaking at any one time that I think if we want to comprehensively catalog the Year in Review in oncology, it kind of behooves us to do that. Dr. Nathan Pennell: Some other things that are coming up because we now have manuscripts that are going to be coming in year-round, and just to kind of make it easier on the editorial staff, we're going to be forming an editorial board. And in addition to our pool of reviewers who get ASCO points, please feel free to go online to the ASCO volunteer portal and sign up if you are interested in participating. So, moving forward, I'm really excited to see where things are going to go. Dr. Don Dizon: Well, that's great. That's great. And I do remember talking about whether or not we needed to have an editorial board. At least when I was there, having this carried by three people was always better than having it carried by one person. And I think as you expand the potential for submissions, it will be very helpful to have that input for sure. And then it gives another opportunity for more members to get involved in ASCO as well. Dr. Nathan Pennell: Absolutely. People want involvement, and so happy to provide that. Dr. Don Dizon: Yes. Dr. Nathan Pennell: Is there anything we didn't cover that you would like to mention before we wrap up? Dr. Don Dizon: Well, I will say this, that ASCO and through its publications not only has had this real emphasis on multidisciplinary management of cancers, especially where it was relevant, but it also always had a stand to ensure representation was front and center and who wrote for us. And I think every president, every chair that I've worked with naturally embraced that idea of representation. And I think it has been a distinct honor to say that during my tenure as EIC, we have always had a plethora of voices, of authors from different countries, of genders, that have participated in the construction of those books. And it stands as a testament that we are a global community and we will always be one. Dr. Nathan Pennell: Well, thank you for that. And I'm happy to continue that as we move forward. Well, Don, thank you. It's been great speaking with you. You played such a pivotal role in the Ed Book's evolution and I'm so glad you were able to join me for our inaugural episode. Dr. Don Dizon: Well, I'm just tickled that you asked me to be your first guest. Thank you so much, Nate. Dr. Nathan Pennell: And I also want to thank our listeners for joining us today. We hope you'll join us again for more insightful views on topics you'll be hearing at the Education Sessions from ASCO meetings throughout the year, as well as our periodic deep dives on advances that are shaping modern oncology. Have a great day. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Follow today's speakers:   Dr. Nathan Pennell  @n8pennell @n8pennell.bsky.social   Dr. Don Dizon @drdondizon.bsky.social  Follow ASCO on social media:   @ASCO on X (formerly Twitter)   ASCO on Bluesky  ASCO on Facebook   ASCO on LinkedIn   Disclosures:  Dr. Nathan Pennell:      Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron     Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi  Dr. Don Dizon: Stock and Other Ownership Interests: Midi, Doximity Honoraria: UpToDate, American Cancer Society Consulting or Advisory Role: AstraZeneca, Clovis Oncology, Kronos Bio, Immunogen Research Funding (Institution): Bristol-Myers Squibb          

Dr. Vamsi Velcheti and Dr. Charu Aggarwal discuss the evolution of ctDNA as a critical tool in precision oncology and its implications for lung cancer management, including its potential role in the early-stage setting. TRANSCRIPT Dr. Vamsi Velcheti: Hello. I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I am a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health.  The management of small cell lung cancer has rapidly evolved over the past few decades, and today, molecular testing and biomarker testing for lung cancer are absolutely critical in terms of designing treatment options for our patients with metastatic non-small cell lung cancer. Today, I'm delighted to be joined by Dr. Charu Aggarwal for a discussion on ctDNA (circulating tumor DNA) and the role of ctDNA in lung cancer management. Dr. Aggarwal is the Leslye Heisler Professor of Lung Cancer Excellence and section chief of thoracic and head and neck oncology at University of Pennsylvania Abramson Cancer Center.  You'll find our full disclosures in the transcript of that episode.  Dr. Agrawal, it's great to have you on the podcast today. Thank you for being here. Dr. Charu Aggarwal: Thank you for having me. Dr. Vamsi Velcheti: Let's start off with setting the stage for ctDNA technology. These technologies have rapidly evolved from experimental conceptual stage to essential clinical tools for day-to-day clinical practice. Could you briefly discuss how recent advancements in ctDNA technologies are shaping our approach to precision medicine, especially in lung cancer? Dr. Charu Aggarwal: Absolutely. And you know, I think we need to just level set a little bit. What exactly is circulating tumor DNA? This is a way to assess exactly that. Every tumor sheds little pieces of tumor-derived DNA into the bloodstream, and this occurs in a variety of solid tumors. But now we have the technology to be able to derive this DNA that's actually being shed from the tumor into the bloodstream, these minute fragments of DNA, take them out, amplify them and sequence them with a variety of different mechanisms. They can be DNA sequencing alone, they can be DNA and RNA sequencing, they can be whole transcriptome sequencing. The technology, as you rightly pointed out, Dr. Velcheti, has significantly improved from just being able to look at circulating tumor DNA to now being able to amplify it, sequence it, and use it to offer personalized therapy. I think lung cancer is definitely the poster child for such an approach as we have a lot of data that has shown clinical utility and validity of being able to use circulating tumor DNA next-generation gene sequencing to guide therapy. Dr. Vamsi Velcheti: There have been so many technological leaps. It's really impressive how far we've come to advance these sequencing platforms. Recent advances with AI and machine learning are also playing important roles in interpreting ctDNA data. How are these computational advances really enhancing clinical decision-making in day-to-day clinical practice? Dr. Charu Aggarwal: I think while we have firmly established the role of ctDNA in the management of patients with metastatic lung cancer, some of the approaches that you talked about are still experimental. So let me backtrack a little bit and set the stage for how we use ctDNA in clinical practice right now. I think most patients, when they come in with a new diagnosis of stage IV lung cancer, we want to test for biomarkers. And this should actually be the established standard. Now included in the NCCN guidelines and actually also international guidelines, is to consider using blood-based testing or plasma-based testing to look for biomarkers, not just tissue-based testing which had been our historical standard, but to use these plasma guided approaches to identify the seven to nine biomarkers that may be truly implicated in either first- or second-line therapy that are called as your immediately actionable mutations.  What you're talking about is AI computational methods. I think there's a lot of excitement about how we can use genomic signatures that are derived from either tissue or ctDNA-based biomarker testing, combine it with radiomic features, combine it with histologic features, look at H & E patterns, use AI algorithmic learning to be able to actually predict recurrence scores, or can we actually come up with predictive signatures that may be extremely helpful?  So, I think some of the techniques and technologies that you're talking about are incoming. They are provocative. I think they're very exciting, but very early. Dr. Vamsi Velcheti: I think it's really amazing how many advances we have with these platforms. You know, the challenge really is the significant gap in terms of uptake of molecular testing. Even today, in 2025, there are significant gaps in terms of all metastatic lung cancer patients being tested for all biomarkers.  So, why do you think there's such a challenge in testing patients with lung cancer? In most academic practices, we try to achieve 100% testing for all our patients, but we know from recent studies that that's not the case across the country. What do you think the gaps are? Dr. Charu Aggarwal: Biomarker testing is so essential, like you pointed out, for us to be able to guide the right therapy for our patients. And we see this in our practice every day as you and I see patients with lung cancer, that a large proportion of our patients either don't get tested or they start therapy before their test results come back. So, I think this is a real problem.  However, to add some optimism to this problem, I do think that we are making a move in the right direction. So, four or five years ago, there was a lot of data being presented at national meetings, including ones from the American Society of Clinical Oncology, where we saw that, nationally, the rates of biomarker testing were probably in the rate of 40 to 50%. However, now with the availability of both tissue and plasma, I do think that the rates of biomarker testing are increasing. And if you were to survey a sample or even perform retrospective data research, I believe that the number is closer to 70% of all patients with metastatic non-small cell lung cancer.  And you know, you asked why is it not 100%? I think there are many reasons. I think the number one reason is tissue availability. Many times, the biopsies are small, or the tumor is very necrotic. So, either the tissue quantity itself is small, or the tissue quantity is insufficient to perform gene sequencing. And that's exactly where plasma comes in. When you don't have tissue availability, we have shown, as have others, that you can use plasma effectively to increase the proportion of patients who are not only tested but also receive the right therapy. I think there are also other barriers, including inertia. You know, I think this is both patient and physician inertia, where patients want to get started quickly, they don't want to wait. Physicians are very busy and sometimes want to be able to deliver treatment as soon as possible. We have seen there are some institutional barriers. Not every institution has in-house gene sequencing testing. So how do you really operationalize, send out these tests in a fast, efficient manner so that you get results back? Is it a pathologist who sends out the test? Is it the medical oncologist? Is it the pulmonologist or the interventionalist? I think there is this need to develop reflex testing mechanisms which some institutions do really well and some don't. And then finally, there are financial implications as well. How do we do this in a most cost-efficient fashion?  So there are many barriers, but I'm happy to say that we are making a move in the right direction as we are understanding that it's important to do it, it's easy to do it maybe with a value add of plasma, and finally, as you said, you know, as these technologies become more available, they're actually getting more cost-effective. Dr. Vamsi Velcheti: Dr. Aggarwal, you've been at the cutting edge of these advanced platforms and testing. So, what do you do in UPenn? How do you handle all these barriers and what is your workflow for patients in University of Pennsylvania? Dr. Charu Aggarwal: One of the things that I mentioned to you was there may be institutional barriers when it comes to gene sequencing. So, we actually, several years ago now, instituted a very robust reflex testing paradigm where almost all of our patients, regardless of stage, with a non-squamous non-small cell lung cancer diagnosis, would automatically be reflexively sent to our molecular pathology lab where they would get gene sequencing both for the DNA as well as with an RNA fusion-based platform. And the reason we did this was because we wanted to expedite and reduce the turnaround time. We also wanted to ensure that we were not just doing DNA testing, which I think is really important for our listeners here. There are many fusions as well as certain skipping mutations like MET exon 14 that may be missed on DNA testing alone. So, it's really incredibly important to run both DNA and RNA samples.  So, we do this routinely, and based on our research and others, what we also do routinely is that we send concurrent tissue and liquid biopsies or plasma MGS testing upon initial diagnosis. For example, if a patient comes in with a diagnosis of stage IV non-small cell lung cancer, their tissue might already be at my molecular pathology lab based on the reflex mechanism that I just described to you. But upon their initial meeting with me, we will send off plasma. And I will tell you this, that Penn is not just one institution, right? We have a large network of sites. And as part of my research, one of the things that we wanted to do was implement wide scale means to improve biomarker testing. And we have done this with the use of technology like you mentioned, Dr. Velcheti: How can we actually use AI? How can we leverage our electronic medical record to identify these patients? So, we have a nudge-based mechanism which actually facilitates the pending of orders for biomarker testing for patients with new diagnosis of metastatic non-small cell lung cancer. And we are looking at our rates of biomarker testing but also rates of completion of biomarker testing before first-line therapy started. So many of our participating sites are clusters for our randomized control trial to increase molecular testing. And I'm really excited about the fact that we're able to implement it not just at our main satellite, downtown Penn Hospital, but also across our community. Dr. Vamsi Velcheti: I think that's great. Thank you so much for those insights, Dr. Aggarwal. I think it's so important because having the best technology is just not enough. I think implementation science is actually a real thing. And I think we need to all learn from each other, advance these things.  So, I want to ask you about the new emerging paradigm in terms of using ctDNA. Of course, in the metastatic setting, we've been using ctDNA for molecular profiling for a while now. But the recent data around monitoring early-stage disease, especially post-operative monitoring, is an exciting area. There are a lot of opportunities there. Could you please talk us through the emerging data in lung cancer and how do we incorporate ctDNA-based monitoring MRD or should we even do that right now? Is the data ripe enough for us to kind of deploy this in a clinical setting? Dr. Charu Aggarwal: I think using ctDNA in the early-stage setting is our next frontier in lung cancer. I think naturally we have been able to successfully deploy this in the stage 4 setting. It made a meaningful difference in the lives of our patients, and we are a little bit behind the A ball in terms of how MRD is used in lung cancer. Because, you know, colorectal cancer has already done large-randomized trials based on ctDNA and MRD. It's routinely used in hematological malignancy. So, it makes sense that we should start to use it.  However, when I say this, I say this with excitement, but also a little bit of gentle caution saying that we actually don't quite have the prospective randomized data just yet on how to deploy. Yes, intuitively we would say that if you detect ctDNA and MRD, that patient is at higher risk. So, we identify that, but we actually don't know what to do with the second part of that information once you identify a patient with high risk. Are there other techniques that we can then come in with or other drugs that we can come in with to modify that risk? And that's the thing that I think we don't have right now. The other thing that we don't have right now is the timing of the assay, when to use it. Is it to be tested in the pre-op setting? Is the post-op test the best timing, or is it monitoring and dynamics of ctDNA that are most important? And the third thing I will say in terms of precautionary cause is that we don't know which test just yet. There are actually a few commercially available tests out in the market right now. We know about them and I'm sure our community colleagues know about them. Some of them even have Medicare approval. However, many of these tests are currently tissue informed. We don't have tissue uninformed tests. And what does that mean? Tissue uninformed means that you actually take a piece of tumor tissue, you sequence that tumor and based on the gene profile of that tumor, you actually design a panel that can then be used to track the mutations in the blood-based pack. This requires, as the name implies, a tumor. So can this be used in the pre-op setting is a large question. Because coming back to the idea of tissue availability, you and I both know that when we get FNAS and we use it for PDL-1 testing and we use it for gene sequencing, there often isn't enough tissue left for us to then either do whole genome sequencing or even whole transcriptome sequencing, which may be required to build some of these assays.  I think the future lies in this idea of tumor uninformed assays because if we could go to a blood only or a plasma only approach using novel signatures like proteomics or methylation, I think that's where the future is. But we're still a little bit early in the discovery stages of those, as well as to come are the validation stages so that we can be confident that these blood-only assays may actually give us an answer.  So, with those three cautionary notes, I would say that optimism is still very high. I think ctDNA MRD is the right place to think about. We need to do this for our patients to better identify high-risk patients and to think about means to escalate treatment for them. Dr. Vamsi Velcheti: Yeah, I completely agree, and I think with all the changes and evolution of treatments in the management of early-stage lung cancer now with neoadjuvant and adjuvant, there's really a need for an escalation and de-escalation of therapies post-operatively. And I think it's a huge opportunity. I think we all could learn from our colorectal colleagues. I think they've done a really good job at actually doing prospective trials in this setting. I think we're kind of a little behind here.  Dr. Charu Aggarwal: I think in the metastatic setting there are ongoing trials to look at this exact question. How do you choose an appropriate first-line therapy, a monitor ctDNA at the six-week trial? It's being evaluated in a trial called the “Shedders” trial, where if patients are still ctDNA positive at six weeks, then you can escalate treatment because they haven't “cleared” their ctDNA. There has been a lot of research that has shown that lack of ctDNA clearance in the metastatic setting may be a poor prognostic factor. We and others have shown that if you do clear your ctDNA or if you have a reduction in ctDNA load overall, that that is directly related to both an improved progression-free survival and overall survival. This has been shown with both tissue informed and uninformed assays. So I think it's very clear that yes, you can track it. I think the question is: Can you apply that data to the early-stage setting? And that's an open research question. A lot of groups are looking at that and I think it's completely reasonable, especially to determine duration of therapy, to determine optimal timing, optimal timing of scans even. And I think these are just such interesting questions that will be answered in the future. Dr. Vamsi Velcheti: And also like a kind of early detection of resistance patterns that might inform early initiation of combination strategies. And I think it's a lot of opportunities I think yet to be explored. A lot of exciting things to come and I'm sure we'll kind of see more and more data in the next few years.  Dr. Aggarwal, thank you so much for sharing your fantastic insights today on the ASCO Daily News Podcast. It's been a pleasure to have you on the podcast today. Hope to see you at ASCO. Dr. Charu Aggarwal: Thank you so much. This was great and I remain so excited by all of the possibilities to improve outcomes for our patients. Dr. Vamsi Velcheti: Thank you to all the listeners for your time today. If you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Follow today's speakers:  Dr. Vamsidhar Velcheti  @VamsiVelcheti  @vamsivelcheti.bsky.social Dr. Charu Aggarwal @CharuAggarwalMD   Follow ASCO on social media:  @ASCO on X (formerly Twitter)  ASCO on Bluesky ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. Vamsidhar Velcheti:  Honoraria: Glavanize Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, AstraZeneca/MedImmune, GSK, Amgen, Taiho Oncology, Novocure, Takeda, Janssen Oncology, Picture Health, Regeneron Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline  Dr. Charu Aggarwal: Consulting or Advisory Role: AstraZeneca, Daiichi Sankyo/AstraZeneca, Regeneron/Sanofi, Pfizer, Boehringer Ingelheim, Takeda, Arcus Biosciences, Gilead Sciences, Novocure, Abbvie Speakers' Bureau: AstraZeneca (an immediate family member) Research Funding (Inst): Merck Sharp & Dohme, AstraZeneca/MedImmune, Daiichi Sankyo/AstraZeneca, Lilly@Loxo, Candel Therapeutics  

Dr. Ebony Hoskins and Dr. Andreas Obermair discuss the surgical management of gynecologic cancers, including the role of minimally invasive surgery, approaches in fertility preservation, and the nuances of surgical debulking. TRANSCRIPT Dr. Ebony Hoskins: Hello and welcome to the ASCO Daily News Podcast, I'm Dr. Ebony Hoskins. I'm a gynecologic oncologist at MedStar Washington Hospital Center in Washington, DC, and your guest host of the ASCO Daily News Podcast. Today we'll be discussing the surgical management of gynecologic cancer, including the role of minimally invasive surgery (MIS), approaches in fertility preservation, and the nuances of surgical debulking, timing, and its impact on outcomes. I am delighted to welcome Dr. Andreas Obermair for today's discussion. Dr. Obermair is an internationally renowned gynecologic oncologist, a professor of gynecologic oncology at the University of Queensland, and the head of the Queensland Center for Gynecologic Cancer Research. Our full disclosures are available in the transcript of this episode. Dr. Obermair, it's great speaking with you today. Dr. Andreas Obermair: Thank you so much for inviting me to this podcast. Dr. Ebony Hoskins: I am very excited.  I looked at your paper and I thought, gosh, is everything surgical? This is everything that I deal with daily in terms of cancer in counseling patients. What prompted this review regarding GYN cancer management? Dr. Andreas Obermair: Yes, our article was published in the ASCO Educational Book; it is volume 44 in 2024. And this article covers some key aspects of targeted precision surgical management principles in endometrial cancer, cervical cancer, and ovarian cancer. While surgery is considered the cornerstone of gynecologic cancer treatment, sometimes research doesn't necessarily reflect that. And so I think ASCO asked us to; so it was not just me, there was a team of colleagues from different parts of the United States and Australia to reflect on surgical aspects of gynecologic cancer care and I feel super passionate about that because I do believe that surgery has a lot to offer. Surgical interventions need to be defined and overall, I see the research that I'm doing as part of my daily job to go towards precision surgery. And I think that is, well, that is something that I'm increasingly passionate for. Dr. Ebony Hoskins: Well, I think we should get into it. One thing that comes to mind is the innovation of minimally invasive surgery in endometrial cancer. I always reflect on when I started my fellowship, I guess it's been about 15 years ago, all of our endometrial cancer patients had a midline vertical incision, increased risk of abscess, infections and a long hospital stay. Do you mind commenting on how you see management of endometrial cancer today? Dr. Andreas Obermair: Thank you very much for giving the historical perspective because the generation of gynecologic oncologists today, they may not even know what we dealt with, what problems we had to solve. So like you, when I was a fellow in gynecologic oncology, we did midline or lower crosswise incisions, the length of stay was, five days, seven days, but we had patients in hospital because of complications for 28 days. We took them back to the operating theaters because those are patients with a BMI of 40 plus, 45, 50 and so forth. So we really needed to solve problems. And then I was exposed to a mentor who taught minimal invasive surgery. And in Australia he was one of the first ones who embarked on that. And I can remember, I was mesmerized by this operation, like not only how logical this procedure was, but also we did rounds afterwards. And I saw these women after surgery and I saw them sitting upright, lipstick on, having had a full meal at the end of the day. And I thought, wow, this is the most rewarding experience that I have to round these patients after surgery. And so I was thinking, how could I help to establish this operation as standard? Like a standard that other people would accept this is better. And so I thought we needed to do a trial on this. And then it took a long time. It took a long time to get the support for the [LACE - Laparoscopic Approach to Cancer of the Endometrium] trial. And in this context, I just also wanted to remind us all that there were concerns about minimal invasive surgery in endometrial cancer at the time. So for example, one of the concerns was when I submitted my grant funding applications, people said, “Well, even if we fund you, wouldn't be able to do this trial because there are actually no surgeons who actually do minimally invasive surgery.” And at the time, for example, in Australia, there were maybe five people, a handful of people who were able to do this operation, right? This was about 20 years ago. The other concern people had was they were saying, could minimally invasive surgery for endometrial cancer, could that cause port side metastasis because there were case reports. So there were a lot of things that we didn't know anyway. We did this trial and I'm super happy we did this trial. We started in 2005, and it took five years to enroll. At the same time, GOG LAP2 was ramping up and the LACE trial and GOG LAP2 then got published and provided the foundations for minimally invasive surgery in endometrial cancer. I'm super happy that we have randomized data about that because now when we go back and now when people have concerns about this, should we do minimally invasive surgery in P53 mutant tumors, I'm saying, well, we actually have data on that. We could go back, we could actually do more research on that if we wanted to, but our treatment recommendations are standing on solid feet. Dr. Ebony Hoskins: Well, my patients are thankful. I see patients all the time and they have high risk and morbidly obese, lots of medical issues and actually I send them home most the same day. And I think, you know, I'm very appreciative of that research, because we obviously practice evidence-based and it's certainly a game changer. Let's go along the lines of MIS and cervical cancer. And this is going back to the LACC [Laparoscopic Approach to Cervical Cancer] trial.  I remember, again, one of these early adopters of use of robotic surgery and laparoscopic surgery for radical hysterectomy and thought it was so cool. You know, we can see all the anatomy well and then have the data to show that we actually had a decreased survival. And I even see that most recent updated data just showing it still continued. Can you talk a little bit about why you think there is a difference? I know there's ongoing trials, but still interested in kind of why do you think there's a survival difference? Dr. Andreas Obermair:  So Ebony, I hope you don't mind me going back a step. So the LACC study was developed from the LACE trial. So we thought we wanted to reproduce the LACE data/LAP2 data. We wanted to reproduce that in cervix cancer. And people were saying, why do you do that? Like, why would that be different in any way? We recognize that minimally invasive radical hysterectomy is not a standard. We're not going to enroll patients in a randomized trial where we open and do a laparotomy on half the patients. So I think the lesson that really needs to be learned here is that any surgical intervention that we do, we should put on good evidence footing because otherwise we're really running the risk of jeopardizing patients' outcomes. So, that was number one and LACC started two years after LACE started. So LACC started in 2007, and I just wanted to acknowledge the LACC principal investigator, Dr. Pedro Ramirez, who at the time worked at MD Anderson. And we incidentally realized that we had a common interest. The findings came totally unexpected and came as an utter shock to both of us. We did not expect this. We expected to see very similar disease-free and overall survival data as we saw in the endometrial cancer cohort. Now LACC was not designed to check why there was a difference in disease-free survival. So this is very important to understand. We did not expect it. Like, so there was no point checking why that is the case. My personal idea, and I think it is fair enough if we share personal ideas, and this is not even a hypothesis I want to say, this is just a personal idea is that in endometrial cancer, we're dealing with a tumor where most of the time the cancer is surrounded by a myometrial shell. And most of the time the cancer would not get into outside contact with the peritoneal cavity. Whereas in cervix cancer, this is very different because in cervix cancer, we need to manipulate the cervix and the tumor is right at the outside there. So I personally don't use a uterine manipulator. I believe in the United States, uterine manipulators are used all the time. My experience is not in this area, so I can't comment on that. But I would think that the manipulation of the cervix and the contact of the cervix to the free peritoneal cavity could be one of the reasons. But again, this is simply a personal opinion. Dr. Ebony Hoskins: Well, I appreciate it. Dr. Andreas Obermair: Ebony at the end of the day, right, medicine is empirical science, and empirical science means that we just make observations, we make observations, we measure them, and we pass them on. And we made an observation. And, and while we're saying that, and yes, you're absolutely right, the final [LACC] reports were published in JCO recently. And I'm very grateful to the JCO editorial team that they accepted the paper, and they communicated the results because this is obviously very important. At the same time, I would like to say that there are now three or four RCTs that challenge the LACC data. These RCTs are ongoing, and a lot of people will be looking forward to having these results available. Dr. Ebony Hoskins: Very good. In early-stage cervical cancer, the SHAPE trial looked at simple versus radical hysterectomy in low-risk cervical cancer patients. And as well all know, simple hysterectomy was not inferior to radical hysterectomy with respect to the pelvic recurrence rate and any complications related to surgery such as urinary incontinence and retention. My question for you is have you changed your practice in early-stage cervical cancer, say a patient with stage 1B1 adenocarcinoma with a positive margin on conization, would you still offer this patient a radical hysterectomy or would you consider a simple hysterectomy? Dr. Andreas Obermair:  I think this is a very important topic, right? Because I think the challenge of SHAPE is to understand the inclusion criteria. That's the main challenge. And most people simplify it to 2 cm, which is one of the inclusion criteria but there are two others and that includes the depth of invasion. Dr. Marie Plante has been very clear. Marie Plante is the first author of the SHAPE trial that's been published in the New England Journal of Medicine only recently and Marie has been very clear upfront that we need to consider all three inclusion criteria and only then the inclusion criteria of SHAPE apply. So at the end of the day, I think what the SHAPE trial is telling us that small tumors that would strictly fulfill the criteria of a 1B or 1B1 cancer of the cervix can be considered for a standard type 1 or PIVA type 1 or whatever classification we're trying to use will be eligible. And that makes a lot of sense. I personally not only look at the size, I also look at the location of the tumor. I would be very keen that I avoid going through tumor tissue because for example, if you have a tumor that is, you know, located very much in one corner of the cervix and then you do a standard hysterectomy and then you have a positive tumor margin that would be obviously, most people would agree it would be an unwanted outcome. So I'd be very keen checking the location, the size of the tumor, the depths of invasion and maybe then if the tumor for example is on one side of the cervix you can do a standard approach on the contralateral side but maybe do a little bit more of a margin, a parametrial margin on the other side. Or if a tumor is maybe on the posterior cervical lip, then you don't need to worry so much about the anterior cervical margin, maybe take the rectum down and maybe try to get a little bit of a vaginal margin and the margin on the uterus saccals. Just really to make sure that you do have margins because typically if we get it right, survival outcomes of clinical stage 1 early cervix cancer 1B1 1B 2 are actually really good. It is a very important thing that we get the treatment right. In my practice, I use a software to record my treatment outcomes and my margins. And I would encourage all colleagues to be cognizant and to be responsible and accountable to introduce accountable clinical practice, to check on the margins and check on the number on the percentage of patients who require postoperative radiation treatment or chemo radiation. Dr. Ebony Hoskins: Very good. I have so many questions for you. I don't know the statistics in Australia, but here, there's increased rising of endometrial cancer and certainly we're seeing it in younger women. And fertility always comes up in terms of kind of what to do. And I look at the guidelines and, see if I can help some of the women if they have early-stage endometrial cancer. Your thoughts on what your practice is on use of someone who may meet criteria, if you will. The criteria I use is grade 1 endometrioid adenocarcinoma. No myometria invasion. I try to get MRI'd and make sure that there's no disease outside the endometrium. And then if they make criteria, I typically would do an IUD. Can you tell me what your practice is and where you've had success? Dr. Andreas Obermair: So, we initiated the feMMe clinical trial that was published in 2021 and it was presented in a Plenary at one of the SGO meetings. I think it was in 2021, and we've shown complete pathological response rates after levonorgestrel intrauterine device treatment. And so in brief, we enrolled patients with endometrial hyperplasia with atypia, but also patients with grade 1 endometrial adenocarcinoma. Patients with endometrial hyperplasia with atypia had, in our series, had an 85 % chance of developing a complete pathological response. And that was defined as the complete absence of any atypia or cancer. So endometrial hyperplasia with atypia responded in about 85%. In endometrial cancer, it was about half, it was about 45, 50%. In my clinical practice, like as you, I see patients, you know, five days a week. So I'm looking after many patients who are now five years down from conservative treatment of endometrial cancer. There are a lot of young women who want to get pregnant, and we had babies, and we celebrate the babies obviously because as gynecologist obstetricians it couldn't get better than that, right, if our cancer patients have babies afterwards. But we're also treating women who are really unfit for surgery and who are frail and where a laparoscopic hysterectomy would be unsafe. So this phase is concluded, and I think that was very successful. At least we're looking to validate our data. So we're having collaborations, we're having collaborations in the United States and outside the United States to validate these data. And the next phase is obviously to identify predictive factors, to identify predictors of response. Because as you can imagine, there is no point treating patients with a levonorgestrel intrauterine joint device where we know in advance that she's not going to respond. So this is a very, very fascinating story and we got our first set of data already, but now we just really need to validate this data. And then once the validation is done, my unit is keen to do a prospective validation trial. And that also needs to involve international collaborators. Dr. Ebony Hoskins: Very good. Moving on to ovarian cancer, we see patients with ovarian cancer with, say, at least stage 3C or higher who started neoadjuvant chemotherapy. Now, some of these patients are hearing different things from their medical oncologist versus their gynecologic oncologist regarding the number of cycles of neoadjuvant chemotherapy after getting diagnosed with ovarian cancer. I know that this can be confusing for our patients coming from a medical oncologist versus a gynecologic oncologist. What do you say to a patient who is asking about the ideal number of chemotherapy cycles prior to surgery? Dr. Andreas Obermair: So this is obviously a very, very important topic to talk about. We won't be able to provide a simple off the shelf answer for that, but I think data are emerging.  The ASCO guidelines should also be worthwhile considering because there are actually new ASCO Guidelines [on neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer] that just came out a few weeks ago and they would suggest that we should be aiming for R0 in surgery. If we can maybe take that as the pivot point and then go back and say, okay, so what do need to do to get the patient to zero?  I'm not an ovarian cancer researcher; I'm obviously a practicing gynecologic oncologist. I think about things a lot and things like that. In my practice, I would want a patient to develop a response after neoadjuvant chemotherapy. So, if a patient doesn't have a response after two or three cycles, then I don't see the point for me to offer her an operation. In my circle with the medical oncologists that I work with, I have a very, very good understanding. So, they send the patient to me, I take them to the theater. I take a good chunk of tissue from the peritoneum. We have a histopathologic diagnosis, we have a genomic diagnosis, they go home the same day. So obviously there is no hospital stay involved with that. They can start the chemotherapy after a few days. There is no hold up because the chances of surgical complication in a setting like this is very, very low. So I use laparoscopy to determine whether the patient responds or not. And for many of my patients, it seems to work. It's obviously a bit of an effort and it takes operating time. But I think I'm increasing my chances to make the right decision. So, coming back to your question about whether we should give three or six cycles, I think the current recommendations are three cycles pending the patient's response to neoadjuvant chemotherapy because my aim is to get a patient to R0 or at least minimal residual disease. Surgery is really, in this case, I think surgery is the adjunct to systemic treatment. Dr. Ebony Hoskins: Definitely. I think you make a great point, and I think the guideline just came out, like you mentioned, regarding neoadjuvant. And I think the biggest thing that we need to come across is the involvement of a gynecologic oncologist in patients with ovarian cancer. And we know that that survival increases with that involvement. And I think the involvement is the surgery, right? So, maybe we've gotten away from the primary tumor debulking and now using more neoadjuvant, but surgery is still needed. And so, I definitely want to have a take home that GYN oncology is involved in the care of these patients upfront. Dr. Andreas Obermair: I totally support that. This is a very important statement. So when I'm saying surgery is the adjunct to medical treatment, I don't mean that surgery is not important. Surgery is very important. And the timing is important. And that means that the surgeons and the med oncs need to be pulling on the same string. The med oncs just want to get the cytotoxic into the patients, but that's not the point, right? We want to get the cytotoxic into the patients at the right time because if we are working under this precision surgery, precision treatment mantra, it's not only important what we do, but also doing it at the right time. And ideally, I I would like to give surgery after three cycles of neoadjuvant chemotherapy, if that makes sense. But sometimes for me as a surgeon, I talk to my med onc colleagues and I say, “Look, she doesn't have a good enough response to her treatment and I want her to receive six cycles and then we re-evaluate or change medical treatment,” because that's an alternative that we can swap out drugs and treat upfront with a different drug and then sometimes they do respond. Dr. Ebony Hoskins:  I have maybe one more topic. In the area I'm in, in the Washington D.C. area, we see lots of endometrial cancer and they're not grade 1, right? They're high-risk endometrial cancer and advanced. So a number of patients with stage 3 disease, some just kind of based off staging and then some who come in with disease based off of the CT scan, sometimes omental caking, ascites. And the real question is we have extrapolated the use of neoadjuvant chemotherapy to endometrial cancer. It's similar, but not the same. So my question is in an advanced endometrial cancer, do you think there's still a role, when I say advanced, I mean, maybe stage 4, a role for surgery? Dr. Andreas Obermair: Most definitely. But the question is when do you want to give this surgery? Similar to ovarian cancer, in my experience, I want to get to R0. What am I trying to achieve here? So, I reckon we should do a trial on this. And I reckon we have, as you say, the number of patients in this setting is increasing, we could do a trial. I think if we collaborate, we would have enough patients to do a proper trial. Obviously, we would start maybe with a feasibility trial and things like that. But I reckon a trial would be needed in this setting because I find that the incidence that you described, that other people would come across, they're becoming more and more common. I totally agree with you, and we have very little data on that. Dr. Ebony Hoskins: Very little and we're doing what we can. Dr. Obermair, thank you for sharing your fantastic insights with us today on the ASCO Daily News Podcast and for all the work you do to advance care for patients with gynecologic cancer. Dr. Andreas Obermair: Thank you, Dr. Hoskins, for hosting this and it's been an absolute pleasure speaking with you today. Dr. Ebony Hoskins: Definitely a pleasure and thank you to our listeners for your time today. Again, Dr. Obermair's article is titled, “Controversies in the Surgical Management of Gynecologic Cancer: Balancing the Decision to Operate or Hesitate,” and was published in the 2024 ASCO Educational Book. And you'll find a link to the article in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers: Dr. Ebony Hoskins @drebonyhoskins Dr. Andreas Obermair @andreasobermair Follow ASCO on social media:       @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn       Disclosures:   Dr. Ebony Hoskins: No relationships to disclose. Dr. Andreas Obermair: Leadership: SurgicalPerformance Pty Ltd. Stock and Ownership Interests: SurgicalPerformance Pty Ltd. Honoraria: Baxter Healthcare Consulting or Advisory Role: Stryker/Novadaq Patents, Royalties, and Other Intellectual Property: Shares in SurgicalPerformance Pty Ltd. Travel, Accommodation, Expenses: Stryker    

Dr. John Sweetenham and Dr. James Foran discuss the evolving treatment landscape in acute myeloid leukemia, including new targeted therapies, advances in immunotherapy, and the current role for allogeneic transplantation. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. There has been steady progress in the therapies for acute myeloid leukemia (AML) in recent years, largely based on an increasing understanding of the molecular mechanisms which underlie the disease. On today's episode, we'll be discussing the evolving treatment landscape in AML. We'll explore risk group stratification, new targeted therapies, advances in immunotherapy for AML, and also a little about the current role for allogenic transplantation in this disease.  I'm delighted to welcome Dr. James Foran to this discussion. Dr. Foran is a professor of medicine and chair of the Myeloid Malignancies and Blood and Marrow Transplant Disease Group at the Mayo Clinic Comprehensive Cancer Center. He's based in Jacksonville, Florida.  Our full disclosures are available in the transcript of this episode.  James, it's great to have you join us on the podcast today, and thanks so much for being here. Dr. James Foran: I'm delighted and thank you for the invitation. Thank you very much. Dr. John Sweetenham: Sure, James, let's get right into it. So, our understanding of the molecular mechanisms underlying AML has resulted not only in new methods for risk stratification in this disease, which have added refinement to cytogenetics, but also has resulted in the development of many new targeted agents. Understanding that this is a complex area of investigation, and our time is somewhat limited, can you give us a high-level update on the current state of the art in terms of how risk factors are being used for treatment selection now? Dr. James Foran: Absolutely. I think in the past, you know, we had things broken down pretty simply into make a diagnosis based on morphology, do cytogenetics, break patients into the groups of those who were more likely to benefit from therapy – so-called favorable risk – those where the intensive therapies were less likely to work – so-called poor adverse risk, and then this large intermediate group that really had variable outcomes, some better, some worse. And for a long time, the progress was in just identifying new subtle cytogenetic risk groups. And then, late 1990s, we began to understand that FLT3 mutations or NRAS mutations may be more adverse than others that came along. In the first part of this millennium, in the, you know, 2000-2010 range, a lot of work was being done to understand better or worse risk factors with single genes. The ability to do multiplex PCR, and then more recently NGS platforms, have allowed us to really look at many genes and identify many mutations in patients. At the beginning that was used just to sort of refine – who did a little better, who did a little worse with intensive therapy – helped us decide who may benefit more from an allogeneic transplanter for whom that would not be necessary.  But the good news is that really, we're now starting to target those mutations. One of the first molecularly targeted treatments in leukemia was FLT3 mutations, where we knew they were adverse. Then along came targeted treatments. I was involved in some of those early studies looking at sunitinib, sorafenib, more recently midostaurin, now quizartinib, FDA approved, and gilteritinib in the relapse refractory setting.  So we're moving into a state where we're not just refining prognosis, we're identifying targets. You know, it's been slow progress, but definite incremental progress in terms of outcomes by looking for FLT3 mutations, then looking for IDH mutations, and more recently, mutations involving NPM1 or rearrangement of what we used to call the MLL gene, now the lysine methyltransferase 2A or KMT2A rearrangement, where we now have targets. And it's not just for refinement of prognosis, but now we're identifying therapeutic targets for patients and ways to even look for measurable residual disease which is impacting our care. Dr. John Sweetenham: That's great, James. And I'm going to expand on that theme just a little bit and perhaps ask you to elaborate a little bit more on how the introduction of these new therapies have specifically impacted frontline therapy. And a couple of ancillary questions maybe to go along with that: First of all, is ‘7+3' a standard therapy for anybody in 2025? And maybe secondly, you know, could you comment also maybe briefly on older patients with AML and how you think maybe the treatment landscape is changing for them compared with, say, 5 or 10 years ago? Dr. James Foran: I'll start with the therapy and then work my way back. So we've had ‘7+3' cytarabine daunorubicin or cytarabine anthracycline since 1976, and we're still using it as the backbone of our intensive therapy. There is still an important role for it, particularly in younger or fitter patients, and particularly for those with intermediate or favorable risk genetic groups or cytogenetic risk groups just because we achieve high rates of remission. Our 30-day induction mortality rates are lower now than they were 10 and 20 years ago. Our supportive care is better. And we still have a busy inpatient hospital service here at Mayo Florida and my colleagues in Rochester and Arizona as well giving intensive therapy. So that remains the backbone of curative therapy for younger adults. We are trying to be a little more discriminating about who we administer that to. We are trying to add targeted agents. We know from, now, two different randomized trials that the addition of a FLT3 inhibitor, either midostaurin or more recently quizartinib, has a survival advantage in patients with a FLT3 mutation, or for quizartinib, a FLT3/ITD mutation. And so yes, ‘7+3' remains important.  Off protocol for somebody who just comes in with acute leukemia in a 40-year-old or 30-year-old or even early 60s and fit, we would still be considering ‘7+3' therapy and then waiting for an expedited gene mutation panel and an expedited cytogenetics panel to come back to help us discriminate is that a patient for whom we should be giving a FLT3 inhibitor? I think there's a little more nuance about when we do a day 14 bone marrow, do they really matter as much anymore? I still do them. Some of my colleagues find them less important. But we're still giving intensive therapy. We're still giving high-dose ARA-C consolidation for younger patients who achieve complete remission.  In older adults, it's a different story. You know, it was only in the early part of the 2000s – 2004, 2007 range – where we really got buy-in from randomized studies that low-dose therapy was better than no therapy. There was a lot of nihilism before then about therapy for older adults, especially over age 75. We know that low-dose ARA-C is better than nothing. It looked like azacitidine was better than ARA-C or at least equivalent or slightly better. But with the advent of venetoclax it was a game changer. I ran a national randomized study of intensive therapy in AML. It was the last national randomized study of intensive therapy in older patients right before venetoclax got approved. And we were very excited about our results, and we thought we had some really interesting clinical results. And suddenly that's a little bit obsolete in patients over 70 and particularly over age 75 because of the high remission rates with azacytidine venetoclax or hypomethylating agents, so-called HMAs and venetoclax and the survival advantage. Now, it's not a home run for everybody. We quote 60% to 70% remission rates, but it's a little different based on your cytogenetics and your mutation profile. You have to continue on therapy so it's continuous treatment. It's not with curative intent, although there are some people with long-term remission in it. And the median survival went from 10 months to 15 months. So home run? No, but definitely improved remissions, meaningful for patients off transfusions and better survival. So right now it's hard to find an older adult who you wouldn't give azacitidine and venetoclax or something similar, decitabine, for instance, and venetoclax, unless somebody really was moribund or had very poor performance status or some reason not to. And so ‘7+3' is still relevant in younger adults. We're trying to get better results with ‘7+3' by adding targeted agents and azacitine and venetoclax in older adults.  I think the area of controversy, I guess there are two of them, is what to do in that overlap age between 60 and 75. Should people in that age still get intensive therapy, which we've used for years – the VIALE-A trial of aza-venetoclax was age 75 plus – or with cardiac comorbidities? And I think if you're 68 or 72, many of us are starting to bias towards aza-venetoclax as generally being better tolerated, generally being more outpatient, generally being slow and steady way to get a remission. And it doesn't stop you from going to transplant for somebody who might still be a candidate.  The other area of controversy is somebody under 60 who has adverse cytogenetics where we don't do very well with ‘7+3,' we still give it and we might do just as well with decitabine venetoclax. A lot of us feel that there's equipoise in the 60 to 75 group where we really can ask a question of a randomized study. Retrospective studies might suggest that intensive therapy is a little better, but there are now a couple of randomized studies happening saying, “Can we replace ‘7+3' in that intermediate age with aza-venetoclax?” And for younger adults similarly, we're looking to see how we apply that technology. Those are the areas where we're really trying to investigate what's optimal for patients and that's going to require randomized trials. Dr. John Sweetenham: Oh, that's great, thank you. And I'll just extend that question a little bit more, particularly with respect to the new targeted therapies. How much are they impacting the treatment of these patients in the relapse and refractory setting now? Dr. James Foran: Oh, they're definitely impacting it. When I trained and probably when you trained, AML was still a medical emergency. But that was the thing that you admitted to the hospital immediately, you started therapy immediately. The rule was always that's the one thing that brings the fellow and the consultant in at night to see that new patient on a Friday or Saturday. Now, we'll still admit a patient for monitoring, but we try not to start therapy for the first three or five or seven days if they're stable, until we get those genetics and those genomics back, because it helps us discriminate what therapy to pursue. And certainly, with FLT3 mutations, especially FLT3/ITD mutations, we're adding FLT3 inhibitors and we're seeing a survival advantage. Now, on the surface, that survival advantage is in the range of 7% or 10%. But if you then pursue an allogeneic transplant in first remission, you're taking disease where we used to see 30%, 40% long-term survival, maybe less, and you're pushing that to 60%, 70% in some studies. And so we're now taking a disease that– I don't want to get off topic and talk about Ph+ ALL. But that's a disease where we're actually a little excited. We have a target now, and it used to be something really adverse and now we can do a lot for it and a lot about it.  The other mutations, it's a little more subtle. Now, who knew until 2010 that a mutation in a sugar metabolism gene, in isocitrate dehydrogenase, or IDH was going to be so important, or even that it existed. We know that IDH1 and IDH2 mutations are still a minority of AML, certainly less than 10% to 15%, maybe overall. But we're able to target those with specific IDH1 and IDH2 inhibitors. We get single-agent responses. There are now two approved IDH1 inhibitors on the market. We don't yet have the randomized data that adding those to intensive therapy is better, but we're getting a very strong hint that it might be better in older adults who have an IDH mutation, maybe adding those is helpful and maybe adding those to low-intensity therapy is helpful. Those studies are ongoing, and we're also trying with low-intensity treatments to add these agents and get higher remission rates, deeper remissions, longer remissions. I think a lot of work has to be done to delineate the safety of that and the long-term efficacy. But we're getting hints it's better, so I think it is impacting.  The other area it's impacting is when you pick up adverse mutations and those have crept into our classification systems like an ASXL1 mutation or RUNX1 mutation for instance, or some of the secondary AML mutations like BCOR and others, where that's helping us discriminate intermediate-risk patients who we think aren't going to do as well and really helping us select a group who's more likely to get benefit from allogeneic transplant or for whom at least our cure rates without allo transplant are low. And so I think it's impacting a lot. Dr. John Sweetenham: Great. And I'm going to pick up now, if I may, on a couple of things that you've just mentioned and continue the theme of the relapsed and refractory setting. We've started to see some reports which have looked at the role of immune strategies for patients with AML, in particular CAR T or NK cells. Can you comment a little on this and let us know whether you think either these two strategies or other immune strategies are likely to have a significant role in AML in the future? Dr. James Foran: They are, but I think we're still a step behind finding the right target or the right way to do it. If you think of allogeneic transplantation as the definitive immune therapy, and we know for adverse AML we can improve survival rates and cure rates with an allotransplant, then we know inherently that immune therapy matters. And so how do we do what they've done in large cell lymphoma or in CD19 targeting for B cell malignancies? How do we bring that to acute myeloid leukemia? There have been a number of efforts. There have been at least 50 trials looking at different targets. CD33, CD123, CD7, others, CLL-1. So, there have been a number of different trials looking at how to bind a CAR T or a CAR T construct that can be active. And we have hints of efficacy. There was kind of a provocative paper in the New England Journal of Medicine a year ago in April of last year from a Chinese group that looked at a CD7-based CAR T and it was 10 patients, but they used CD7 positive acute leukemia, AML or ALL and had a CD7-targeted CAR T and they actually incorporated that with a haploidentical transplant and they had really high remission rates. People tolerated it quite well. It was provocative. It hasn't yet been reproduced on a larger scale, but the strong hints that the strategy is going to work.  Now, CD33 is a little tricky to have a CAR T when CD33 is expressed on normal hematopoietic cells. CD123 likewise. That's been something where there's, I think, still promise, but we've struggled to find the trials that make that work. Right now, there's a lot of interest in leveraging NK cells and looking, for a couple of reasons, but NK cells are attractive and NK cell markers might be attractive targets. NK cells might have similar degrees of immune efficacy. It's speculative, but they are likely to have less cytokine release syndrome and less neurotoxicity than you see with CAR T. And so it's kind of attractive to leverage that. We have had some ongoing trials looking at it with bispecifics and there certainly are trials looking at it with CAR NK-based strategies. One of the antigens that people looked at is the NK group 2D. NK group 2D or NKG2D is overexpressed in AML and its ligands overexpressed. And so that's a particular potential target. So, John, it's happening and we're looking for the hints of efficacy that could then drive a pivotal trial to get something approved.  One of the other areas is not restricting yourself just to a single antigen. For instance, there is a compound that's looking at a multi-tumor-associated antigen-specific T-cell therapy, looking at multiple antigens in AML that could be overexpressed. And there were some hints of activity and efficacy and actually a new trial looking at a so-called multi-tumor associated antigen-specific T cell therapy. So without getting into specific conflicts of interest or trials, I do think that's an exciting area and an evolving area, but still an investigational area. I'll stop there and say that we're excited about it. A lot of work's going there, but I'm not quite sure which direction the field's going to pivot to there. I think that's going to take us some time to sort out. Dr. John Sweetenham: Yeah, absolutely. But as you say, exciting area and I guess continue to watch this space for now.  So you've mentioned allogeneic stem cell transplants two or three times during this discussion. Recognizing that we don't have an imatinib for AML, which has kind of pushed transplant a long way further back in the treatment algorithm, can you comment a little on, you know, whether you think the role of stem cell transplantation is changing in AML or whether it remains pretty much as it was maybe 10 years ago? Dr. James Foran: By the way, I love that you use imatinib as an introduction because that was 6 TKIs ago, and it tells you the evolution in CML and you know, now we're looking at myristoyl pocket as a target, and so on. That's a great way to sort of show you the evolution of the field.  Allogeneic transplant, it remains a core treatment for AML, and I think we're getting much smarter and much better about learning how to use it. And I'm just going to introduce the topic of measurable residual disease to tell you about that. So I am a little bit of a believer. Part of my job is I support our allogeneic transplant program, although my focus is acute myeloid leukemia, and I've trained in transplant and done it for years and did a transplant fellowship and all that. I'm much more interested in finding people who don't need a transplant than people who do. So I'm sort of looking for where can we move away from it. But it still has a core role. I'll sidestep and tell you there was an MDS trial that looked at intermediate or high-risk MDS and the role of allogeneic transplant that shows that you about double your survival. It was a BMT CTN trial published several years ago that showed you about double your three-year survival if you can find a donor within three months and get to a transplant within six months. And so it just tells you the value of allotransplant and myeloid malignancy in general. In AML we continue to use it for adverse risk disease – TP53 is its own category, I can talk about that separately – but adverse risk AML otherwise, or for patients who don't achieve a really good remission. And I still teach our fellows that an allotransplant decreases your risk of relapse by about 50%. That's still true, but you have to have a group of patients who are at high enough risk of relapse to merit the non-relapse mortality and the chronic graft versus host disease that comes with it. Now, our outcomes with transplant are better because we're better at preventing graft versus host disease with the newer strategies such as post-transplant cyclophosphamide. There are now new FDA-approved drugs for acute and chronic graft versus host disease, ruxolitinib, belumosudil, axatilimab now. So we have better ways of treating it, but we still want to be discriminating about who should get it.  And it's not just a single-minded one-size-fits-all. We learned from the MORPHO study that was published in the JCO last year that if you have FLIT3-positive AML, FLIT3/IDT-positive AML, where we would have said from retrospective studies that your post-transplant survival is 60% give or take, as opposed to 15% or 20% without it, that we can discriminate who should or shouldn't get a transplant. Now that trial was a little bit nuanced because it did not meet its primary endpoint, but it had an embedded randomization based upon MRD status and they used a very sensitive test of measurable residual disease. They used a commercial assay by Invivoscribe that could look at the presence of a FLT3/ITD in the level of 10 to the minus 5th or 10 to the minus 6th. And if you were MRD-negative and you went through a transplant, you didn't seem to get an advantage versus not. That was of maintenance with gilteritinib, I'll just sort of put that on there. But it's telling us more about who should get a transplant and who shouldn't and who should get maintenance after transplant and who shouldn't.  A really compelling study a year ago from I don't know what to call the British group now, we used to call them the MRC and then the NCRI. I'm not quite sure what to call their studies at the moment. But Dr. Jad Othman did a retrospective study a year ago that looked at patients who had NPM1 mutation, the most common mutation AML, and looked to see if you were MRD positive or MRD negative, what the impact of a transplant was. And if you're MRD negative there was not an advantage of a transplant, whereas if you're MRD positive there was. And when they stratified that by having a FLT3 mutation that cracked. If you had a FLT3 mutation at diagnosis but your NPM1 was negative in remission, it was hard to show an advantage of a transplant. So I think we're getting much more discriminating about who should or should not get a transplant by MRD testing for NPM1 and that includes the patients who have a concomitant FLT3 mutation. And we're really trying to learn more and more. Do we really need to be doing transplants in those who are MRD-negative? If you have adverse risk genetics and you're MRD-negative, I'll really need good data to tell me not to do a transplant, but I suspect bit by bit, we'll get that data. And we're looking to see if that's really the case there, too. So measurable residual disease testing is helping us discriminate, but there is still a core role of allogeneic transplant. And to reassure you, compared to, I think your allotransplant days were some time ago if I'm right. Dr. John Sweetenham: Yes. Dr. James Foran: Yeah. Well, compared to when you were doing transplants, they're better now and better for patients now. And we get people through graft versus host disease better, and we prevent it better. Dr. John Sweetenham: That's a great answer, James. Thanks for that. It really does help to put it in context, and I think it also leads us on very nicely into what's going to be my final question for you today and perhaps the trickiest, in a way. I think that everything you've told us today really emphasizes the fact that the complexity of AML treatment has increased, primarily because of an improved understanding of the molecular landscape of the disease. And it's a complicated area now. So do you have any thoughts on what type of clinical environment patients with AML should be evaluated and treated in in 2025? Dr. James Foran: Yeah, I want to give you a kind of a cautious answer to that because, you know, I'm a leukemia doctor. I work at a leukemia center and it's what we focus on. And we really pride ourselves on our outcomes and our diagnostics and our clinical trials and so on. I am very aware that the very best oncologists in America work in private practice and work in community practice or in networks, not necessarily at an academic site. And I also know they have a much harder job than I have. They have to know lung cancer, which is molecularly as complicated now as leukemia, and they have to know about breast cancer and things that I don't even know how to spell anymore. So it's not a question of competence or knowledge. It's a question of infrastructure. I'll also put a little caveat saying that I have been taught by Rich Stone at Dana-Farber, where I did a fellowship a long time ago, and believe Rich is right, that I see different patients than the community oncologists see with AML, they're seeing different people. But with that caveat, I think the first thing is you really want to make sure you've got access to excellence, specialized hematopathology, that you can get expedited cytogenetics and NGS testing results back. There was a new drug, approved just a few months ago, actually, for relapsed AML with a KMT2A rearrangement, revumenib. We didn't talk about the menin inhibitors. I'll mention them in just a second. That's a huge area of expansion and growth for us. But they're not found on NGS platforms. And normal cytogenetics might miss a KMT2A-rearrangement. And we're actually going back to FISH panels, believe it or not, on AML, to try to identify who has a KMT2A-rearrangement. And so you really want to make sure you can access the diagnostic platforms for that.  I think the National Referral Labs do an excellent job. Not always a really fast job, but an excellent job. At my institution, I get NGS results back within three days or four days. We just have an expedited platform. Not everybody has that. So that's the key, is you have to be able to make the diagnosis, trust the pathologist, get expedited results. And then it's the question of trying to access the targeted medications because a lot of them are not carried in hospital on formulary or take time to go through an insurance approval process. So that's its own little headache, getting venetoclax, getting gilteritinib, getting an IDH1 inhibitor in first line, if that's what you're going for. And so I think that requires some infrastructure. We have case managers and nurses who really expedite that and help us with it, but that's a lot of work. The other piece of the puzzle is that we're still with AML in the first month and maybe even the second month. We make everybody worse before we make them better. And you have to have really good blood bank support. I can give an outpatient platelet transfusion or red cell transfusion seven days a week. We're just built for that. That's harder to do if you're in a community hospital and you have to be collaborating with a local blood bank. And that's not always dead easy for somebody in practice. So with those caveats, I do find that my colleagues in community practice do a really good job making the diagnosis, starting people on therapy, asking for help. I think the real thing is to be able to have a regional leukemia center that you can collaborate with, connect with, text, call to make sure that you're finding the right patients who need the next level of diagnostics, clinical trial, transplant consults, to really get the best results.  There was some data at ASH a couple of years ago that looked at – the American Society of Hematology and ASCOs had similar reports – that looked at how do we do in academic centers versus community practice for keeping people on therapy. And on average, people were more likely to get six cycles of therapy instead of three cycles of therapy with azacitidine venetoclax at an academic center. Now, maybe it's different patients and maybe they had different cytogenetics and so on, but I think you have to be patient, I think you have to collaborate. But you can treat those patients in the community as long as you've got the infrastructure in place. And we've learned with virtual medicine, with Zoom and other platforms that we can deliver virtual care more effectively with the pandemic and beyond. So I think we're trying to offer virtual consults or virtual support for patients so they can stay in their home, stay in their community, stay with their oncologists, but still get access to excellent diagnostics and supportive care and transplant consults, and so on. I hope that's a reasonable answer to that question. It's a bit of a nuanced answer, which is, I think there's an important role of a leukemia center, and I think there's a really fundamental role of keeping somebody in the community they live in, and how we collaborate is the key to that. And we've spent a lot of time and effort working with the oncologists in our community to try to accomplish that.  John, I want to say two other things. I didn't mention in the molecular platforms that NPM1 mutations, we can now target those on clinical trials with menin inhibitors. We know that NPM1 signals through the Hoxa9/Meis1 pathway. We know that similar pathways are important in KMT2A rearrangements. We know that there are some other rare leukemias like those with NUP98 rearrangement. We can target those with menin inhibitors. The first menin inhibitor, revuminib, was approved by the FDA for KMT2A. We have others going to the FDA later this year for NPM1. There are now pivotal trials and advanced expanded phase 1/2 studies that are showing 30% response rates. And we're looking to see can we add those into the first-line therapy. So, we're finding more targets.  I'll say one last thing about molecular medicine. I know I'm a little off topic here, but I always told patients that getting AML was kind of like being struck by lightning. It's not something you did. Now, obviously, there are risk factors for AML, smoking or obesity or certain farm environments, or radioactive exposures and so on. But bit by bit, we're starting to learn about who's predisposed to AML genetically. We've identified really just in the last five or eight years that DDX41 mutations can be germline half the time. And you always think germline mutations are going to cause AML in a younger patient, but the median age is 60 to 70 just like other AMLs. They actually might do pretty well once they get AML. We've reported that in several papers. And so we're trying to understand who that has a RUNX1 mutation needs germline testing, who with a DDX41 needs germline testing. And we're trying to actually come up with a cleaner pathway for germline testing in patients to really understand predisposition, to help with donor selection, to help with family counseling. So I think those are other areas where a leukemia center can contribute for somebody in who's community practice to understand genomic or genetic complexity in these patients. And we're starting to develop the databases that support that. Dr. John Sweetenham: Yeah, great. Thanks, James. I loved your answer about the clinical environment too. And I know from a patient-centric perspective that I know that patients would certainly appreciate the fact that we're in a situation now where the folks taking care of them will make every effort to keep them close to home if they possibly can.  I want to thank you, James, for an incredible review of a very complex subject and I think you did a great job. I think we all will have learned a lot. And thanks again for being willing to share your insights with us today on the ASCO Daily News Podcast. Dr. James Foran: John, it's my pleasure. And as you know, I'll do anything for a latte, so no problem at all. Dr. John Sweetenham: Okay. I owe you one, so thank you for that.  And thank you to our listeners for your time today. You'll find links to the studies we've discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:  Dr. John Sweetenham  Dr. James Foran Follow ASCO on social media: @ASCO on Twitter ASCO on Bluesky ASCO on Facebook  ASCO on LinkedIn  Disclosures:    Dr. John Sweetenham:    No relationships to disclose Dr. James Foran: Stock and Other Ownership Interests: Aurinia Pharmaceuticals Consulting or Advisory Role: Peerview, CTI BioPharma Corp, Remix Therapeutics, Cardinal Health, Medscape, Syndax, Autolus Therapeutics Research Funding (Inst.): Chordia Therapeutics, Abbvie, Actinium Pharmaceuticals, Kura Oncology, Sellas Life Sciences, Novartis, Roivant, Celgene/Bristol-Myers Squibb, Astellas Pharma, SERVIER Travel, Accommodations, Expenses: Peerview

JCO PO author Dr. Hatim Husain at University of California San Diego, shares insights into his JCO PO article, “Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRASG12C-Mutated Non–Small Cell Lung Cancer: A Case Series and Literature Review”, one of the top downloaded articles of 2024. Host Dr. Rafeh Naqash and Dr. Husain discuss how to utilize real-world and clinical trial data to discern the safety of adagrasib (another KRASG12C inhibitor), following sotorasib discontinuation due to hepatotoxicity. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Stephenson Cancer Center.  Today, I'm very excited to be joined by Dr. Hatim Hussain, Professor of Medicine at the University of California, San Diego, and author of the JCO Precision Oncology article, “Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRAS-G12C-Mutated Non-Small Cell Lung Cancer: A Case Series and Literature Review.” This was one of the top downloaded articles of 2024. And the other interesting thing is we generally don't do podcasts for case reports or case series, so this is one of the very few that we have selected for the podcast.  And at the time of the recording, our guest disclosures will be linked in the transcript.  Dr. Hussain, welcome to our podcast and thank you for joining us today. Dr. Hatim Husain: Thank you Dr. Naqash. Such a pleasure to be here and to speak with you all. Dr. Rafeh Naqash: And for the sake of this podcast, we'll refer to each other using our first names. So again, as I mentioned earlier that this is one of the very few case reports that we have selected for podcasts in JCOPO and the intention was very deliberate because it caters to something that is emerging where we are trying to treat more KRAS mutant patients with different KRAS inhibitors. And you tried to address one very unique aspect of it in this article which pertains to toxicity, especially hepatotoxicity. So for the sake of our listeners who tend to be community oncologists, trainees, academic faculty, can you tell us what are KRAS inhibitors? What is KRAS-G12C? And how do some of these approved KRAS inhibitors try to inhibit KRAS-G12C? Dr. Hatim Husain: Sure. For a long time actually we've not had a selective way to inhibit mutant KRAS. And over the last several years actually now, we've seen some dramatic advances here, particularly with the FDA approval of some of the selective inhibitors against the G12C variant. So KRAS-G12C is an isoform of KRAS that is most common in lung cancer and in fact actually is a transversion mutation in the KRAS gene that is a product of the carcinogen of tobacco. And in fact, the incidence of KRAS-G12C in lung cancer, it's quite astounding where as many KRAS-G12C patients there are, there can be, as you know, more than EGFR patients in certain populations and cohorts. The medicines sotorasib and adagrasib were rationally designed to be selective KRAS-G12C inhibitors. And the way that they do this is that they lock the KRAS protein in the OFF state. KRAS is a protein that oscillates between an ON and an OFF state and by virtue of locking the protein in an OFF state, it has shown inhibition of downstream signaling and mitigation of tumor growth and, in fact, tumor cell death. Dr. Rafeh Naqash: I absolutely love the way you describe the ON and OFF state, the oscillation where the ON is bound to the GTP and the OFF is bound to the GDP. The two KRAS inhibitors as currently FDA approved, as you mentioned, are RAS OFF inhibitors and they're emerging KRAS inhibitors that are RAS ON. So now, as we have known from previous data related to immunotherapy and EGFR TKIs such as osimirtinib where toxicity tends to be a compounded effect when you have osimertinib given within a certain timeline of previous checkpoint therapy, we've seen that in the clinic as the data for these KRAS inhibitors is emerging, you talk about some very interesting aspects and data about what has been published so far with regards to prior use of immunotherapy or chemo immunotherapy and the subsequent use of KRAS inhibitors. Could you elaborate upon that? Dr. Hatim Husain: Sure. So for this population of patients, the first line approved strategy is a strategy that most cases will incorporate immune therapy and chemotherapy. Immune therapy can have some important responses for patients with KRAS-G12C. This may be due to the fact that KRAS-G12C patients may have a higher incidence of prior smoking, perhaps higher mutation burdens in some patients, and perhaps immunogenicity is defined in that context. So the standard of care in the first line currently includes immune therapy or immune therapy and chemotherapy. Where the current FDA approvals for selective G12C inhibitors are are after the first line of therapy. There are a number of trials exploring these medicines in the first line to see if they may be incorporated into a future treatment paradigm. Dr. Rafeh Naqash: Thank you for that explanation. Now, going to what you published in this manuscript, can you help us understand the context of why you looked at this? Even though the data just comprises a case series of a handful of patients, but the observations are very interesting and these are real world scenarios where we often tend to be in situations where an individual has had toxicity on a certain drug and may have some response to that drug, but at the same time, the toxicity is challenging. And then you try to debate whether another drug in the same class might be beneficial without those toxicities. So you've tried to address that to some extent using this data set. So can you elaborate upon the question, the methodology, what you tried to look at, and important observations that you have? Dr. Hatim Husain: Yes, our paper was actually inspired by one of my patients. My patient was a patient who had received chemotherapy and immune therapy and actually in the past, even, you know, additional lines of immune therapies, it was really coming to the edge of where standard treatments would exist. It was right at the same time that these selective inhibitors had been approved and the patient had received sotorasib. And what was remarkable was, when given sotorasib, patient had a very high peak and spike in the transaminases. And we would do different trials of strategies around dose, around interruptions. And it was becoming quite difficult, actually, for the patient to proceed with additional therapy. It was around similar times, actually, and I do want to make a note that the patient was progressing, driven in large fact by the fact that we've had to interrupt the medicine. So we feel and believe that the patient had had inadequate dosing because of the level of toxicity that the patient was having with transaminase increase. So it was around the same time that adagrasib was first commercially available that we were at that point, and we did a trial of adagrasib post-sotorasib, largely driven by necessity, without having additional options to provide this patient in our environment. What was remarkable was when the patient received the adagrasib, there were no spikes in transaminases similar to what we had seen before. And that really led us thinking and to say, “Is this adverse event of transaminase increase or hepatotoxicity, is this a class effect with KRAS-G12C inhibitors, or is it more nuanced than that? Are there different, perhaps, mechanisms by which the medicines may work that may more or less differentially contribute to this adverse event?” And so that inspired us to kind of do a larger analysis, kind of really reach out to a larger network of physicians to gather insights and to gather responses in patients who had had a serial approach of sotorasib and then adagrasib.  What we found in this process was, in fact, actually there were many more cases of patients who resembled my patient, where the sequence of sotorasib going to adagrasib may have demonstrated differential contribution of hepatotoxicity in that context. And that really motivated us to put the publication together to due diligence, and in the publication spend a lot of time to kind of outline each patient case in detail around metrics surrounding time from last immune therapy, the number of days on sotorasib, the best response to sotorasib, the interval between sotorasib and adagrasib, the duration of adagrasib and then the grade of hepatotoxicity seen in each of the contexts, and particularly kind of the adagrasib and patient disease status as well. We were quite inspired by the effort to try to, if we do not have randomized data in comparison of one medicine to another, which we do not at this juncture, we do not have a randomized analysis to really diligently and rigorously compare the rates of AEs across each medicine, and even in sequence, we do not have that with immune therapy. But what we felt was trying to get more analysis of this sequential approach of, if patients had received a medicine, had to be taken off because of toxicity and then actually tried on a new medicine, what were those rates? We felt like that was at least some information to try to get at this question. Dr. Rafeh Naqash: And you bring forward a very important point, which is, a lot of times in the real world setting we don't have cross trial comparisons that can be fully applicable, or we don't have trials that compare two drugs of the same class with respect to the AE profile or efficacy. And observations like the one that you described that led to this study are extremely critical in trying to help answer these questions.  From a data standpoint, and you allude to it to some extent in your manuscript, the trials that are trying to address combination of KRAS-G12C with immunotherapy, especially sotorasib or adagrasib, can you elaborate on that data, what has been published so far and summarize it for our listeners? Dr. Hatim Husain: So there is data from clinical trials looking at patients actually who have received concomitant immune therapy and sotorasib. What was seen in this, in a real world analysis, was that some patients actually who had received sotorasib within a close proximity of immune therapy, as well as a larger study actually which showed in combination there were higher rates of hepatotoxicity in that context. In fact, there were rates of grade 3 hepatotoxicity. And I think built upon that data there's a recognition in the field that we have to be very diligent in terms of even the clinical trial designs in how to understand the pairing between immune therapy and selective G12C inhibitors. There are many trials that are ongoing, one of the studies that is ongoing is known as the KRYSTAL-7 study, which is evaluating adagrasib in combination with pembrolizumab in the first line. And we await more information on that strategy as well. In the context of sotorasib, because of some of the trials that have shown higher rates of hepatotoxicity, there are some additional trials now looking at sotorasib in combination with chemotherapy, and those also have some information that have been reported as well. Dr. Rafeh Naqash: From a drug development standpoint, as you mentioned, there's always a tendency to combine something with something else. And in my practice, and I'm sure in your practice too, when we do early phase trials, many trials are still focused on choosing the maximum tolerated dose, which may be something that we need to gradually move away from as we try to implement these combinations of multiple antibodies plus some of these target agents from maybe the biological optimal dose rather than the maximal tolerant dose is a better way to look at the drugs, the pharmacokinetic profile, and then see what is likely the safest combination with the most appropriate target engagement. Do you have any thoughts on that or insights on that from a drug development perspective? Dr. Hatim Husain: It's a wonderful question and I think it is a very insightful question and understanding of where we are in space right now. And I agree with you that historically, cancer drug development was really hinged upon medicines that perhaps required higher doses to see a benefit or to inch out kind of marginal increases upon where we were at. Now, in combination with medicines that have non-overlapping mechanisms of action, the concept is: Can there actually be more synergy across an approach using combinatorial strategies rather than just additive effects? And I think that in some cases this is being studied with immune therapy, in some cases actually even in the context of other novel mechanisms for cancer therapy. I think that in my practice, I will really try to see how a patient at an approved dose will respond. But definitely I'm open to the concept that there may be a dose that doesn't have to be the maximally tolerated dose, but rather the dose that responses can be seen and perhaps actually at a lower dose than what drives many toxicities. Dr. Rafeh Naqash: I often describe this to my patients as individual patient dose optimization outside of a clinical trial, where I'm sure you've probably done this, where in older adults maybe a lower dose of osimertinib is tolerated better, or a lower dose of sotorasib or adagrasib for that matter, tolerated better with perhaps a similar level of efficacy, since we don't have comparisons between doses and efficacy so far.  So I think in the bigger picture, as we discussed in a nutshell, what I would really like the listeners to understand is as we try to move towards this field of precision medicine targeting more and more of the undruggable genes, there's bound to be a certain level of toxicity patterns that we'll start observing. So I think these real world scenarios which may not be addressed using clinical trials because it is in the real world setting where you cycle one treatment after another after another, which may or may not be allowed in most trials and the real world setting can inform, in certain cases, subsequent trial designs. So I think the most important message, at least that I took from your manuscript, was that these real world observations can make a huge difference and inform practice, even though the data sets may be small. Of course, you want to validate some of these findings in a bigger, broader setting, but proof of concept is there. And I think next time I see an individual in my clinic where I see better toxicity, I'll definitely try to talk to them about subsequent treatment with another KRAS inhibitor, maybe adagrasib or something else, if and when appropriate.  Do you have any closing thoughts on some of these things that we discussed? Dr. Hatim Husain: I just want to leave the audience actually with this concept that sometimes we group targeted therapy side effects as being class effects unanimously. And I do think actually that each inhibitor may have different off target effects on where medicine may act. We don't truly understand the mechanism of hepatotoxicity in the context of selective KRAS-G12C inhibitors. One of the hypotheses may be due to off target cysteine reactivity in the numerous off target binding sites that certain medicines may have over others. And just even qualitatively which off target binding sites there may be, and how that may lead to either immunogenic responses and other organs or such. So I do think that we do need more research to understand the mechanism. But I think where we are at right now in this space is not assuming that all medicines are going to have the exact same toxicity. I think especially when patients may not have other options, this is something to consider as well. Dr. Rafeh Naqash: Thank you so much. Now, outside of the scientific insights, Hatim, I know you a little bit from before. And knowing the kind of work that you've done in precision medicine, I'm really interested to know about where you started, how you started, how things have been, and what kind of advice you have for junior faculty fellows who are interested in this field of precision medicine that is becoming more and more exciting as we progress in the oncology space. Dr. Hatim Husain: Thank you, Rafeh. I will say, actually as a medical student, I was actually very interested in oncology, partly because it was then and still remains one disease or a constellation of diseases that just has such a high psychological burden on patients. And through the experiences I've had, I really can understand and relate with that concept. I did my medical school at Northwestern, residency at the University of Southern California, and then my oncology fellowship at Johns Hopkins University.  And now I've been on faculty at University of California, San Diego, for about 12 years now. It's been a great experience paralleled with the fact that during these last 12 years, I've really seen how the developments in precision oncology, both targeted therapy as well as immune therapy, have really blossomed and unfolded. A large area of my research in my career has kind of focused on cancer genome and integration of novel technologies to really see how they may have clinical application. When I was in my fellowship and as a young faculty, the liquid biopsy was actually coming into development. And this was hinged upon information that had come forward in the prenatal space where some patients actually who were undergoing prenatal testing during pregnancy were found to have complex karyotypes and genomic alterations and then retrospectively found to have cancer.  And doing my fellowship at Johns Hopkins, some of the pioneers in liquid biopsy were my mentors and really kind of instilled in me that passion for really thinking through how cancer genomics can be integrated through time. And some of the research that I have been doing has been looking at clonal evolution of cancer, how cancer is changing over time, and how we can think through the right surveillance strategies to really understand how that change is occurring. The dynamics of ctDNA in retrospective cohorts have been studied and shown that, you know, there can be associations between progression-free survival and other clinical endpoints. The current paper that we are speaking about parallels that in a certain way where, rather than say, looking at clonal evolution and say, the efficacy answer of sotorasib first and then adagrasib and how frequently can adagrasib salvage patients, this looks at it from a different angle around toxicity. And I think that is a key point because, at my core, I really do enjoy the clinical aspect of complex decision making on behalf of patients weighing efficacy and toxicity that they may have as they try to get the best quality of life through this journey. Dr. Rafeh Naqash: Thank you again, Hatim, for all those insights, both from the scientific perspective as well as personal perspective. We appreciate that you chose JCOPO as the destination for your work.  And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Hatem Husain Disclosures Consulting or Advisory Role: AstraZeneca, Foundation Medicine, Janssen, NeoGenomics Laboratories, Mirati Speakers' Bureau: AstraZeneca, Janssen Institution Research Funding: Pfizer, Bristol-Myers Squibb, Regeneron, Lilly Travel, Accommodations, Expenses: AstraZeneca, Janssen, Foundation Medicine  

Host Dr. Shannon Westin and guests Dr. Bill Aronson discuss the article "High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial" and how Omega-6 are predominant in the American diet while the study significantly lowered the intake of Omega- 6 fats. TRANSCRIPT  Dr. Shannon Westin: Hello everyone and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Dr. Shannon Westin, GYN Oncologist by trade and one of the grateful Social Media Editors of the JCO. And I am very excited to welcome a special guest today, Dr. William Aronson. He is professor of Urology in the UCLA Department of Urology, the Chief of Urology at Olive View UCLA Medical Center, and Chief of Urologic Oncology at the Veterans Administration West Los Angeles. Welcome, Dr. Aronson. Dr. William Aronson: Thank you, Shannon, and delighted to be here. Dr. Shannon Westin: We are so excited to have you discussing your manuscript, “High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial,” which was published in the Journal of Clinical Oncology on December 13, 2024. So let's get right to it. First of all, you know we have a very mixed audience, so can you just level set for us and speak about the population you studied in this important trial - that low risk, favorable, intermediate risk prostate cancer. How common is that? How is it defined? That would really help. Dr. William Aronson: I would say about 50% of the patients that we diagnose with prostate cancer either have low risk disease or what we call favorable intermediate risk disease. So when the pathologists look at the cancer under the microscope, they assign what's called a Gleason grade. Grade 3 is the slower growing type of prostate cancer, grade 5 is the fastest growing type, and grade 4 is somewhere in between. So a low risk group would be only the grade 3, the slower growing type. And the favorable intermediate risk group would actually be the grade 3+4, which means they mostly see the low risk type in there, but they also see the slightly faster growing type, grade 4. So this is what we typically see. We see these patients on a very regular basis when they're newly diagnosed with prostate cancer. Dr. Shannon Westin: Okay, got it. And then can you walk us through just what the management options are typically for this patient population? Dr. William Aronson: So typically for what we call the low risk group, the patients with a low PSA and only that grade 3 type, slower growing type of prostate cancer, the standard recommendations are active surveillance. So typically, we'll periodically monitor these patients with PSA blood testing and periodically do prostate biopsies depending upon the patient's other medical problems. Dr. Shannon Westin: So I think it would also be really helpful just to understand what your typical management options are for this patient population. Dr. William Aronson: So for patients with low risk prostate cancer, they only have the Gleason Grade 3+3 with a low PSA. The standard practice is observation. And so these men will periodically see them and measure their PSA values. And periodically, they'll undergo prostate biopsy to make sure they're not getting progression of their disease. For men with favorable intermediate risk prostate cancer, that's a little different. In some practices, the patient and the urologist will decide to do active surveillance. In other scenarios, these patients will definitely elect treatment, either with radical prostatectomy or radiation therapy or other treatments that are available. Dr. Shannon Westin: So your manuscript notes that there was a high level of interest in dietary supplements and approaches among patients with prostate cancer that do elect for active surveillance. Prior to the results of CAPFISH-3, did we have any data to support those types of recommendations? Dr. William Aronson: We actually don't have any long term prospective randomized trials that support that recommendation. There have been a number of very interesting epidemiologic studies, for example, suggesting maybe a plant-based diet might be helpful. Or a number of other studies suggesting maybe more tomato-based products like tomato sauces or tomato paste may be helpful. But no prospective longer term randomized trials that were positive. Dr. Shannon Westin: Okay, that makes sense. So what led you all to explore the high omega-3, low omega-6 fatty acid diet in this trial? Dr. William Aronson: After our initial omega-6 studies, we subsequently did some studies where we raised the omega-3 from fish oil and lowered the 6, looking at a more favorable ratio of the omega-3 to omega-6. And once again, we found that in our animal models, there was a significant delay in progression of prostate cancer. That then led us to perform a clinical trial. It was a short term trial in men prior to undergoing radical prostatectomy. And in these men, they were randomly assigned to one of two groups, either a western high fat diet or a low fat diet with fish oil. And we found after just four to six weeks, a significant change in the Ki67 level in their radical prostatectomy tissue. And Ki67 is actually a strong indicator of prostate cancer progression, spread, or even death from prostate cancer. Dr. Shannon Westin: Well, and I think that leads us really nicely into the design of the current study. So why don't you walk us through how CAPFISH-3 was designed. And you've already spoken a little bit about your primary endpoint. Dr. William Aronson: Based on the results of what we saw in the lab and what we saw in our short term clinical trial, we decided to perform a one year trial, a longer term trial in men on active surveillance. And these men were randomly assigned to either a diet with slight reduction in dietary fat, specifically reduction in the omega-6 intake as well as increase in foods with omega-3 and fish oil capsules. The other group, we asked the men to just not take fish oil capsules, but they could eat whatever else they wanted during the course of the study. Men in the diet where we lowered the omega-6 and raised the omega-3, they were seen by a dietitian once a month to really ensure that they were compliant with that intervention, which they were. The other intriguing part of our study, which I think is super important, is the precision that was used when these men underwent prostate biopsy. So, at baseline and at one year, when these men underwent prostate biopsy, they had the same site within the prostate biopsied. That's important because it's not so easy to find the same site within the prostate because of heterogeneity throughout the prostate. And so we were able to obtain that high level of precision as they were in an active surveillance program at UCLA with Dr. Leonard Marks. Dr. Shannon Westin: So we spoke a little bit about what's important about the Ki67 index as your primary endpoint. Can you talk a little bit about what the study found with your intervention? Dr. William Aronson: So we found that the Ki67 index increased by 24% in the control group and decreased by 15% in the low omega-6, high omega-3 group with fish oil capsules. So that ended up resulting in a statistically significant change between the groups favoring the low omega-6, high omega-3 group. Dr. Shannon Westin: And then what were the secondary endpoints that CAPFISH-3 explored? Anything of note that you want to review for the listeners? Dr. William Aronson: So a number of positive secondary endpoints from the trial. Firstly, we saw that the triglyceride levels were lower, which is what can typically be seen with omega-3 intake. We also saw reduced levels of a cytokine, a circulating factor in the bloodstream called ‘macrophage colony stimulating factor'. And that's particularly interesting because there's a certain type of macrophage which is well known to be involved in prostate cancer progression in men with more advanced prostate cancer, and we've been able to inhibit that in our animal models and in our tissue culture studies. And it was especially interesting to see that we did have an effect on this particular cytokine in this prospective randomized trial. We did not see changes in a number of other measures, including Gleason grade or PSA. These are measures that we use in clinical practice. To see an effect on those would have required a longer term and larger study to be performed. Dr. Shannon Westin: That makes sense. I think it's always great to try to get as much of these types of translational data as we can. But sometimes you just have to do what is reasonable and you get what you get. It looks to me like this regimen was fairly well tolerated. Did you obtain any patient reported outcomes or feedback on the trial? Dr. William Aronson: So, there were four patients in the fish oil group that did have some side effects, and we withdrew them from the study. They did have some effects on their upset stomach, and a number of men also had some diarrhea as well. And so for those four patients, we did withdraw them from the study. Dr. Shannon Westin: And then I guess the last question I have is really, what's next for this intervention? Are we ready to move this to the clinic or what do you see as next steps? Dr. William Aronson: Well, this next step that we're working on right now is to better understand exactly what happened in these patients. So we have blood, we have tissue, we're doing genetic studies on these patients. So that's really the first step, in our mind, to better understand what happened before moving to the next step. I'm particularly intrigued about trying this intervention in men with more advanced prostate cancer, specifically because of what we see, this particular diet and how it's affecting the patient's immune system and how that may favorably affect their course of their prostate cancer. Dr. Shannon Westin: Well, great. Well, thank you so much for taking the time to chat with us about such an important clinical trial, and I really appreciate all the work you're doing and hope to get to see you soon. Dr. William Aronson: Well, thanks for having me, Shannon. It's really an exciting finding and I think it's something that clinicians and patients are going to be super interested in. Dr. Shannon Westin: We love straightforward interventions that actually make a difference, so you guys are to be congratulated for that. And I just want to thank all of you for listening. Thanks again, and I hope you enjoyed this episode of JCO After Hours. Be sure to check out our other podcast offerings wherever you get your podcasts. Have an awesome day.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Aronson Disclosures: Stock and Other Ownership Interests Johnson and Johnson Speakers' Bureau Company name: Janssen Oncology, Bayer, Blue Earth Diagnostics, AstraZeneca, Pfizer/Astellas Research Funding: Lantheus Medical Imaging UCLA Health Article Video

Dr. Shaalan Beg and Dr. David Wang discuss key abstracts in GI cancers from the 2025 ASCO Gastrointestinal Cancers Symposium, including major advances in CRC, neoadjuvant approaches in esophageal cancer, and innovative studies on ctDNA. TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg. I'm a medical oncologist and an adjunct associate professor at UT Southwestern Medical Center in Dallas. Today, we're bringing you some key highlights from the 2025 ASCO Gastrointestinal Cancers Symposium, and I'm delighted to be joined by the chair of GI25, Dr. David Wang. Dr. Wang is a GI medical oncologist at the University of Michigan. Our full disclosures are available in the transcript of this episode.  Dr. Wang, thanks for coming on the podcast today. Dr. David Wang: Well, thank you. It's a pleasure to be here. Dr. Shaalan Beg: GI25 featured major therapeutic advances across the spectrum of GI malignancies, and it was exciting to hear about innovations and novel approaches that are shaping the future of our field. Before we start talking about specific abstracts, could you share some of your key highlights from the meeting? Dr. David Wang: Sure. Our theme this year was “Breaking Boundaries to Enhance Patient Centered Care.” Past years' themes have focused more on precision oncology, but we wanted to broaden our focus on patients and to be more holistic, which kind of led us into some of the Intersection [sessions] that we had. Each day started with a different Intersection. The first one was “Emerging Therapies in GI Cancers”, where invited speakers talked about bispecific antibody drug conjugates, theranostics, CAR T and other cell-based therapies. The second day was on “Personalized Risk Assessment for GI Cancers,” and this included looking at polygenic risk scores for colorectal cancer, microRNAs and liquid biopsies such as exosomes and pancreatic cancer and non-endoscopic screening modalities in esophageal cancer. And on our final day, we wanted to talk about “Integrative Oncology and Integrative Medicine,” looking at evidence-based uses of acupuncture and supplements in patients who are receiving treatment for cancer, mindfulness-based practices and exercise. And of course, we had a fantastic keynote talk by Dr. Pamela Kunz from the Yale School of Medicine titled, “Disrupting Gastrointestinal Oncology: Shattering Barriers with Inclusive Science.” She highlighted the intersection of science, patient care, and health and gender equity. And I would encourage your podcast listeners to access the lecture in ASCO's Meeting Library if they haven't yet had a chance to hear Dr. Kunz's wonderful lecture.  We were really happy this year because the attendance hit a new record. We had over 5,000 people attend either in person or virtually from their home or office, and we had almost 1,000 abstracts submitted to the meeting, so these were either record or near record numbers. We offered a lot of different networking opportunities throughout the meeting, and attending found these to be incredibly rewarding and important and this will continue to be an area of emphasis in future meetings. Dr. Shaalan Beg: Let's take a deeper dive into the exciting studies presented at GI25. The late breaking abstract LBA143 was CheckMate-8HW. This was the first results of NIVO + IPI versus NIVO monotherapy for MSI-high metastatic colorectal cancer. What are your thoughts about this study? Dr. David Wang: Yeah, so we know that colorectal cancer patients with MSI-high tumors don't necessarily respond well to chemotherapy. And we were fortunate because last year CheckMate-8HW actually looked at two different arms – so this was NIVO + IPI compared to standard of care chemotherapy and showed its very significant improvement in median progression-free survival. And that was actually published in the New England Journal of Medicine back in November of 2024. This year's presentation actually focused now on NIVO + IPI versus NIVO monotherapy. And as you know IPI+NIVO can be quite toxic. So this was an important analysis to be done. So we know that NIVO is definitely more easily tolerated. So what was interesting was that the 2-year and 3-year progression-free survival not surprisingly favored IPI+NIVO and this was statistically significant. And the overall response rate was also better with IPI+NIVO versus NIVO alone. I know we're always concerned about toxicities and there were higher grade 3 and 4 toxicity incidences in the combination arm versus the monotherapy arm, but overall, only about 28 additional events in several hundred patients treated. So I think that's well-tolerated. Our discussant Dr. Wells Messersmith actually said that, with this new data, he would consider doing combination immunotherapy in any patient that presented in the front line with MSI-high or deficient mismatch repair colorectal cancer that was metastatic. Dr. Shaalan Beg: One of the focuses for directing first-line therapy for colorectal cancer has been right and left sided colon cancer because we know these are two different cancers with their own unique molecular subtypes. We heard on Abstract 17, the DEEPER trial, the final analysis of modified FOLFOXIRI plus cetuximab versus bevacizumab for RAS wild-type and left sided metastatic colorectal cancer. How do you summarize the findings of this study and what should our readers be aware of? Dr. David Wang: Interestingly, this was a phase 2 study and the emphasis of the abstract was actually a subgroup analysis of those patients with RAS wild-type and BRAF wild-type as well as left sided cancers. So, I think the entire study enrolled 359 patients, but the analysis that was discussed at the meeting really focused on 178 patients that fit that characteristic. Very similar to what we've seen in prior studies, left-sided tumors have better response to cetuximab versus bevacizumab. And if you flip it so that you now are looking at right sided tumors, targeting EGFR is actually detrimental. The depth of response was better with cetuximab in these left sided RAS and BRAF mutant tumors. And so the lead author actually suggested that this could be a new first-line standard of care. And the question is, is there a benefit of doing this triple agent regimen with modified FOLFIRINOX? We know there's a lot more toxicity with that. Not clear that there's a benefit for that over FOLFOX, maybe in younger patients that could tolerate it. When our discussant, again Dr. Wells Messersmith, spoke about this, he said that, in his practice he would, again, favor cetuximab over bevacizumab in combination with chemo, these left-sided RAS and BRAF wild-type tumors, but that he would actually prefer a doublet versus a triplet chemo regimen, and that is consistent with the current NCCN guidelines. Dr. Shaalan Beg: Another area where colorectal cancer has been a wonderful model to study new technology has been in the area of circulating tumor DNA (ctDNA). And the BESPOKE CRC trial is looking to see if ctDNA can inform adjuvant treatment decisions for stage II and III colorectal cancer. And in Abstract 15, we heard final results of the BESPOKE CRC sub-cohort. What were the findings there? Dr. David Wang: BESPOKE CRC is another one of these important ctDNA studies. It was an observational study, not a randomized trial, but it did provide a lot of different insights to us. We know that there were over 1,700 patients enrolled, and so it was reported that this is the largest ctDNA study in colorectal cancer performed in the United States. And they were able to analyze over 1,100 patients.  Some of the key findings were that postoperative adjuvant therapy management decisions actually changed in 1 out of 6 patients, so that's pretty significant. In terms of surveillance, we know that patients who have ctDNA positivity, this is prognostic of recurrence. In terms of patients who have positive ctDNA post-surgery, it looked like, at least in this observational study, the majority of patients who received any benefit were those who had positive ctDNA. So adjuvant therapy, even in stage II and stage III patients seemed to only benefit those patients who have positive ctDNA. I think that does raise the question, and this also was brought up in the discussion, which is “Can we de-escalate adjuvant therapy in terms of patients who are ctDNA-negative post-op?” And Dr. Richard Kim from Moffitt felt that we are not yet there. Obviously, we need randomized control trials where we are taking ctDNA results and then randomizing patients to receive adjuvant or non-adjuvant to really know the difference.  Other questions that come up with use of ctDNA include: What do you do with these patients who turn positive? This study for BESPOKE actually followed patients out to two years after surgery. So what you do with a positive ctDNA result wasn't really clear. It seems to suggest that once you turn positive, patients go on to more intensive surveillance. You know, again as an observation, patients who did turn positive were able to go to metastasis-directed therapy much more quickly. And again, this was supposedly to improve their curative intent therapy. And I think the other question that has been brought up all the time is, is this really cost effective? Patients want to know, and we want to give patients that information, but I think we're still stuck with what to do with a positive ctDNA level in a patient that's on surveillance because no randomized control studies have actually suggested that we need to start systemic therapy right away. Dr. Shaalan Beg: Yeah. And I guess in terms of practice informing or practice changing, these results may not give us a clear answer. But because a lot of patients are asking for these tests, it does give us some real world experiences on what to expect in terms of conversion of these positive into negative and the outcome so we can have a shared decision making with our patients in the clinic and then come up with a determination on whether ctDNA for molecular residual disease is something which would be worthwhile for the care of our patient. But more to come, I guess, in coming years to answer different problems around this challenge. Dr. David Wang: Yes, I agree. Dr. Shaalan Beg: The BREAKWATER trial looked at the use of encorafenib, cetuximab and chemotherapy for BRAF V600E-mutant metastatic colorectal cancer. We've covered this combination for a second- third-line treatment in metastatic colorectal cancer previously. Abstract 16 from GI25 was evaluating the use of this regimen in the first-line space. Everyone was looking forward to these results, and what did the investigators present? Dr. David Wang: I think this is, as you mentioned, a nice follow up to later lines of therapy where Dr. Kopetz from MD Anderson pioneered use of encorafenib, cetuximab and binimetinib in the BEACON trial. Everybody was kind of curious what would happen now if you use encorafenib plus cetuximab plus chemotherapy in the first-line setting. And so this is an interim analysis that was pre-planned in the phase 3 open label BREAKWATER trial. And even though there were three arms, and so the three arms were encorafenib plus cetuximab, encorafenib plus cetuximab plus FOLFOX, or standard of care chemo, only two arms were presented in the abstract. So basically looking at encorafenib plus cetuximab and FOLFOX-6 versus standard of care therapy, and the overall response rate was statistically significant with a 60.9% overall response rate encorafenib plus cetuximab plus chemo arm versus standard of care chemo was only 40%. The interim overall survival also was different. It was 92% versus 87% at 6 months and 79% versus 66% at 12 months, again favoring the chemotherapy plus encorafenib plus cetuximab. In terms of the statistics, the p was 0.0004. However, the pre-plan analysis required the p-value to be 1x10 to the -8. And so even though this looks really good, it hasn't quite met its pre-specified significance level. The good thing is that this is only interim analysis and the study is ongoing with future analysis planned.  So the real question is: Does it matter when we actually use this regimen? We know that the regimen's approved in the second third-line setting. What about in the first line? And there was some preclinical data that the discussant reviewed that shows that patients actually benefit if this is done in the first-line setting. For example, there was some preclinical data showing that even FOLFIRI, for example, can upregulate RAS, which would make tumors more resistant to this combination. This was thought to be practice-changing in a patient that has B600E showing up treatment naive that we should probably consider this regimen. And actually this did receive accelerated FDA approval about a month ago. Dr. Shaalan Beg: Yeah, and for what it's worth, I put up a Twitter poll asking my Twitter followers on how the BREAKWATER trial results will change their approach for newly diagnosed BRAF mutated colorectal cancer. We got 112 responses; 72% said that they will incorporate encorafenib, cetuximab, FOLFOX for their frontline BRAF mutated patients. But 23% said that they would like to wait for overall survival results. Dr. David Wang: Wow, that's interesting. They really want that 1x10 to the -8. Dr. Shaalan Beg: I guess so. All right. Let's change gears and talk about esophageal cancer. LBA329 was the SCIENCE study which presented preliminary results from a randomized phase 3 trial comparing sintilimab and chemoradiotherapy plus sintilimab versus chemoradiotherapy for neoadjuvant resectable locally advanced squamous esophageal cancer. Where are we in this space? Dr. David Wang: Okay. So, yeah, this was an interesting trial. Again, just to set the context, esophageal squamous cell carcinoma is more prevalent in Asia. And the study sites as well as the patients were mostly from Asia. So this was again a phase 3 trial with interim results. They only rolled 146 out of the planned 420 for this interim analysis. And yeah, they're using immune checkpoint inhibitor that we don't use in the United States, sintilimab, combined with their two standards of neoadjuvant therapy, either chemotherapy, which is more common in Asia, or or chemoradiation, which is more common in the US and Western Europe, versus chemoradiation. And so they actually had two primary endpoints, but only were reporting one. So their two primary endpoints were pathCR and the other one was event-free survival. The event-free survival, again, was not reported at the meeting.  What they found was that in terms of pathCR rate, if you take the two arms that are really informative about that, chemoradiation plus sintilimab versus chemoradiation alone, the pathCR rate was 60% versus 47%. We know that chemo alone doesn't induce as much of a pathCR rate, and that was 13%. So it was found that the delta in terms of pathCR between the chemoradiation arms, one with sintilimab and one without, was significant. And this actually confirms data again from Asia, like for the ESCORT-NEO trial where it used another immune checkpoint inhibitor pembrolizumab in addition to neoadjuvant chemo.  So as our discussant for this abstract said, yes, we know that radiation combined with chemotherapy improves pathCR rates, but we have recent data from the ESOPEC trial, we don't know that that necessarily will translate to overall survival. So again, waiting for additional enrollments and longer term follow up before incorporating this into clinical care here. Dr. Shaalan Beg: So David, how do the results of the SCIENCE trial compare with our practice in the United States and ongoing studies asking questions for neoadjuvant therapy for esophageal carcinoma in the United States? Dr. David Wang: I think obviously immune checkpoint inhibitor in the new adjuvant setting is important. Jennifer Eads at UPenn is running that EA2174 which is looking at chemoradiation plus or minus nivolumab, and then in non-pathCR responders randomized to adjuvant nivolumab per CheckMate 577 or nivolumab with intensification adding ipilimumab. We know that the ESOPEC trial just came out, and was published actually during the meeting, and that really focuses on adenocarcinomas. So adenocarcinomas of the GE junction, distal esophagus, now, we would probably treat very similarly to gastric using perioperative FLOT. However, the standard in the US for esophageal squamous cell carcinoma remains neoadjuvant chemoradiation. We know that squamous cell carcinomas are more exquisitely sensitive to radiotherapy. And then obviously in those patients who don't achieve a pathologic complete response, the expectation would be that they would go on to receive nivolumab per CheckMate 577. Again, the thought is that these tumors are more sensitive to immunotherapy given their higher incidences of mutational changes. And so again, this kind of goes along with the positive results seen in the SCIENCE trial that we just discussed with sintilimab but also EFFECT-neo with pembrolizumab. Obviously, we await the results of Jennifer's trial. Dr. Shaalan Beg: And the last abstract I was hoping we could get your perspective on was Abstract 652, which is a Phase 3 study of everolimus plus lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumors, the STARTER-NET trial. What were the results of this study? Dr. David Wang: So, I just want to give a shout out because we did have a session at this year's GI ASCO that looked at more rare tumors. So appendiceal tumors, neuroendocrine tumors, those kinds of things. So again, I would encourage your listeners to listen to that session if they have interest in that. Another type of rare tumor was adenosquamous tumors.  But in terms of the STARTER-NET trial, this was again an interim analysis of his phase 3trial and it was looking at combining everolimus plus lanreotide versus everolimus. So we know that in pancreatic-gastric neuroendocrine tumors, if you have low Ki-67, a well differentiated tumor, that the standard of care really is a somatostatin analog, and sometimes if they're more aggressive, we kind of consider molecular targeted therapy with everolimus. This was asking the question of whether we should do the combination on the frontline. And what was interesting is in this study, the patients were actually more of a poor prognostic set. So they had Ki-67 up to 20% or these were patients that actually had multiple liver lesions. And what they found was a median for progression free survival was improved with a combination out to 29.7 months versus 11.5 months with the somatostatin analog alone, and that the overall response rate was 23% versus 8.3%, again, favoring the combination. If you looked at subgroup analysis, it was actually those patients who had Ki-67 greater than 10%, so the more aggressive tumors, or those with diffuse liver lesions that had the most benefit. So I think that would be the patient population I would consider this new combination with using would be those patients again with poorer prognosis neuroendocrine tumor phenotype. Dr. Shaalan Beg: Thank you very much, Dr. Wang, for sharing your insights with us today and your great work to build a robust GI Cancers Symposium this year. Dr. David Wang: Well, thank you. I mean that really is a cooperative effort. We appreciate all the members of the GI25 Program Committee as well as the ASCO staff that just made it an outstanding meeting. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed today on the transcript of this episode.  Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:  Dr. Shaalan Beg @ShaalanBeg  Dr. David Wang Follow ASCO on social media:   @ASCO on Twitter  @ASCO on BlueSky ASCO on Facebook   ASCO on LinkedIn   Disclosures:  Dr. Shaalan Beg:  Employment: Science 37  Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine  Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals  Dr. David Wang: Honoraria:  Novartis Consulting or Advisory Role: Novartis, Cardinal Health, Bristol-Myers Squibb, BeiGene, Eisai  

Dr. Jasmine Sukumar and Dr. Dionisia Quiroga discuss advances in adjuvant therapy for patients with early breast cancer and BRCA1/2 mutations, including how to identify patients who should receive genetic testing and the significant survival benefits of olaparib that emerged from the OlympiA trial. TRANSCRIPT Dr. Jasmine Sukumar: Hello, I'm Dr. Jasmine Sukumar, your guest host of the ASCO Daily News Podcast today. I'm an assistant professor and breast medical oncologist at the University of Texas MD Anderson Cancer Center. On today's episode, we'll be exploring advances in adjuvant therapy for high-risk early breast cancer in people with BRCA1/2 germline mutations. Joining me for this discussion is Dr. Dionisa Quiroga, an assistant professor and breast medical oncologist at the Ohio State University Comprehensive Cancer Center.  Our full disclosures are available in the transcript of this episode.  Dr. Quiroga, it's great to have you on the podcast. Thanks for being here. Dr. Dionisia Quiroga: Thank you. Looking forward to discussing this important topic. Dr. Jasmine Sukumar: Let's start by going over who should be tested for BRCA1/2 genetic mutations. How do you identify patients with breast cancer in your clinic who should be offered BRCA1/2 genetic testing? Dr. Dionisia Quiroga: So, guidelines on who to offer testing to somewhat differ between organizations at this point. I would say, generally, I do follow our current ASCO-Society of Surgical Oncology (SSO) Guidelines, though. Those guidelines recommend that BRCA1/2 mutation testing be offered to all patients who are diagnosed with breast cancer and are 65 years old or younger. For those that are older than 65 years old, there are additional factors to really take into account to decide on who to recommend testing for. Some of this has to do with personal and family history as well as ancestry. The NCCN also has their own specific guidelines for who to offer testing to. For example, people assigned male at birth; those who are found to have a second breast primary; those who are diagnosed at a young age; and those with significant family history should also be offered BRCA1/2 testing.  I think, very important for our discussion today, ASCO and SSO also made a very important point that all patients who may be eligible for PARP inhibitor therapy should be offered testing. So clearly this includes a large amount of our patient population. In my practice, we often refer to our Cancer Genetics Program. We're fortunate to have many experienced genetic counselors who can complete pre-test and post-test counseling with our patients. However, in settings where this may not be accessible to patients, it can also be appropriate for oncology providers to order the testing and ideally perform some of this counseling as well. Dr. Jasmine Sukumar: Thank you Dr. Quiroga. Let's next review where we are in current clinical practice guidelines. What current options do we have for adjuvant therapy specific to people with high-risk early breast cancer and BRCA1/2 genetic mutations? Dr. Dionisia Quiroga: Our current guidelines recommend adjuvant olaparib for one year for individuals with HER2-negative high risk breast cancer. This approval largely came from the data and the results of the OlympiA trial. This was a prospective phase 3, double blind, randomized clinical trial. It enrolled patients who had been diagnosed with HER2-negative early-stage breast cancer who also carried germline pathogenic or likely pathogenic variants of either the BRCA1 and/or BRCA2 genes. The disease also had to be considered high-risk and there were several criteria that had to be evaluated to deem whether or not these patients were high-risk. For example, those who are treated with neoadjuvant chemotherapy, if they had disease that was triple-negative, they needed to have some level of invasive residual disease at time of surgery. Alternatively, if the disease was hormone receptor-positive, they needed to have residual disease and a calculated CPS + EG score of 3 or higher. This scoring system is something that estimates relapse probability on the basis of clinical and pathologic stage, ER status, and histologic grade, and this will give you a score ranging from 0 to 6. In general, the higher the score, the worse the prognosis. This calculator though is available to the public online to allow providers to calculate this risk.  For the subset of patients who received adjuvant chemotherapy, for them to qualify for the OlympiA trial, if they had triple-negative disease, they needed to have a tumor of at least 2 cm or greater and/or have positive lymph nodes for disease. For hormone receptor-positive disease that was treated with adjuvant chemotherapy, they were required to have four or more pathologically confirmed positive lymph nodes at time of surgery. From this specified pool, patients were then randomized 1:1 to get either adjuvant olaparib starting at 300 mg twice a day or a matching placebo twice a day after they had completed surgery, chemotherapy and radiation treatment if needed. Dr. Jasmine Sukumar: And what were the outcomes of this study? Dr. Dionisia Quiroga: The study ended up enrolling over 1,800 patients and from these 1,800 patients, 70% had a BRCA1 mutation while 30% had a BRCA2 mutation. About 80% of the patients had triple-negative disease compared to hormone receptor-positive disease. Interestingly, about half of all patients enrolled had received neoadjuvant chemotherapy while the other half received adjuvant chemotherapy.  Looking at the outcomes, this was overall a very positive study. We actually now have outcomes data from a median of about 6 years out. This was just reported in December at the 2024 San Antonio Breast Cancer Symposium. There was found to be a 9.4% absolute difference in six-year invasive disease-free survival favoring the olaparib arm over the placebo arm. What was also interesting is that this was consistent across multiple subgroups of patients and the benefit was really seen whether or not they had hormone receptor-positive or triple-negative disease. The absolute difference in distant disease-free survival was also high at 7.8% and additionally favored olaparib. Most importantly, there was found to be a significant overall survival benefit. The six-year overall survival was 87.5% in the olaparib group compared to 83.2% in the placebo group. This translates to about a 4.4% difference and a relative 28% overall survival benefit in using olaparib.  Now, future follow up is going to be very important. Follow up for this study is actually planned to continue out until June 2029 so we can continue to observe if these survival curves will continue to branch apart as they have so far at each follow up. And I think this is especially important for those patients diagnosed with hormone receptor-positive cancers because we know those patients are at particular risk for later recurrences.  As an additional side note, the researchers also noted that there were fewer primary malignancies in the olaparib group, not just of the breast but also primary ovarian or fallopian tube cancers as well, which is not completely surprising knowing that this drug is also heavily used and beneficial in different types of gynecologic cancers. Ultimately, the amount of adverse events reported have been low with only about 9.9% of patients receiving olaparib needing to discontinue drug due to adverse events, and this is compared to 4.2% reported in the placebo group. Dr. Jasmine Sukumar: You mentioned that the OlympiA trial showed an overall survival benefit, but interestingly the OlympiAD trial looking at olaparib versus chemotherapy in patients with advanced metastatic HER2-negative breast cancer did not show a significant overall survival benefit. Could you discuss those differences? Dr. Dionisia Quiroga: I agree, that's a very good point. So OlympiA's comparator arm was, of course, a placebo. So while this isn't the same as comparing to chemotherapy, it does still potentially suggest that there is a degree of benefit that olaparib can provide when it's introduced in the early local disease setting compared to advanced metastatic disease. I think we need more future trials looking at potential other combinations to see if we can improve the efficacy of PARP inhibitors in the metastatic setting. Dr. Jasmine Sukumar: For patients who do choose to proceed with use of adjuvant olaparib due to the promising efficacy, what side effects should oncologists counsel their patients about? Dr. Dionisia Quiroga: The most common notable side effects, I would say with olaparib and other PARP inhibitors are really cytopenias. Gastrointestinal side effects such as nausea and vomiting can occur as well as fatigue. There are some less common but potentially more serious side effects that we should counsel our patients on. This includes pneumonitis. So counseling patients on if they're short of breath or experiencing cough to let their provider know. Venous thromboembolism can also be increased rates of occurrence. And then of course myelodysplastic syndromes or acute myeloid leukemia is something that we often are concerned about. That being said, I think it should be noted that interestingly in the OlympiA trial so far, there have been less new cases of MDS and AML in the olaparib group than actually what's been reported in the placebo group at this median follow up of over six years out. So we'll need to continue to monitor this endpoint over time, but I do think this provides some reassurance. Dr. Jasmine Sukumar: Since the initiation of the OlympiA trial, other adjuvant treatments have also been studied and FDA approved for non-metastatic HER2-negative breast cancer. So for example, the CREATE-X trial established adjuvant capecitabine as an FDA approved treatment option in patients with triple-negative breast cancer who had residual disease following neoadjuvant chemotherapy. So if a patient with triple-negative breast cancer with residual disease is eligible for both adjuvant olaparib and adjuvant capecitabine treatments, how do you decide amongst the two? Dr. Dionisia Quiroga: If a patient's eligible for both, I honestly often favor olaparib, and I do this because I find the data for adjuvant olaparib a little bit more compelling. There are also differences in toxicity profile and treatment duration between the two that I think we should discuss with patients. For example, olaparib is supposed to be taken for a year total, whereas with capecitabine we typically treat for six to eight cycles with each cycle taking three weeks. There are some who may also sequence the two drugs in very high-risk disease. However, this is very much a data free zone. We don't have any current clinical trials really comparing these two or if sequencing of these agents is appropriate. So I don't currently do this in my own clinical practice. Dr. Jasmine Sukumar: Nowadays, almost all patients with stage 2 to 3 triple-negative breast cancer will be offered neoadjuvant chemotherapy plus immune checkpoint inhibitor therapy pembrolizumab per our KEYNOTE-522 trial data. With our current approach, pembrolizumab is continued into the adjuvant setting regardless of surgical outcome, so that patients receive a year total of immunotherapy. So in patients with residual disease and a BRCA germline mutation, do you suggest using adjuvant olaparib concurrently with pembrolizumab? Do we have any data to support that approach? Dr. Dionisia Quiroga: I do. I do use them concurrently. If a patient is eligible for adjuvant olaparib, I would use it the same way as if they were not on pembrolizumab. That being said, there are no large studies currently that have shown what the benefit or the toxicity of pembrolizumab plus olaparib are for early-stage disease. However, we do have some safety data of this combinatorial approach from other studies. For example, the phase 2/3 KEYLYNK-009 study showed that patients with advanced metastatic triple-negative breast cancer who were receiving concurrent pembrolizumab and olaparib had a manageable safety profile, particularly as the toxicities of these drugs alone don't tend to overlap. Dr. Jasmine Sukumar: And what about endocrine therapy for those that also have hormone receptor-positive disease? Dr. Dionisia Quiroga: Adjuvant endocrine therapy should definitely be continued while patients are on olaparib if they're hormone receptor-positive. An important component of this will also likely be ovarian suppression, which should include recommendation of risk reducing bilateral salpingo oophorectomy due to the risk of ovarian cancer development in patients who carry BRCA1/2 gene mutations. In most cases, this should happen at age 40 or before for those that carry a BRCA1 mutation, and at age 45 or prior for those with BRCA2 mutations. Dr. Jasmine Sukumar: And do you also consider adjuvant bisphosphonates in this context? Dr. Dionisia Quiroga: Yes. Like adjuvant endocrine therapy, adjuvant bisphosphonates were also instructed to be given according to standard guidelines in the OlympiA trial, so I would recommend use of bisphosphonates when indicated. You can refer to the ASCO Ontario Health Guidelines on Adjuvant Bone-Modifying Therapy Breast Cancer to guide that decision in order to utilize this due to multiple clinical benefits. It doesn't just help in terms of adjuvant breast cancer treatment but also reduction of fracture rate and down the line, improved breast cancer mortality.  Dr. Jasmine Sukumar: Particularly in hormone receptor-positive breast cancer, another adjuvant therapy option that was not available when the OlympiA trial started are the CDK4/6 inhibitors, ribociclib and abemaciclib, based on the NATALEE and monarchE studies. So how do you consider the use of these adjuvant therapy drugs in the context of olaparib and BRCA mutations? Dr. Dionisia Quiroga: Yeah, so we are definitely in a data-free zone here. And that's in part because the NATALEE and the monarchE studies are still ongoing and reporting data out at the same time that we're getting updated OlympiA data. So unlike some of our other adjuvant treatments that we discussed, where olaparib could be safely given concurrently, the risk of myelosuppression and using both a CDK4/6 inhibitor and a PARP inhibitor at the same time would be too high. In some cases, even if a patient has a BRCA1/2 mutation, they may not meet that specified inclusion criteria that OlympiA set for what they consider to be high-risk disease. And we know from the NATALEE and the monarchE trial there are also different markers that they use to denote high-risk disease. So it's possible, for example, in the NATALEE trial that looks specifically at adjuvant ribociclib, they included a much larger pool of hormone receptor-positive early-stage breast cancers, including a subset that did not have positive axillary lymph nodes.  In cases where patients would qualify for both olaparib and a CDK4/6 inhibitor, I think this is worth a nuanced discussion with our patients about the potential benefits, risks and administration of these drugs. I think another point to bring up is the cost associated with these drugs and the length of time patients will be on for, because financial toxicity is always something that we should bring up with patients as well. When sequencing these in high-risk disease, my practice is to generally favor olaparib first due to the overall survival data. There is also some data to support that patients with BRCA1/2 germline mutations may not respond quite as well to CDK4/6 inhibitors compared to those without. But again, this is still outside of the purview of current guidelines. Fortunately, we have more potential choices for patients, and that's a good thing, but shared decision making also needs to be key. Dr. Jasmine Sukumar: And while our focus today is on adjuvant treatment for people who carry germline BRCA mutations, what about other related gene mutations such as PALB2 pathogenic variant? Dr. Dionisia Quiroga: That's a great question. Clinical trials in the advanced metastatic setting have shown that there is efficacy of olaparib in the setting for PALB2 mutations. This is largely based on the TBCRC 048 phase 2 trial and that provided a Category 2B NCCN recommendation for patients with these PALB2 gene mutations. However, we're really still lacking enough clinical data for use in early-stage disease, so I don't currently use adjuvant olaparib in this case. I am definitely eager for more data in this area as the efficacy of PARP inhibitors in PALB2 gene mutations is very compelling. I think also, in the same line, there's been some data for somatic BRCA1/2 mutations in the metastatic setting, but we still have a lack of data for the early stage setting here as well. Dr. Jasmine Sukumar: Thank you Dr. Quiroga, for sharing your valuable insights with us today on the ASCO Daily News Podcast. Dr. Dionisia Quiroga: Thank you, Dr. Sukumar. Dr. Jasmine Sukumar: And thank you to our listeners for your time today. You'll find links to the studies discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers:   Dr. Dionisa Quiroga @quirogad @quirogad.bsky.social Dr. Jasmine Sukumar @JasmineSukumar  @jasmine.sukumar.bsky.social Follow ASCO on social media:  @ASCO on X   @ASCO on Bluesky    ASCO on Facebook    ASCO on LinkedIn    Disclosures: Dr. Dionisia Quiroga:  No relationships to disclose Dr. Jasmine Sukumar: Honoraria: Sanofi (Immediate Family Member)  

In the latest episode of the Dads with Daughters podcast, we had a heartfelt and enlightening discussion with Kevin Lavelle, co-founder and CEO of Harbor. Kevin shared his experiences and reflections on raising two healthy children—an 8-year-old son and a 6-year-old daughter—while managing the demands of a thriving career. Kevin emphasized the importance of being present for his children despite the time constraints of being an entrepreneur. He has found fulfillment in volunteering as a soccer coach for his son and accompanying his daughter to gymnastics. His philosophy of being "appropriately selfish" underscored the necessity of self-care to be effective in caring for one's family. The Fleeting Nature of Childhood Both Kevin and our host, Dr. Christopher Lewis, resonate on how quickly time passes with young children. Recounting poignant moments like the birth of his son and profound moments in his entrepreneurial journey, Kevin appreciated the urgency of cherishing every moment with family. He shared a personal anecdote about working on a term sheet in the delivery room, highlighting the blend of work and personal life that many modern parents experience. This understanding deepened after a personal loss—his wife's mother—which reinforced the irreplaceable value of family time. Dr. Lewis echoed this sentiment, encouraging fathers to prioritize building strong relationships with their children over work commitments. Challenges of Modern Parenting Kevin tackled the complex challenge of raising respectful and capable children in today's world. He discussed the necessity of discipline, the influence of external factors such as peers and media, and the struggle of maintaining different parenting standards than others. Kevin and his wife take pride in their children's respectful behavior in public, yet they find themselves constantly correcting behaviors influenced by their environments. Dr. Lewis and Kevin also explored the concept of “deprogramming,” or correcting behaviors developed when children are outside the home. This underscores the dynamic landscape parents must navigate to maintain their values. Promoting Healthier Families Through Better Sleep A significant portion of the podcast focused on Kevin's venture, Harbor, which aims to improve parental well-being through better sleep. Inspired by his own experience with sleep deprivation, Kevin developed a product integrating professional guidance and innovative technology. The system offers a reliable baby monitoring solution, avoiding common issues with existing products, and introduces a concept of a remote night nanny service. This service is designed to be affordable and leverages professionally trained nurses to help parents manage nighttime challenges, ensuring better sleep for all family members. Fatherhood's Essential Bonds Kevin concluded by sharing his views on fatherhood—emphasizing a connection, love, and support as the bedrock of raising well-rounded children. He credited his own parents, his wife, and his children as his inspiration, and he offered advice to fellow fathers: Enjoy spending time with your children and cherish the fleeting nature of childhood. Parents today face numerous challenges, but as Kevin's journey illustrates, with mindfulness, appropriate self-care, and innovative solutions, the joys of parenting can indeed be balanced with professional success. For those seeking additional support, the podcast encourages engagement with resources like the Fatherhood Insider and the Dads with Daughters community. For Fathers, By Fathers: A Beacon of Support Dads with Daughters remains committed to helping fathers navigate the beautiful complexities of raising daughters to be strong, independent women. Tune in for more inspiring stories and practical advice from fathers like Kevin Lavelle.   TRANSCRIPT Dr. Christopher Lewis [00:00:05]: Welcome to dads with daughters. In this show, we spotlight dads, resources, and more to help you be the best dad you can be. Dr. Christopher Lewis [00:00:15]: Welcome back to the Dads with Daughters podcast where we bring you guests to be active participants in your daughters' lives, raising them to be strong, independent women. Really excited to have you back again this week. As always, every week, I love being on this journey with you. You and I are walking on this path to help our daughters to be those amazing women that we want them to be as they get into their adult years, and it's a process. It's definitely a process that we walk through to be able to be that dad that we wanna be and to be engaged and to be present and to be there for our daughters as they get older. And you don't have to walk that alone. That's why this podcast exists. It's here to help you to walk alongside other fathers that are either going through the process right now, have gone through the process, or other individuals that have resources that can help you again to be that dad that you wanna be. Dr. Christopher Lewis [00:01:12]: Every week, I love being able to bring you different guests, different people with different experiences that are fathering in different ways. And today, we got another great guest. Kevin Lovell is with us today, and Kevin is the cofounder and CEO of Harbour. It is a company that we're gonna learn more about today. But I love their tagline, we create happier parents and healthier families one restful night at a time. And how many of you remember, especially those young first few years when you felt like a zombie? I'm just going to put it plainly, and you felt like you were not getting any sleep, and probably you weren't getting a lot of sleep. But we're going to talk about this venture that he has been on for the last few years and what he's doing. But first 1st and foremost, we're gonna learn about him as a dad. Dr. Christopher Lewis [00:01:58]: So I'm really excited to have him here. Kevin, thanks so much for being here. Kevin Lavelle [00:02:01]: Thank you. A great opportunity. Dr. Christopher Lewis [00:02:02]: Well, Kevin, it's my pleasure having you here today. And one of the things that I love doing first and foremost is turning the clock back in time. And I know you've got 2 kids. We're gonna focus on your daughter today, but I know you've got a son as well. You got an 8 year old son and a 6 year old daughter. So you had your son first. Now I wanna go back to that first moment that you found out that you were going to be a father to a daughter. What was going through your head? Kevin Lavelle [00:02:26]: Really fun memory. My my wife and I, our son was a little over I don't know. He was maybe 16 months old when we found out we were going to have another child, and we both did that thing. And and I think we meant it. Then we said, you know, whether it's a boy or a girl, it doesn't matter. We're just gonna be so happy that, you know, have another. And to each their own, I wasn't into a big gender reveal party, but I did think it would be fun to learn together. And so we had her doctor email the results to someone on my team at Mizzen and Maine, and I asked him to go get flowers, you know, pink for a girl, blue for a boy, and put them in our garage so that when I came home, I was traveling, I could bring the flowers covered in a trash bag into the house and we could look at them together because my wife loves flowers. Kevin Lavelle [00:03:14]: That was the way that we were gonna learn together. And right as I was about to pull into the garage, I just had this overwhelming thought, god, I hope it's a girl. And, you know, I didn't I hadn't said anything. And right as I went to pick the flowers up in our garage, they basically kind of fell open, and I saw it was pink. And I was just overcome with joy, and I had to pretend that I didn't know. But I walked in and I opened it up, and my my wife was, absolutely overjoyed as well. And at the time, my my first company was an apparel company, so my my colleague had also put a pink shirt in there, one of our pink shirts as a company. So that was a fun way to tie that together. Kevin Lavelle [00:03:54]: And shortly after she learned it was a girl, she said, I really wanted it to be a girl. And I was like, I did too. And by the way, I found out in the garage. And so, a very fond memory, not just learning that it was going to be a girl and and, you know, knowing that we now had a son and a daughter, but, a very memorable time in our lives. And it was a very rough pregnancy for my wife. And I don't know how true this is or an old wives tale that, you know, when it's a girl, they they suck all the pretty and all the life out of you because they're they're bringing it into themselves. And we were joking because it was a much rougher pregnancy with my daughter than my son. So we we we kind of felt it might have been a girl. Dr. Christopher Lewis [00:04:30]: Now I talk to a lot of dads, and a lot of the fathers talk about the fact that they are that there is fear going into being a father to a daughter. Whether found or unfound, it's there. So as you think about the years that you've had with your daughter thus far and you think about your own experiences, what's been your biggest fear in raising a daughter? Kevin Lavelle [00:04:53]: The most direct fear as she gets older, women are more vulnerable in society and all of history than men. That's just the nature of humanity and the nature of life. And so, higher fear that she could have something terrible happen to her than to my son. Although, as parents in an ever crazier and changing world, certainly, the fear exists, for both of them. But my focus, and my wife and I have the same belief, is help our kids there's a phrase, prepare the child for the road and not the road for the child. And I see it so often, especially in some of the schools that we have been in. Whether it's parents or teachers or both, they want to make sure that everything is perfect for their child rather than, how do I make my child resilient and capable of addressing whatever it is that life will bring to them. And so, everything that we can do to make them more resilient and just prepared and understand the risks that exist in the world while not being afraid of the world. Kevin Lavelle [00:05:52]: You could hide out real easily and miss out on a lot of the wonderful things that life has to offer. And and we want them to face the world with head held high and and know what they're capable of. Dr. Christopher Lewis [00:06:02]: Now you're a busy guy. You're a CEO, entrepreneur. You have been involved with a couple of ventures and a couple of companies in your time as a father. And it not only takes time, effort, but it takes balance. So talk to me about what you've had to do to be able to balance all that you're doing in starting and creating a new company, but also in trying to be that engaged father that you wanna be. Kevin Lavelle [00:06:30]: There are lots of people much more smarter and accomplished than me than that probably have lots of specific tips and tricks. But I'll say the thing that has resonated or or stuck with me the most is accepting that I will never get it all done. And I could work round the clock and miss out on life in front of me. We lost my wife's mother now about a decade ago. And that was very young to lose her. And just understanding that life is very short and very precious. And so don't miss out on don't miss out on what's in front of you. And the age old adage, the nights are long, especially when it comes to sleeplessness in those early years, but the years are short. Kevin Lavelle [00:07:10]: And I had quite a few people say that to me when my kids were, you know, 6, 9 months old. And you're not sleeping. And it is a level of exhaustion. Even if your kids are doing well sleeping through the night, it's just so all consuming and difficult and everything is new and stressful. Sometimes, when people tell that to you in that time of life, you're like, thanks. That's super helpful. I'm barely making it in a given day. But just continuing to come back to how fortunate we are. Kevin Lavelle [00:07:35]: We have 2 healthy kids. That is in and of itself a miracle. And then, prioritizing as much as I can. I've been volunteer soccer coach for my son, taking my daughter to her gymnastics classes, and just trying to soak up the time with them because it's moving very quickly. And there's never going to be enough hours in the day to do all the things that I want to do. But making sure that when I'm with them, try to be as as present as possible. I could talk about this for hours, but those would be the biggest things that that really stand out to me. And then, I think I'd also just add, with that said, I heard a Naval Ravikant years ago podcast with somebody was saying that he does a good job of, I think in his own words, he said being appropriately selfish. Kevin Lavelle [00:08:18]: And it comes down to this analogy of put your own oxygen mask on first. If you're not sleeping and eating and taking care of your body and your mind, then you can't take care of your family. You can't be there for them. You can't be a leader. And so, I think some people end up losing sight of that and forget that they still need to have some fun. They still need to take care of themselves. They need to get sleep. Then they need to be able to sit down and read a book or chat with friends. Kevin Lavelle [00:08:44]: And and you it is very easy to lose sight of that, especially in the days of of of young kids. And ultimately, looking at some of my friends whose kids are a bit older, and they're starting to adjust to the fact that they don't spend much time with their kids anymore even though they still live at home. And so that window of time is is very short. Dr. Christopher Lewis [00:09:02]: It is very short. And as your kids get older, you look back and say, dang it. Because, hopefully, you have taken the time to be able to build those really strong relationships, spent the time, and not focus on work or not focus on the things that you think are important at the time to be able to provide for your family, but what you come to find. And I see that even though I've been a very engaged father throughout my entire kids' lives. But as you get into the teenage years and they start pulling away, and you're not able to have as many opportunities to be able to connect and engage on a regular basis, you treasure the moments that you do have to be able to create those opportunities and have those opportunities. And they look and feel a little bit different, But you definitely want to grab them, hold them, and keep doing those things with them when they give you that opening to do it. Now I asked you about if there were any things that you were afraid of and fear in that regard. But being a parent is not always easy. Dr. Christopher Lewis [00:10:07]: We just talked about and we'll talk more about the fact of sleep and the importance of sleep. But it's not always easy to be a father to a son, a father to a daughter. What would you say has been the hardest part for you in being a father to a daughter? Kevin Lavelle [00:10:21]: If I had to sum it up, I think overall, I would pick up 2 different angles to this. And I can hone in on it being daughter specific and also being a father specific. It's not specifically daughter related, but it is very much a central struggle to being a parent. And it's something that I see, I don't say this on a high horse, but it's something I see a lot of other parents neglect. And I can see it coming back to bite them, which is raising good, capable kids who are respectful and that you want to spend time with is there's a pretty significant amount of time that is frustrating and you have to be, you have to be the parent. You have to be the adult. You have to be the rule enforcer. You have to constantly give feedback and it's frustrating and it's challenging. Kevin Lavelle [00:11:03]: But when you don't do that, each passing day, week, month, and year, it's harder to raise good, respectful kids that are capable and, you know, you want to spend time with. Jordan Peterson, I think it was in his 12 Rules For Life, talked about you don't let your kids do things that make you like them less because you love them more than anyone else in the world. And if you let their bad behavior go, their obnoxious behavior, even annoying tendencies, if you don't help them correct those, well, guess what the rest of the world's gonna do? They're not really gonna like them either. They're not gonna want to engage with them. They're not gonna want to be friends with them. They're not gonna wanna help them, mentor them, etcetera. And so I think about this a lot, especially when I have those frustrating conversations or interactions that I have to work very hard to help them grow and flourish. And that means I'm bearing a lot of the brunt of that so that they, in the rest of the world, have people like them and want to be around them. Kevin Lavelle [00:12:01]: And one of the things that my wife and I are most proud of on an ongoing basis is when people are around our kids, they are genuinely surprised at how wonderful they are to be around. They're very respectful. We can go to very nice restaurants with them without an iPad. And they do great. And that I don't know how many times we went to a restaurant where it wasn't awesome before it started to be good. And now, it's great. And so, you know, I think with that, that is not necessarily daughter specific. I'll go with now daughter specific. Kevin Lavelle [00:12:33]: And the other key piece here is you don't raise your kids in a vacuum. And our kids go to school with other kids whose parents are fine with different approaches to language and respect and electronics and vanity and spending. And there's a when our kids spend time with certain kids, they come home with very annoying or inappropriate kind of phrases or responses. And it's getting a little bit better because they know what, they tend to understand more of what's right and wrong and what is and isn't acceptable. But when they are in school all day or they spend time with certain kids, they come home with things that we have to then work to correct. And it's not a huge problem. But, you know, when you send your kids out into the world, you have to remember they're out in the world without you. And that's why it's so important to build those innate characteristics. Kevin Lavelle [00:13:25]: And especially on the little girl front, some parents have no problem with makeup and music and things that are just not appropriate for my daughter's age. And then she's struggling with this back and forth of, well, I see my friends do it and their parents are okay with it. And you have to say, while being respectful, you can't really say, well, those are not good parents in our view. Because there's a way to say that that inspires better decision making. And there's a way to say that that could make them look down upon or feel differently about folks. That's that's not not helpful. People can parent hard, but they want to parent. My job is to take care of my kids. Dr. Christopher Lewis [00:14:03]: Well, and the other thing that I think that all of us have to understand is that each of us come into parenting without a rule book, without a guide book. And depending on the model that you saw in your own experience as a child yourself, the other parents that you surround yourself with, you start to identify and create ways in which you parent based on those. And sometimes parents don't realize what they're doing or are not doing, and unless someone points it out to them as well. But I completely understand what you're saying because sometimes you do have to do that deprogramming with your kids when they get back into your home or if they've spent time even when they go to grandparents and they come home, and the rules are different there. And then they come back and are like, well, grandma and grandpa said it was okay, so why not here? And you have to deal with that as well. So I completely understand what you're saying in that regard. Now we've been talking and kinda hinting about the importance of sleep. And as I mentioned at the beginning, you are the CEO and cofounder of Harbor. Dr. Christopher Lewis [00:15:11]: It is a organization company that is working to create happier parents and healthier families, as I said, one restful night at a time. And I remember those days with both my kids feeling like a zombie when you're trying to go to work, and you're coming home, and, you know, you're getting a few hours of sleep. And, you know, those things are very challenging, and those those days and nights can be long. And that being said, I wanted to ask you about Harbor because, like you said, you spent quite a few years at Mizzen and Main, which is a clothing company. And you pivoted after this to open your own organization and create your own company in that regard and beyond what you did at Mizzen and Main to something completely different. So talk to me about that origin story of Arbor. And what made you decide to move away from clothing and move toward something that we're talking about in regards to helping parents to get better sleep, to be able to stay connected with their children, and be able to create this new product? Kevin Lavelle [00:16:17]: So when my son was born, it was a very memorable time in my life. Also, similar to that very visceral memory of finding out my second was gonna be a girl. We were in the throes of fundraising for Mizzen and Maine. We were assigned the term sheet with our private equity firm in the delivery room for my son. And I remember pieces of that very vividly. And one of them was, I'm not the person who's going to decide the car seat or the stroller. I was helpful with my wife there where she wanted me to. But I'm more of the tech person, and I did a lot of research. Kevin Lavelle [00:16:49]: And there was a company called Nanit that had a lot of recognition and press about their very innovative baby monitor. It's a Wi Fi camera with an app on your phone. And I thought, oh, that's really neat. I like apps on my phone. That's convenient. But while someone was a couple, I don't know, weeks or months old, I can't remember the exact date that it happened. And he was in his own room. And I woke up one morning and the app on my phone, because you have to sleep next to your phone, which I don't like doing to begin with, but you have to sleep next to your phone so the app audio runs in the background. Kevin Lavelle [00:17:18]: The app had just crashed. And look, apps crash. They're not a 100% reliable. And I panicked and ran across the house. And, of course, he was fine. Kids are more resilient than we give them credit for. But it was a very alarming realization that this thing that I'm supposed to be able to rely on, you I can't. And so we went out that day and bought an old school Motorola camera and an old school Motorola monitor that was direct local only communication. Kevin Lavelle [00:17:46]: It does not use the Internet in any way, shape, or form. But we kept a Wi Fi camera. I got rid of the Nanit and ended up just using a Google Home device, a Nest camera, because my wife and I worked together at Mizzen and Maine. And when she came back to work, we wanted to be able to check-in on the nanny with a babysitter. You just you wanna be able to know. And not that I wanna be monitoring 20 fourseven, but technology is supposed to make our lives better. And there have been a lot of promises that have largely failed to deliver for parents. So this idea of why do I have 2 separate systems to be able to just know that I'm monitoring my kid and record and rewind and check out from outside the house? I talked to a lot of parents over the last 8 years and just sort of getting feedback and wondering what they were using. Kevin Lavelle [00:18:32]: And I found out that 20 to 30 plus percent of my friends did the same thing that I did, was have multiple systems. And in an industry and in a time of life when parents want the best for their kids, baby registries are between $3 and probably $15,000 worth of products as a first time parent. Cribs and strollers and car seats and multiple strollers and formula and and pumps and on and on and on and on. The best that parents have to offer or the best that parents have accessible to them is hacking together multiple systems that don't communicate with each other and blah blah blah. So I wanted to solve this problem since my son was born. And so what we've built is a camera and a 10 inch monitor that connect directly to each other without Internet. And both devices also connect to the Internet. So you get the best of both worlds. Kevin Lavelle [00:19:29]: It's a dedicated device that alerts you if you lose connection. And everything connects to the Internet when it's available. So we have an app. You can record. You can rewind. You get all of those benefits and features as well. I've got one right over here. I should have had it right next to me. Kevin Lavelle [00:19:44]: But it is a 10 inch monitor. So you can actually watch up to 4 different streams on one screen. You can control the zoom and the volume of each independently. There's nothing like that that exists today. And I can tell you, however bad the experience was with a Wi Fi camera with 1 child with 2, it's it's almost impossible on a tiny little iPhone screen. And we can watch up to 4. And then we put privacy first. So our camera and our tablet are both built outside of China. Kevin Lavelle [00:20:10]: They're both built with non Chinese silicon. The chips inside the device is basically the thing that powers it from a processor perspective. And then the chip in the camera is able to do all of the advanced analytics and kind of signal to noise sorting that makes our product really unique on the device locally. Meaning, it does not go through our cloud to process your information. And the the best way to think about that is like on a self driving car on a Tesla, they have cameras that process everything locally. Because if you had to send to the Internet, is that a red light or a green light? Obviously, that's not very safe from a decision making time frame. And then we also put a memory chip in the camera. So all of your memories are stored locally on the device itself. Kevin Lavelle [00:20:52]: If you wanna use our app, obviously, if you're outside the house, you will access it, and that will be remote. We're not storing it. We're not processing it. Unlike every other Wi Fi camera that exists, you are paying them to store your footage on their cloud. And in many cases, third party clouds that may not have the same level of security that you would expect. So very unique device, very unique monitor. We've really positioned ourselves as something that does not exist today for parents and started shipping mass production units to customers in September of 2024. And it's going great so far. Kevin Lavelle [00:21:24]: We've shipped thousands of devices in just a few months. And then the other thing I'll touch on very briefly for framing is that's exciting and and we think a game changer for parents. And it's been very well received. But we are using it as the foundation for what we have called a remote night nanny. So if you can afford it, an in home night nanny or night nurse is one of life's greatest blessings. It's also unaffordable for almost everybody. And a lot of people who can afford it don't want someone else in their house, or they heard a horror story and they don't feel comfortable with it. Or even if they can afford it, they can't really find someone that they would trust to come in and help take care of their child. Kevin Lavelle [00:21:57]: And the main purpose of an in home night nanny is they will listen to your baby monitor in another room, and they will go in when it is necessary and appropriate to go in. So if your child starts to fuss or cry a little bit, they'll look at the monitor. Okay. Nothing's wrong. And they basically start a timer and they wait 5, 10, 15 minutes depending on age and stage. Because if you hear a child cry and immediately run-in, you delay their ability to learn how to sleep because sleep is a skill. Just like talking and walking, you have to kind of fumble through it and you and you find your way and you develop the skill of sleeping. There's a lot of really bad information out there on the Internet about sleep. Kevin Lavelle [00:22:36]: And sleep experts, legitimate ones, know you have to help the child learn how to sleep. And so, the challenges in home night nannies, if you can find 1, are $300 to $700 a night depending on where you live in the country. And it's very hard to find them as well. So, what we're doing is because we have built the hardware, after you onboard into our system, you can hire our professionally trained night nurses remotely. You press a button on the monitor, sort of like arming an alarm system, and that turns over the controls of your monitor to our professionally trained night nurses. We turn the volume on your monitor down to 0 all night long and only wake you up when a professionally trained night nurse says it's time to go in. So if something is wrong, like something falls in the crib or the baby's arm gets out of the swaddle and gets stuck in the crib slot, we're gonna wake you up immediately. Otherwise, we're gonna start the timer and we're going to wait until it is time for you to go in. Kevin Lavelle [00:23:33]: And what we have found is the 1st night, parents are adjusting to, okay, this is a little different and a little a little new. But the 2nd night, parents are telling us they've things like, I haven't slept this well since my 1st trimester. And that's because it's not just that I'm not hearing something. Because you may not go in all night long, but your child is going to make noises all night long. Kids make a lot of noise. And if you don't remember it, good for you. That's fortunate. But kids can fuss and cry off and on for hours. Kevin Lavelle [00:24:03]: Now, they're still getting sleep in between, but you're not as a parent. But what we're finding is parents are telling us, especially moms, to have a professional be the one that is helping me know when to go in rather than that anxiety and that guilt and that shame that comes with being a parent and not knowing what to do, It allowed me to really actually get deep, restful sleep for the first time in a long time. And because we have built the hardware, we have a lot of fail safes built in, the system just turns itself back on if it loses connection, And we're hiring professionally trained nurses so that we can have 1 nurse work with multiple families at the same time and bring the cost down to about 5% of the cost of an in home night nanny. So that's Harbor. A lot more to talk about there, but that's a good good roundup of what we've built here. No. Dr. Christopher Lewis [00:24:51]: It sounds like an amazing product, and I have not used it, and I don't need it now. And my kids would be really weirded out if I was using it at this point in their lives. But that being said, when they were very young, this sounds like a game changer. Now one question that I had when you were talking about the technology and, you know, how you had your app and that you were trying to keep it on a phone and and that it was running and then lose power and you you know, all of that story that you told. With your system, are you running off of your Wi Fi in your home, or are you running off of the Wi Fi off your phones? Because if the power goes out, then, you know, how does that all work? Kevin Lavelle [00:25:31]: Yeah. So a couple of points on the technical side. The camera and the monitor or multiple cameras are going to run off your home Wi Fi when it is strong and available. If you don't have Wi Fi, so as a point of comparison, if you have one of these Wi Fi baby monitor systems and you travel to a hotel, you can't use it because hotels will not let you tap your devices onto their Wi Fi. You can put your phone on it, but you can't run your devices on their networks from a security perspective. So the message boards online are full of parents who said, you know, just got to our hotel and realized I can't use my Nanette. I can't use my Owlette. And I had to run to Walmart to get a baby monitor because, you know, get adjoining rooms. Kevin Lavelle [00:26:11]: You gotta be able to look in. And so the camera and the monitor, one camera and one monitor, creates its own Wi Fi signal to communicate directly with each other while not requiring a separate Wi Fi network. So it has direct local communication that doesn't require the Internet. But when you're at home and your your routers are appropriately configured and and everything is running, it will just run through your home home Wi Fi. And one of the benefits there is home Wi Fi tends to be stronger. You've got it across the entire house. And our that feed does not leave your home. So if it's running on your home WiFi, it does not leave your home. Kevin Lavelle [00:26:50]: Again, we are not swearing or processing anything. If your router goes down, if your Internet goes down, then your camera will fail over to direct local communication. So when it's running through your home WiFi, it's saying, okay. I'm running through home WiFi. I've got good signal strength. All of that's measured. When it can't find that home WiFi or it's not working, then it says connect directly to the monitor. Now with a power outage, at that point in time, if you were running an app on your phone, the camera is going to fail because no baby monitor cameras come with batteries. Kevin Lavelle [00:27:23]: I'll say none. Virtually none do because batteries are a severe fire risk, especially if it's running 247. And that's why, generally, you will not see batteries in cameras in homes. And so if there's a power outage, you wouldn't necessarily be notified if you're just using a WiFi camera. But our monitor would know, hey, I've lost connection with that camera because the cameras no longer has power. I'm going to alert the parents that there's no longer a connection. Now, that doesn't mean you can do anything about it because you don't have power in your house. But now you know, and you can choose to maybe open the doors so that you can still hear, maybe bring the crib into your room. Kevin Lavelle [00:28:02]: That's then a parental decision on what happens next. But the important thing is we empower parents to know what's actually happening. Dr. Christopher Lewis [00:28:09]: And about the night nurses, tell me about how do you identify these individuals? What type of background do they have? How are they trained to be able to provide that kind of service for families? Kevin Lavelle [00:28:18]: So we're recruiting actual nurses who have worked in pediatrics, whether in offices or hospitals. And then in some cases, they have in home night nursing experience where they have worked with families and homes. And in other cases, they just have pediatrics medical experience. And then we are training them from our professionally trained night nursing staff. So, our director of nursing has worked for years in hospitals. She was a pediatric oncology nurse. She worked as an in home care manager and as an in home night nurse. She's a Hmong herself. Kevin Lavelle [00:28:49]: And so she is working with one of our advisors and our team on training those nurses that we're bringing in. Dr. Christopher Lewis [00:28:56]: And as you said, those in home nannies or nurses that you might have inside your home can be very expensive. What's the price point on not only your system, but having this type of monitoring with night nurses to be able to assist parents? Kevin Lavelle [00:29:09]: To buy our camera and our monitor and all of our features, we do not require subscriptions or additional payments. You buy a camera and a monitor, you get everything forever. It's $599, which puts us as roughly price comparable to all the other leading systems on the market today because they require annual subscriptions. And then the remote night nanny experience, right now, is about $30 a night. You have to buy kind of packages of nights, and it works out to about $30 a night. And our long term vision is to get the cost down to $20 a night. Once we have enough people in the system and we can hire the staff and have the systems capable of working with many more families at the same time, we will continue to pass those cost savings on to our customers. And it's kind of cool. Kevin Lavelle [00:29:51]: At $20 a night, you could do 3 months of the remote night nanny for the same cost of about 1 week of an in home night nanny. And so we like to say 95% of the benefit and 5% of the cost of an in home night nanny. Dr. Christopher Lewis [00:30:06]: Well, it's a great value for families and definitely gives families peace of mind in regard to being able to be if you are sleeping and you get that good sleep, you're going to be able to be more present and be able to be much more attuned to what your child needs versus trying to struggle through with the lack of sleep that many parents get, especially for the 1st 6 months, 8 months, year, or more, depending on your child, that sometimes you run into. Kevin Lavelle [00:30:37]: Yeah. I mean, there's a lot of different studies and research, but very significant percentage of couples who get divorced say sleeplessness in the early years of childhood was a major contributing factor. The reality is a lack of sleep contributes to or exacerbates postpartum depression. It has very significant immune system impacts, durability, even to be a safe driver. When you are sleep deprived, whether you have a child or not, sleep deprived drivers can be even more dangerous than drunk drivers. And so, there's a lot from the adult side. And then on the child side, we make a big difference for parents. But on the other side, our monitor system is the kind of help parents and kids get more sleep. Kevin Lavelle [00:31:14]: That's the fundamental nature of our system relative to everything else. The single best thing that you can do for your child is obviously make sure they have appropriate nutrition in those early years, in early months weeks years. The second best thing that you can do for them is make sure that they are getting the appropriate amount of sleep on a consistent basis. And that is really hard to do for most parents for a whole host of very obvious reasons. And so, when you think about a well rested child, certainly, we can imagine they are more pleasant to be around. But from a mental development perspective, from a dysregulation perspective, from an immune system perspective, from a physical health development perspective, all of those, you have to have the right nutrition and you have to have the right sleep. And if you are not supporting your child's ability to sleep through the night, you are very much hampering their health and well-being and development. And I'll say one final note on sleep. Kevin Lavelle [00:32:11]: There are some very bad influencers and sleep gurus that will tell you the minute your child is crying, you need to be in there holding their hands and they will feel abandoned. Science has disproven this again and again and again. And similar to this idea of put your own oxygen mask on first, when moms don't get sleep, the propensity for postpartum depression absolutely skyrockets for all the obvious reasons. And when a mom has postpartum depression, it has a very significant impact on her ability to feed her child, nurture her child, love her child. It's a very difficult thing to go through. Obviously, there's no way that I could go through it, but it is a very understandable position that moms find themselves in. And so, these influencers and sleep gurus who, you know, propagate very bad sleep ideas, they're really harming parents' ability to get the right information and support their their families. And so, our focus is how do we help parents who want help? I'm never going to tell a parent, you're doing it wrong. Kevin Lavelle [00:33:15]: Every parent is responsible for raising their own child and we all have our own way. However, most parents are struggling and need some help. And we are here to provide very clear, unambiguous, science backed information. And we do that for free. At our website, harbor.co, we have a ton of free resources. And our mission is happier parents and healthier families. And so, we have a lot of free resources on our website. If you don't want to buy our baby monitor for any number of reasons, that's fine. Kevin Lavelle [00:33:41]: There's still a lot of great resources that you can find. And we have opportunities for parents to sign up for text based sleep coaching. If they just want to text a nurse and get some help, it's a very affordable $30 a month. You don't have to sign up for big hour long sessions or sign up for our full system, although we offer those as well. Dr. Christopher Lewis [00:33:58]: Well, Kevin, I wanna say thank you for sharing all of that. If people wanna find out more about your system, the night nanny services, or anything else, where should they go? Kevin Lavelle [00:34:10]: Harbor.co. And you can find us on on the socials at harbor sleep. And we have so many great resources there. We have very robust sleep guides for infants and also toddlers. We have also formed a harbor council of pediatric sleep doctors, postpartum counselors, pediatricians, OB GYNs that have written many articles for us. And our goal is if you have a question as a parent, we don't have all the answers yet, but we have pushed a lot of great content for free online to be a great resource for parents as they need it. Dr. Christopher Lewis [00:34:45]: Now we always finish our interviews with what I like to call our fatherhood 5, where I ask you 5 more questions to delve deeper into you as a dad. Are you ready? Yes. In one word, what is fatherhood? Kevin Lavelle [00:34:55]: Joy. Dr. Christopher Lewis [00:34:55]: When was the time that you finally felt like you succeeded at being a father to a daughter? Kevin Lavelle [00:35:01]: I don't think I could point to, like, we were at a theme park or we were at a restaurant. To me, it's those moments where my daughter would look at me, come home from work, come home from traveling, I'm tucking her in at night. And I just see that look in her eye that says, you are my safety, you are my home. The level of connection and love there, that success is a dad. Dr. Christopher Lewis [00:35:24]: Now if I was to talk to your kids, how would they describe you as a dad? Kevin Lavelle [00:35:28]: I believe they would say fun, strong, great. And those are the things that that I hope that they would say at their ages with their vocabulary. Some of the kind of underlying things would be that I'm supportive, that we have a lot of fun together. We laugh, chase them around the house, and that they still really want to spend time with me. They've got friends, but generally, they'd rather spend time with my wife and I than anyone else. Dr. Christopher Lewis [00:35:54]: Now let's go 10 years down the road. What do you want them to say then? Kevin Lavelle [00:35:57]: As I think about this phase of life, we no longer have little kids. They're not toddlers, and they go to school full time. And my wife and I have talked about, like, we did it. We got out of the the infant and toddler and very young kid phase as best as we possibly could have. We have wonderful kids. They're respectful. They're resilient. They like to learn. Kevin Lavelle [00:36:22]: They like to have fun. They're great kids. Now, we need to prepare them to be teenagers. And so, what would I hope to feel like at that point in time? That whatever it is that our kids want to do, whether they want to go to college, whether they want to pursue a sport, whatever it is. That they are ready to go face the world and they are as prepared as they possibly could be. As I said, prepare the child for the road. And that they truly understand, as best as a, you know, 18 year old can, what it means to be happy. That they will not chase the superficial. Kevin Lavelle [00:36:54]: That they will chase the core, the meaningful, the spiritual in whatever way that is for them. Dr. Christopher Lewis [00:37:00]: Now, who inspires you to be a better dad? Kevin Lavelle [00:37:03]: Certainly, I feel like I won the parent lottery. My parents raised me right. And I felt my whole life the appropriate balance of support and safety, but also go forth and conquer. My wife, she is an absolutely incredible mother, and I think a better mother than I am father. And, you know, as cliche as it is, my kids. When they show me that they want to spend time with me and that they want more of me and that they're truly grateful for the life that we have as best as young kids can, that, okay, keep going. I want to do more of it. Dr. Christopher Lewis [00:37:34]: Now, you've given a lot of piece of advice today, things that people can think about and look at ways in which they can incorporate some of those pieces into their own experience as a father. If you are talking to a father, what's one piece of advice you'd want to give to every father out there? Kevin Lavelle [00:37:50]: So for the dads that have kids older than me, I'm not sure how much advice I could give. But for those coming up behind me with with younger kids, I think it's a big part of what we talked about. Raise kids that you want to be around and that they love you. Like, that they are the kids that other people want to spend time with and that they want to spend time with you. That that kind of full circle. And if you do those two things, then you're doing all the other things right. And that's a good kind of metric or or baseline to seek. And as cliche as it is, it goes by really fast. Dr. Christopher Lewis [00:38:27]: It definitely does. Well, Kevin, I just wanna say thank you. Thank you for sharing your journey today. And as Kevin said, if you wanna find out more about him or about his company, go to harbor.co to find out more information about this amazing new technology and resource for you as you are working to be the best dad that you wanna be. Kevin, thanks so much for being here today. Kevin Lavelle [00:38:51]: Thanks for the opportunity and and for the inspiring work you do for dads. Dr. Christopher Lewis [00:38:55]: If you've enjoyed today's episode of the Dads with Daughters podcast, we invite you to check out the fatherhood insider. The fatherhood insider is the essential resource for any dad that wants to be the best dad that he can be. We know that no child comes with an instruction manual and most dads are figuring it out as they go along, and the fatherhood insider is full of resources and information that will up your game on fatherhood. Through our extensive course library, interactive forum, step by step roadmaps, and more, you will engage and learn with experts, but more importantly, dads like you. So check it out at fathering together dot org. If you are a father of a daughter and have not yet joined the dads with daughters Facebook community, there's a link in the notes today. Dads with daughters is a program of fathering together. We look forward to having you back for another great guest next week all geared to helping you raise strong and powered daughters and be the best dad that you can be. Dr. Christopher Lewis [00:39:54]: We're all in the same boat, and it's full of tiny screaming passengers. We spend the time, we give the lessons, we make the meals, We buy them presents and bring your AK. Because those kids are growing fast. The time goes by just like a dynamite blast. Be the best dad you can be. You're the best dad you can be.

JCO PO author Dr. David R. Gandara at UC Davis Comprehensive Cancer Center, shares insights into his JCO PO article, “Plasma Proteome–Based Test for First-Line Treatment Selection in Metastatic Non–Small Cell Lung Cancer,” one of the Top Articles of 2024. Host Dr. Rafeh Naqash and Dr. Gandara discuss how the PROphet® blood test supports first-line immunotherapy treatment decisions for metastatic NSCLC patients. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.  Today, we are absolutely thrilled to be joined by Dr. David R. Gandara, Professor of Medicine Emeritus, Co-Director of the Center for Experimental Therapeutics and Cancer and Senior Advisor to the Director at UC Davis Comprehensive Cancer Center and also the senior author of the JCO Precision Oncology article entitled “Plasma Proteome–Based Test for First-Line Treatment Selection in Metastatic Non–Small Cell Lung Cancer.” This was one of the top performing articles of 2024, which is one of the reasons why we wanted to bring it in for a podcast discussion. At the time of this recording, our guest's disclosures will be linked in the transcript.  David, it is an absolute pleasure to have you today. For somebody like you who's led the field of lung cancer over the years, I'm really excited that you are going to be talking to us about this very interesting article, especially given that I think you're one of the big proponents of liquid biopsies and plasma-based testing. So, for the sake of our listeners - which comprises of academic oncologists, community oncologists, trainees - could you tell us where the biomarker landscape for non-small cell lung cancer is currently, and then we can try to take a deeper dive into this article. Dr. David Gandar: Okay. Well, thank you, Rafeh. It's a pleasure to be with you here today. And I think the current landscape for biomarkers for immunotherapy in non-small cell lung cancer is a mess. There's no better way to describe it. That makes this paper describing a new plasma proteomic assay even more important. So I'll just give you a perspective. There are 14 trials, phase three trials, that were done in first line non-small cell lung cancer advanced stage of immunotherapy versus chemotherapy and some other aspects, although they vary tremendously. Some of them were checkpoint monotherapy, some combined with chemotherapy, some combined with CTLA-4 inhibitors and so forth. 12 out of the 14 were positive, 12 got FDA approval. So there are 12 different options that an oncologist could use. Some of them were squamous cell only, some non-squamous, some used PD-L1 as a biomarker driven part of the study. Some used TMB, tumor mutational burden, some were agnostic. So when you put all of this together, an oncologist can pick and choose among all these various regimens. And by and large, it's PD-L1 that is the therapeutic decision maker.  ASCO actually, I think, has done the very best job of making a guideline, and it's, as you well know, called a living guideline, it's dynamic. And it is much easier to interpret, for me and I think for oncologists, than some of the other guidelines. It's got a green light and a red light, it may be kind of orange. And so the green light means this is a strong recommendation by the guideline committee. The orange means it's weak. For this purpose, non-small cell lung cancer, advanced stage, only a very few of the recommendations were green. It's mainly monotherapy and patients with cancers with a PD-L1 over 50%. In our surveys, at our meetings, less than 50% of oncologists in the United States are following these guidelines. Why? Because they don't trust the biomarker. And TMB has the same sort of limitations. They're not bad biomarkers, they're incomplete. They're only looking at a part of the story. So that means we need a new biomarker. And this is one that, I think, the data are quite impressive and we'll discuss it more. Dr. Rafeh Naqash: Absolutely. Like you said, abundance of many therapy options, but not necessarily everything works the same in different subsets of PD-L1 positivity or different subsets of patients with different levels of tumor burden. And like you said, again, difficulty in trying to identify the right biomarker. And that's a nice segue to this PROphet test that you guys ran. So can you tell us a little bit about the plasma proteomic assay? Because to the best of my knowledge, there's not a lot of validated plasma proteomic assays. A lot has been done on the tumor tissue side as far as biomarkers are concerned, but not much on the blood side, except for maybe ctDNA MRD testing. So what was the background for trying to develop a plasma-based proteomic test? And then how did this idea of testing it in the lung cancer setting come into play? And then we can go into the patient population specifics, the cohort that you guys have. Dr. David Gandara: Okay. Well, of course there's a company behind this assay, it's called OncoHost, and I'm a consultant for them. And they came to me two years ago and they said, “We have something different from anyone else.” And they explained the science to me, as well as some other lung cancer experts here in the United States. I'm not a proteomic expert, of course, but they developed an AI machine learning platform to assess plasma proteins in normal people and in people with cancer, and specifically then in people with non-small cell lung cancer. They identified over 7,000 proteins that had cancer implications for therapy, for resistance, for prognosis, etc., and they categorized them based on the literature, TCGA data, etc., and used this machine learning process to figure out which proteins might be most specific for non-small cell lung cancer. And that's where they started. And so out of that 7,000 proteins, where they've identified which ones are angiogenic, which ones are involved with EMT or cell cycle or whatever it might be, they distilled it down to 388 proteins which they thought were worth testing in non-small cell lung cancer. And that's when I became involved.  They had a retrospective cohort of patients that had been treated with various immunotherapies. They looked at the analytic validation first, then applied it to this cohort. It looked good. Then they had a very large cohort, which they split, as you usually do with an assay, into a test set and then a validation set. For the test set, they wanted something more than a response. They wanted some indicator of long term benefit because that's where immunotherapy differentiates itself from chemotherapy and even targeted therapy. And so they picked PFS at 12 months. And I became involved at that point and it looked really good. I mean, if you look at the figures in the manuscript, the AUC is superb about their prediction and then what actually happened in the patient. And then in this paper, we applied it to a validation set of over 500 patients in a prospective trial, not randomized, it's called an observational trial. The investigator got to pick what they thought was the best therapy for that patient. And then in a blinded fashion, the proteomic assay experts did the analysis and applied it to the group.  And so what that means is some of the patients got chemotherapy alone, some got checkpoint immunotherapy monotherapy, some got in combination with chemotherapy. None of the patients in this study got a CTLA-4 inhibitor. That work is ongoing now. But what the study showed was that this assay can be used together with PD-L1 as what I would call a composite biomarker. You take the two together and it informs the oncologist about the meaning of that PD-L1. I'll give you an example. If that patient has a PD-L1 over 50% in their cancer and yet the PROphet test is negative, meaning less than 5 - it's a 0 to 10 scale - that patient for survival is better served by getting chemotherapy and immunotherapy. However, if the PROphet test is positive and the PD-L1 is over 50%, then the survival curves really look equivalent. As I said earlier, even in that group of patients, a lot of oncologists are reluctant to give them monotherapy. So if you have a test and the same sort of example is true for PD-L1 0, that you can differentiate. So this can really help inform the oncologist about what direction to go. And of course then you use your clinical judgment, you look at what you think of as the aggressiveness of the tumor or their liver metastases, etc. So again, that's how this test is being used for non-small cell lung cancer. And maybe I'll stop there and then I'll come back and add some other points. Dr. Rafeh Naqash: I definitely like your analogy of this therapy de-escalation strategy. Like you mentioned for PD-L1 high where the PROphet test is negative, then perhaps you could just go with immunotherapy alone. In fact, interestingly enough, I was invited to a talk at SITC a couple of weeks back and this exact figure that you're referring to was one of the figures in my slide deck. And it happened by chance that I realized that we were doing a podcast on the same paper today.  So I guess from a provocative question standpoint, when you look at the PD-L1 high cohort in the subset where you didn't see a survival difference for chemo plus immunotherapy versus immunotherapy alone, do you think any element of that could have been influenced by the degree of PD-L1 positivity above 50%? Meaning could there have been a cohort that is, let's say PD-L1 75 and above, and that kind of skews the data because I know you've published on this yourself also where the higher the PD-L1 above 50%, like 90% PD-L1 positivity survival curves are much better than 50% to 89%. So could that have somehow played a role? Dr. David Gandara: The first thing to say is that PD-L1 and the PROphet score, there's very little overlap. I know that sounds surprising, but it's also true for tumor mutational burden. There's very little overlap. They're measuring different things. The PD-L1 is measuring a specific regulatory protein that is applicable to some patients, but not all. That's why even in almost all of the studies, people with PD-L1 0 could still have some survival benefit. But in this case they're independent. And not in this paper, but in other work done by this group, the PROphet group, they've shown that the PROphet score does not seem to correlate with super high PD-L1. So it's not like the cemiplimab data where if you have a PD-L1 of greater than 90%, then of course the patient does spectacularly with monotherapy. The other thing that's important here is they had a group of around a little less than 100 patients that got chemotherapy alone. The PROphet score is agnostic to chemotherapy. And so that means that you're not just looking at some prognostic factor. It's actually clinical utility on a predictive basis. Dr. Rafeh Naqash: I think those are very important points. I was on a podcast a couple of days back. I think there's a theme these days we're trying to do for JCO Precision Oncology, we're trying to do a few biomarker based podcasts, and the most recent one that we did was using a tissue transcriptome with ctDNA MRD and you mentioned the composite of the PD-L1 and the PROphet test and they use a composite of the tissue transcriptome. I believe they called it the VIGex test as well as MRD ctDNA. And when your ctDNA was negative at, I believe, the three month mark, those individuals had the highest inflamed VIGex test or highest infiltration of T cells, STING pathway, etc. So are there any thoughts of trying to add or correlate tissue based biomarkers or ctDNA based correlations as a further validation in this research with the company? Dr. David Gandara: Right. So there are many things that are being looked at, various composites looking at the commutations that might affect the efficacy of immunotherapy and how they correlate with profit positivity or negativity. And I'll just give the examples of STK11 and KEAP1. As you know, there's some controversy about whether these are for immunotherapy, whether they're more prognostic or predictive. I'm one of the co-authors among many in the recently published Nature paper by Dr. Skoulidis and the group at MD Anderson which report that for KEAP1 positive especially, but also SDK11 mutated getting immunotherapy, that that's where the CTLA-4 inhibitors actually play the greatest role. So realizing that this is still controversial, there are preliminary data, not published yet, that'll be presented at an upcoming meeting, looking at many of these other aspects, P53, SCK11, KEAP1, other aspects, TMB, that's actually already published, I think in one of their papers. So yes, there's lots of opportunities.  The other cool thing is that this isn't a test, it's a platform. And so that means that the OncoHost scientists have already said, “What if we look at this test, the assay in a group of patients with small cell lung cancer?” And so I just presented this as a poster at the world conference in San Diego. And it turns out if you look at the biology of small cell, where neither PD-L1 nor TMB seem to be very important, if you look at the biology of small cell and you form an assay, it only shares 44 proteins out of the 388 with non-small cell. It's a different biology. And when we applied that to a group of patients with small cell lung cancer, again it had really pretty impressive results, although still a fairly small number of patients. So we have a big phase three study that we're doing with a pharmaceutical company developing immunotherapy where we are prospectively placing the PROphet test in a small cell trial.  The platform can also be altered for other cancer types. And at AACR, Dr. Jarushka Naidoo presented really impressive data that you can modify the proteins and you can predict immunotherapy side effects. So this is not like a company that says, “We have one test that's great for everything.” You know how some companies say, “Our test, you can use it for everything.” This company is saying we can alter the protein structures using AI machine learning assisted process to do it and we can have a very informed assay in different tumor types and different situations. So to me, it's really exciting. Dr. Rafeh Naqash: Definitely to me, I think, combining the AI machine learning aspect with the possibility of finding or trying to find a composite biomarker using less invasive approaches such as plasma or blood, definitely checks a lot of boxes. And as you mentioned, trying to get it to prospective trials as an integral biomarker perhaps would be likely the next step. And hopefully we see some interesting, exciting results where we can try to match or stratify patients into optimal combination therapies based on this test.  So now to the next aspect of this discussion, David, which I'm really excited about. You've been a leader and a mentor to many. You've led ISLC and several other corporate group organizations, et cetera. Can you tell us, for the sake of all the listeners, junior investigators, trainees, what being a mentor has meant for you? How your career has started many years back and how it's evolved? And what are some of the things that you want to tell people for a successful and a more exciting career as you've led over the years? Dr. David Gandara: Well, thank you for the question. Mentoring is a very important part of my own career. I didn't have an institutional mentor when I was a junior investigator, but I had a lot of senior collaborators, very famous people that kind of took me under their wing and guided me. And I thought when I basically establish myself, I want to give back by being a mentor to other people. And you wouldn't believe the number of people that I'm even mentoring today. And some of them are not medical oncologists, they're surgeons, they're radiation oncologists, they're basic scientists. Because you don't have to be an expert in that person's field to be a mentor. It helps, but in other words, you can guide somebody in what are the decision making processes in your career. When is it time to move from this institution onward because you can't grow in the institution you're in, either because it's too big or it's too small? So I established a leadership academy in the Southwest Oncology Group, SWOG. I've led many mentoring courses, for instance, for ISLC, now for International Society Liquid Biopsy, where I'm the executive committee liaison for what's called The Young Committee. So ISLB Society, totally devoted to liquid biopsy, six years old now, we have a Young Committee that has a budget. They develop projects, they publish articles on their own, they do podcasts. So what I'm saying is those are all things that I think opens up opportunities. They're not waiting behind senior people, they are leading themselves.  We just, at our International Lung Cancer Congress, reestablished a fellows program where a group of fellows are invited to that Huntington beach meeting. It's now in its 25th year and we spend a day and a half with them, mentoring them on career building. I'll just give you my first, I have the “Letterman Top 10”. So my first recommendation is if all you have is lemons, make lemonade. And what I'm meaning is find what you can do at your institution if you're a junior person, what you can claim to be your own and make the very best of it. But then as you get further along in my recommendations, one of them is learn when to say ‘no'. Because as a junior investigator the biggest threat to your career is saying ‘yes' to everybody and then you become overwhelmed and you can't concentrate. So I'll stop there. But anyway, yes, mentoring is a big part of my life. Dr. Rafeh Naqash: Well, thank you, David. This is definitely something that I'm going to try to apply to my career as well. And this has been an absolute pleasure, especially with all the insights that you provided, not just on the scientific side but also on the personal career side and the mentorship side. And hopefully we'll see more of this work that you and other investigators have led and collaborated on. perhaps more interesting plasma based biomarkers. And hopefully some of that work will find its home in JCO Precision Oncology. Thank you again for joining us today. Dr. David Gandara: My pleasure. Dr. Rafeh Naqash: And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service organization, activity or therapy should not be construed as an ASCO endorsement.   Dr. David Gandara Disclosures: Consulting or Advisory Role Company: Henlius USA, Foundation Medicine, Janssen Pharma, Merck & Co, Mirati Therapeutics, Regeneron, AstraZeneca, Guardant Health, Genentech, Exact Sciences  Research Funding Company: Amgen, Genentech, Astex Pharma  

We say thank you to current Cancer Stories host, Dr. Lidia Schapira, and welcome Cancer Stories new host, Dr. Mikkael Sekeres. TRANSCRIPT Dr. Lidia Schapira: Hello and welcome to JCO's Cancer Stories: The Art of Oncology, which features essays and personal reflections from authors exploring their experience in the field of oncology. I'm your host, Dr. Lidia Schapira, a Professor of Medicine at Stanford University, and with me today is Dr. Mikkael Sekeres, who is a Professor of Medicine and the Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center in Miami. In this episode, we will be discussing his new role as the host for the JCO Cancer Stories: The Art of Oncology podcast. Mikkael, welcome to our podcast and thank you for joining me today. Dr. Mikkael Sekeres: Lidia, what an absolute delight it is to be here with you. And I have to confess, it's also intimidating to think about taking this over from you, given the amazing job you've done over the past few years. Dr. Lidia Schapira: Well, thank you so much for that. This podcast originated as a bit of a dare. When Steve Cannistra, back in 2017, said ‘no' to some idea that I had for changing or expanding the section and issued the dare of why don't you do a podcast instead? And back in 2017, I had no idea. And we were less used to podcasts, so I trained myself. And then this beautiful new form sort of emerged just from my idea and dream of giving our listeners and our readers something new to chew on and to reflect on. Dr. Mikkael Sekeres: Well, it turned out to be prescient, didn't it? I can't tell you how many people I know, especially here in Miami, where we do tend to get caught in traffic and have a long commute time. I'm sure that never happens to you in Palo Alto. Dr. Lidia Schapira: Of course not. Dr. Mikkael Sekeres: But people listen to a lot of podcasts and it's a great way to catch up on personalities and on books and on the news. So good for you. I'm so happy you took the dare and ran with it. Dr. Lidia Schapira: Yes. And the first thought I had was to make it a bit artsy. So we started, for the first couple of years of rounding up everybody we knew who was an actor or had a voice that they used for their art or trade and asked them to read the essays or poems before we had the conversation with the author. Now, we have our own voice actor, so we know what we're going to get every week, and we're not looking for people and knocking on doors and asking very busy actors to donate their time. So it has evolved, as has the writing really. So I wondered if you can reflect a little bit on how you see this section both in the journal and also the conversations we're having in this podcast change and evolve over the years. Dr. Mikkael Sekeres: Let's be honest, we're both writers, right? So as a writer, you're always looking for an outlet for your work. And there aren't a lot of outlets in medical journals. Yet there's this huge audience of doctors and nurses and pharmacists and social workers who read these journals and have this incredible experience with this deluge of humanity we see every single day. So this is an incredible thing, that Art of Oncology was even created a couple decades ago and provided this outlet for people. And what I have noticed is that people have become more daring. So let's play on the dare that you took up to even start this podcast. They've become more daring in what they're willing to write about and in how vulnerable they're willing to be in print. I've seen this in my own career, in my own writing, where 20 years ago I came out of fellowship and very cautiously started to write about some of the experiences that I had. But it was cautious and used more professional language and didn't get into some of the vulnerabilities that we face in treating patients and that we experience in ourselves and in our colleagues. But I think people have been willing to share more of themselves, particularly in the last decade. Dr. Lidia Schapira: I totally agree with you. And one of the things that I've noticed is that we have younger writers and younger authors who are now taught, even during their medical training and postgraduate work, that writing as a way of processing emotionally difficult experiences or sharing interesting thoughts or coming together as a community is really important to create the kind of community of thoughtful practitioners that we need to sustain us while we do this difficult work. So we are having more and more submissions and published work from very young colleagues, trainees. And I find it very interesting, sort of this multi-generational way of expressing the contact with very ill patients and sometimes very moving to think back on the first time you gave bad news for those of us who may have done it a hundred thousand times. Dr. Mikkael Sekeres: So I think you're spot on about this. We're getting younger authors. We're getting folks who are early career, mid career. Now, we're receiving essays from folks who are at the end of their career and want to reflect on that career. And people we wouldn't have expected would write these vulnerable essays either. I wonder if some of the pieces we're getting from younger authors stems from the fact that fellowship programs are finally paying attention to the experience of being a fellow and being a trainee. Dr. Lidia Schapira: Oh, my goodness. It was staring at them all this time. I think when you were a fellow a long time ago, you were one of the advocates of having fellows talk to one another about their experience, right? Dr. Mikkael Sekeres: You have an incredible memory. During our fellowship, we started a Balint Physician Awareness Group. So there's this movement started by the Ballint, a husband and wife team to start to get healthcare providers to reflect on their experience and share that experience with each other to build a community of support. And we started this in our fellowship. And you can imagine the initial reaction to this among the fellowship directors was, “Why do you need that? What do you think you're doing? There's no place for that.” Dr. Lidia Schapira: “And we need our time to train them on the science.” This is maybe an extra. Right? I think many of us have felt that trying to advance anything that deals with humanism or the human side of providing care is considered maybe optional. And I think you and I have been pushing against that for a long time. Dr. Mikkael Sekeres: I think that's exactly right. What I think legitimized it a little bit is we got funding for it from The Schwartz Foundation. We then actually published a study looking at it in JCO because the fellows in our program spent time at two different hospitals. So it was by design, this crossover study where half the fellows got the intervention of the Balint group and half didn't. And it turns out, lo and behold, they actually felt better and had a better experience as a fellow when they had the intervention. Dr. Lidia Schapira: Yeah. It's so interesting that we had to turn it into a randomized control trial or whatever design you picked, but you needed to fit it into the section of the journal that respected the logic and process of scientific research. But that brings me to another point, I think, that we have talked about so much, but I think it's important for us to share with listeners. And that is that the section of the journal that we've created now, it used to be When the Tumor Is Not the Target, and we've shortened the title. The Art of Oncology is not a section for papers that address research or where there is no methods and results section. It is intentionally meant to be different from the rest of the journal. Is that how you see it, too? Dr. Mikkael Sekeres: Oh, my word. Absolutely. And our reviewers occasionally will have a submission that is more of a classic article in how it's structured, and our reviewers will push against it. And sometimes we're able to get back to the author and say, could you write this in a different way, something that's more reflective of Art of Oncology? I think it's meant to be, I don't want to say a break from the way other articles are written, but maybe a different style, a different way of using your brain and reading these articles. And we've seen that they're popular. Sometimes they are the most read article, even in JCO, in a given week, which, of course, we share with each other and gloat a little bit when that happens. Dr. Lidia Schapira: Yes, and it doesn't have to be the article that made you cry. It can also be the article that made you think. That's been my intention as the editor for this section for the last 10 years. I've tried to be very intentional instead of bringing to our readership articles that delve into different parts of this lived experience of giving care. Some are moving more towards ethical conflicts. Some are moving more towards the emotional labor of the work. But some bring out different voices and different perspectives. And I'm proud to say that the submissions we get really come from all over the world. So I wonder, Mikkael, as you're entering into this role now, your decade as editor for this section and host for our podcast is how you view the editorial process. How does your team help the authors bring their best article forward? Dr. Mikkael Sekeres: I took the lead from you, and I'm not saying that just to blow wind in your sail, but you have always given feedback to authors, whether it's a request for a revision and acceptance or turning a piece down. That's been helpful, that's been thoughtful, that's been empathic. And in the end, I know that your goal has always been with these reviews, to give the author advice moving forward. I've tried to take a page out of your book by doing that as well. I go into every piece you shared with me that you do the same thing. When I get a submission, I look at it and I'm so excited about what could be there, what truth this could reveal, what angle of thinking about something that I've never thought about before. And our reviewers go into it the same way as well. These are folks who have read hundreds, if not thousands of essays. They themselves are readers. They're writers. They've had submissions accepted to Art of Oncology. They're looking for pieces that reflect a great truth that we all realize sometimes it's a great truth that no one wants to talk about, and this is the first time somebody's talking about it. Those are the best pieces. When you read it and say, “I thought the same thing,” Or, “I had the exact same experience and no one's ever talked about it before.” We're looking for good writing. We're looking for pieces that are focused on a patient. And you and I have both given talks on narrative medicine. And one of the slides I have in my talk is to remind people that the patient is the most important person in the room and to make that piece focused on the patient's experience and, of course, the writer's reaction to that experience. But in the end, it's all about our patients and their experience. And we're looking for, as you mentioned, perspectives that we haven't seen before. So we want to hear from people who are in training. We want to hear from people in different stages of their careers, people who practice in different settings, people who bring different cultural backgrounds to their own perspective on the practice of oncology. Dr. Lidia Schapira: And if I may point something out to our listeners, you are an artist in being able to bring the bedside verbatims to the page and make them live. I've always admired that in your writing, Mikkael. Can you tell us a little bit about your process for writing and how the role of the editor varies or is different from the role of the writer? Because I've learned a lot about editing, and I think the editor is an interpreter, in a way. I'm fascinated. I was brought up in a household where we spoke four languages, and I was always fascinated by trying to find the right word in a language and struggling with all of that. And I think some of my love for editing, which is different from my love for writing or reading, comes from that, from trying just to find the right word or trying to respect the voice of the author and make it even better or more artistic. Can you tell us a little bit about your process and your relationship to language and writing and editing? Dr. Mikkael Sekeres: It's great to hear you come from a family where you spoke four languages. I am an unfortunate monoglot. I'm terrible with foreign languages. But I come from a family of English majors. My dad was a journalist for the Providence Journal in Rhode island, then an editor for 10 years. My mom was an English major as well. So I always think that as parents, our job is to impart one employable skill to our kids so they don't live in our basement forever. Dr. Lidia Schapira: That's what my father thought, and that's why I'm a doctor and not a philosopher. Dr. Mikkael Sekeres: We joke that we moved to Miami, so there is no basement they can live in. But I always felt in my family, the employable skill was writing. I grew up and when I went to med school, I think, we put on this armor of the language we're learning, and we're very uncomfortable and nervous about the skills that we have. So we use this language to separate ourselves from our uncertainty around medicine. I distinctly remember at one point talking to my parents and saying something that was very complex, using medicalese. And they said to me, “Why are you talking to us like this? We're your parents. You don't have to use that language. Just use language we can understand.” And that always resonated with me. That was kind of a North Star moment for me. That's what's guided my writing. And I have so much respect for the words that my patients use. And I think that's why I try to incorporate it in my essays as well. I always try to have my patient's voice literally there in their words as a focal point. I think as an editor, we go into a piece and we want to learn something. In the end, essays either educate or entertain, and ideally both. So we want to come out of a piece, we want to be either emotionally moved or we want to learn something and hopefully both things. And if I'm reading a piece as an editor and one of those two criteria have been satisfied, then I think it's a piece that's worth giving feedback to and advising revision. But I'm curious. I want to turn this a little bit, Lidia, because you're the one who always asks the questions. Dr. Lidia Schapira: I love asking questions. Dr. Mikkael Sekeres: So I'd like to ask you a question. When did you get started as a writer and a reader? And has that interest and skill changed over the course of your career? Dr. Lidia Schapira: Yes, I must say, I've always been a reader. That's my idea of heaven is a place with an enormous amount of books and a good espresso machine, just to give you an idea. So books have always provided companionship to me. They've provided community. I'm very happy living in a world of ideas, and I love art, and I love the sound of words and beautiful words put together beautifully. So that's basically reading and thinking, to me, are very closely aligned. And I also love and come from a culture, a society where conversation was valued. And I'm very sad that we don't anymore. We don't converse in our typical academic settings because we're so busy, and our language is mostly turned into units of efficiency. So I love the idea of communicating through language. Words, spoken words, things we listen to, things we read, things we write. My relationship to writing has been very undisciplined and inconsistent. And for all the years that I was an editor for this section, I found myself sort of inhibited from writing. And from the moment that I passed the baton on to you, I've been gushing. So I'm working on a book, and hopefully it'll be the first of several. But I've sort of kept my writing very private, and I've only been able to do it when I have a lot of time and no pressure. I'm not the kind of disciplined writer who can set aside time every day to write. I just can't do that. I need to be totally empty and free and be able to disagree with myself and erase a thousand words written on a page because they're just not good enough and start again. Dr. Mikkael Sekeres: I'm fascinated by that comment that you just made. What is it about being an editor that you feel has inhibited you from writing? Dr. Lidia Schapira: I think I was just busy. I was busy, again, immersing myself in the words that I needed to respond to and in the creative process of transforming essays into their best possible publishable form. And I think that's how I've interpreted the work of editors. I have tremendous respect for editors. I now need one to help me with my own work. But I think editors play an incredible role. And I am very happy that you view this role as something that is joyful. And I know that you have the amazing talent to do it. So I'm just very happy that we've made this transition. Dr. Mikkael Sekeres: Can I suggest that you've been giving as an editor also, because I think that your guidance to authors is precious? It's so valuable. Writers are so desperate to have that kind of caring advice. And I wonder if you've devoted all of your creative juices to doing that for the past 10 years at the expense of not being able to write yourself. So I'm so thrilled that you have the opportunity now. I will be the first person to buy your book, to write a review for your book. I can't wait to read it. Dr. Lidia Schapira: We've got a blurber. So now I need a good editor and a therapist, and I'm on my way. So on that note, I think it's time for us to end this lovely conversation, although we could go on for a long time. For our listeners. I want to thank you for having listened to me all these years, and I'm delighted that Dr. Sekeres will continue this wonderful program. And I look forward to listening while I drive, while I walk, and while I just simply am. Thank you for listening to JCO's Cancer Stories: The Art of Oncology. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all of the ASCO shows at asco.org/podcasts. And thank you Mikkael. Dr. Mikkael Sekeres: Thank you so much, Lidia.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Like, share and subscribe so you never miss an episode and leave a rating or review.   Guest Bio: Dr. Mikkael Sekeres is a Professor of Medicine and the Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center in Miami.  

Unlocking Emotional Strength Through Attunement and Support In a recent episode of Dads with Daughters, we had the privilege of hosting Dr. Tovah Klein, an esteemed professor at Barnard and author of the insightful book Raising Resilience: How to Help Our Children Thrive in Times of Uncertainty. Our conversation centered on the vital role fathers play in nurturing resilience and emotional strength in their daughters during challenging times. By delving into the essence of resilience, Dr. Klein offers invaluable advice on how fathers can become pillars of support and emotional stability for their children. The Essence of Resilience Understanding Resilience Dr. Klein defines resilience as the ability to adapt, adjust, and be flexible in the face of life's challenges. It is a critical aspect of a child's development, enabling them to navigate adversity with the emotional backing of their parents or caregivers. Rather than shielding children from every hardship, it's crucial for fathers to allow their daughters to face small adversities, helping them build coping skills and inner strength. Attunement and Emotional Stability Attuning to Emotional Needs Dr. Klein emphasizes the importance of fathers being emotionally attuned to their children. Emotional attunement involves understanding and responding appropriately to a child's emotional cues and needs. For fathers, this means managing their personal stress and emotional states to maintain stability at home. Children require emotional availability and unconditional love to build confidence and mental health, and fathers play a pivotal role in providing this foundation. Shifting Focus and Modeling Healthy Behaviors From Work Stress to Home Serenity A key recommendation from Dr. Klein is the necessity for fathers to shift their focus away from work-related stress before engaging with their children. Modeling healthy behaviors, such as limiting screen time and prioritizing family interactions, sets an example for children to follow. Fathers should strive to be present, listen, and engage in meaningful conversations during everyday moments like car rides or bedtime, turning these instances into opportunities for connection and support. Embracing Vulnerability Teaching Through Vulnerability Dr. Klein underscores the importance of fathers displaying vulnerability. By expressing a range of emotions and acknowledging their struggles, fathers teach their daughters that it's normal to experience and cope with various feelings. This modeling helps children feel validated and understood, fostering emotional intelligence and resilience. Practical Strategies for Coping Handling Academic and Social Pressures When addressing academic struggles or peer conflicts, Dr. Klein advises fathers to listen and validate their children's feelings rather than solve every issue for them. Encouraging daughters to learn from their experiences and take pride in their achievements, even during adversity, builds their problem-solving skills and resilience. Conflict with peers is natural and can lead to stronger friendships as children learn to navigate and resolve disputes on their own. Empowering Fathers, Empowering Daughters As fathers, the role you play in your daughters' lives is immensely significant. By being emotionally attuned, modeling healthy behaviors, and embracing vulnerability, you empower your daughters to develop resilience and emotional strength. These foundational skills enable them to face life's uncertainties with confidence and adaptability. For more resources on enhancing your parenting journey, visit Dr. Klein's website tovahklein.com, and consider joining support communities like The Fatherhood Insider and the Dads with Daughters Facebook group. Together, let's raise a generation of strong, resilient young women. TRANSCRIPT Dr. Christopher Lewis [00:00:05]: Welcome to dads with daughters. In this show, we spotlight dads, resources, and more to help you be the best dad you can be. Dr. Christopher Lewis [00:00:16]: Welcome back to the dads with daughters podcast, where we bring you guests to be active participants in your daughters' wives, raising them to be strong, independent women. Really excited to have you back again this week. As always every week, I love being able to sit down, talk to you, work with you, and walk on this path that you're on. And I call it a path. It's a journey. We're all on it together as we're raising our daughters to be that those strong, independent women that we want them to be. And it's not always going to be easy. There's gonna be bumps in the road. Dr. Christopher Lewis [00:00:46]: And but in the end, each and every one of us is working to try to help our children to be able to be self reliant. And one of the topics we're gonna talk about today, resilient as they get older. And every week I love being able to bring you different guests that can help you to do just that. Sometimes we have dads on. Sometimes we have others that have amazing resources that can help you to do just that. And today we've got another great guest with us today. Dr. Tovah Klein is with us today. Dr. Christopher Lewis [00:01:17]: And Tovah is a professor at Barnard, as well as we're going as well as a author of a new book called raising resilience, How to Help Our Children Thrive in Times of Uncertainty. I'm really excited to have her on and to introduce her to you. Tovah, thanks so much for being here today. Dr. Tovah Klein [00:01:40]: Oh, thank you for having me. I'm excited to be here. Dr. Christopher Lewis [00:01:42]: Well, I'm excited to have you here as well. Because as you heard, this podcast is all about raising strong, independent women. And part of that is being able to give our kids the keys to, well, I'm gonna say the castle in regards to helping them to be resilient in the things that they're going to come up against. And there are definitely going to be things that they're going to come up against. And there's some of those are gonna be positive. Some may be negative and some may be somewhere in between. And I'm really excited to be able to delve a little bit deeper into this book that you've put out into the world. But I think I wanna step back in time just a little bit. Dr. Christopher Lewis [00:02:16]: And first I wanna have you define resiliency because you know, this book is called raising resilience and every person that hears that word resilience may have a different thought in their mind of what that means. And then I'd love to hear your origin story. I wanna hear why this topic and why you wanted to put all the time, passion, effort into putting this out into the world? Dr. Tovah Klein [00:02:37]: So when I think of resilience, what I really think about is the whole person, the whole child. And resilience is not like a trait or a dose or something that you say, you know, I'm 1 or I'm a 6. It's actually a part of who we raise our children to be. It's about adaptability, adjustment, flexibility. You can think of it as opening up their thinking, but it's being able to move with whatever life gives them. And as you just said, life's gonna give them good and not so good. And so, really, when we think about preparing our children for life, we love them, We do all kinds of kind of things for them, but really what we want is for them to be able to handle the hardest parts of life, and that's what we call resilience. It's a process to help them develop it, but also that adjustment, adaptability, flexibility allows them to face hurdles and shift, face hurdles and shift, knowing that they're not alone in the world. Dr. Tovah Klein [00:03:38]: They're not doing this themselves, but with originally a parent or whoever is the main caregiver, and then in life, other people who can be there for them. So that's really how I think about resilience is this dynamic piece of self that gets developed over time. Actually, I've been in the field for almost 3 decades now working first with young children and parents, and my research was always centered around young children and that really important influence of parents on them. And then as careers change, I started working with, you know, older children and parents, and that just broadened my thinking. And one day came to this sudden realization that really what parents were doing is helping children prepare for uncertainty. Like, every single day is uncertain. And I have kind of 2, I would say, areas that I'm passionate about and I've spent my life in. One is kind of everyday, normal development challenges, stressful moments. Dr. Tovah Klein [00:04:41]: And then the other piece, which I always saw as related, was working with families in traumatic situations, so either individual trauma from, you know, abuse or hurts, or fleeing a fire or a flood, but also collective trauma. So children and families after 911, I've done work now in COVID, which when I started conceptualizing the book, I had not yet, but, you know, sort of large scale traumatic events. And when I put those 2 together, I realized that the piece that happens in trauma, whether that's a severe crisis and you've just fled a hurricane and those roads washed out, or you're getting through a normal day with 3 children of different ages and you're trying to get out the door, you're always dealing with uncertainty, and it's very destabilizing. And then that what I got to is, like, oh, then what we're doing every single day in our relationship with our child, whether we know it or not, is helping them prepare for life, which is gonna unfortunately have bad things happen in it, and we want them to be able to handle. We want them to be able to people to turn to. So the book started out really about uncertainty, wrote a proposal, kind of put it aside, you know, life gets in the way, work gets in the way. Then when COVID hit, it really became very clear to me that uncertainty was here to stay, or I thought it was here to stay, and I felt like I needed to get back to this book. But when I started writing, and my contract, you know, got a contract with HarperCollins, the editors kept saying to me, you know, everything you write about is about resilience. Dr. Tovah Klein [00:06:13]: And I pushed back saying, you know, that's really a buzzword. And I'm not interested in that. I'm interested in writing a book about how do we raise decent human in writing a book about how do we raise decent human beings? What does that mean for parents? Dr. Tovah Klein [00:06:19]: What does that mean for children? And what I meant by that was children who grow up with a strong voice and ability to take care of themselves and have confidence and, equally, an ability to look to others and be kind and compassionate and aware of their community. And they said, yes, but everything you're writing about is resilience. And so I said, okay. I'm gonna take it out of that buzzword, and I'm gonna really unpack what does resilience mean, and what does that parent relationship or caregiver relationship mean in terms of raising that child because so much of this is about us as parents, and that had been the life work I've been doing is really studying and working with everyday parents to understand what we bring to this as parents, because that then drives how we see our children, how we either do or don't accept them for who they are, and children have to be accepted for who they are. And so what's the work we we must do on ourselves to understand ourselves so that we become that buffer between the world and what the world gives us and children so that there's stress, but it's not overwhelming stress for children. And that's really how this book came to be. Dr. Christopher Lewis [00:07:37]: Now one of the things in the book that you talk about and that you emphasize is the role of parental attunement in building resilience. How would you say that fathers in particular can attune to their children's emotional needs during challenging times? And what specific strategies can they use to be more emotionally available? Dr. Tovah Klein [00:07:58]: Yeah. It's such an important question because, you know, as you know, as a father and a and a podcaster with fathers listening, for so long, the field of psychology didn't even know that fathers existed, or they were sort of like, oh, yeah. But we know now from experience and equally from the research that a loving parent matters and fathers matter. And so this idea of attunement, particularly when times are stressful, really means starting with self. And I think the the challenge for some dads, I think not always, but is that boys are raised into becoming men who aren't really taught or told, oh, you're supposed to feel feelings. Feelings are okay. This this is human. And so doing the work to say, oh, how am I doing? How am I feeling? Can I ground myself as a dad so that I can turn to my child and figure out what my child needs? Because often as parents, when we're upset, we go for control. Dr. Tovah Klein [00:09:00]: Right? If I'm feeling really rattled, if there's a lot of uncertainty, every parent, male, female, non binary, like, every parent who feels unsteady kind of we kind of go for, what can I control? And when you take a step back as a dad and you say, okay. I'm the one who's stressed here. How can I get a little steadier so I can turn to my child and then say, what does this child need for me to protect them right now? Not protect them by keeping everything out, but by saying, right now, we're not sure what's happening. People are getting sick and we're not sure why, but what I know is that by staying home, I'm gonna keep you safe, and we're gonna still have our meals together, and I'm gonna still put you to bed. It reassures a child that even when there's bad things going on, this parent is close to help them, and that's what children need. We always think of it in young children. Children need it across ages, for us to say I'm here for you even though this is scary or stressful. Dr. Christopher Lewis [00:09:59]: So some of what you were just talking about, those emotional barriers or the walls that sometimes some men put up, it's not always easy for some men to break those down. And to be, as we've talked about on the show before, is vulnerable with those around them. And from what you just said, really, to me, what I'm hearing is the importance of being vulnerable and showing that vulnerability with your kids. Because by showing that vulnerability, it equates to allowing and providing your kids a glimpse of resiliency in many different ways. Dr. Tovah Klein [00:10:36]: Yeah. You'd summarized that very well, actually, which is we have to be vulnerable in order to say, oh, what am I feeling? And, you know, I read something recently that said being vulnerable is the opposite of cool, you know, being cool. Because being cool is kinda putting on, like, armor of some kind. Like, you know, I got this. You know, I'm a cool person. Being vulnerable says, I'm gonna show you and myself all of me. And all of me is not always parts that we're proud of or that we feel good about, but they're part of us. So right now, you're a father and something's going on in your life or in the world, you have to say, look, I'm a little scared, you know, to yourself or to a partner or to a friend. Dr. Tovah Klein [00:11:18]: I'm a little scared, but I know I have to take care of these children. So I'm gonna figure out what that's about so I can turn to my child and say, yeah. This is unknown, and we're gonna figure it out together. And it's that vulnerability that allows us to be full people. What it shows to the child is it's okay to have this range of emotions, of, you know, reactions, and that that's life. Life is not about covering up how you're feeling. Life is not about pretending. Oh, no. Dr. Tovah Klein [00:11:49]: No. No. I'm not upset. It's just the opposite. It's saying, you know, I am upset. And even if I can't do what I wanna do, I know that daddy is gonna love me even though I'm upset right now. And so when fathers model that, children go, oh, it's okay to fall down, to fail, to feel really dumb. Whatever it is, it has to be modeled for them. Dr. Christopher Lewis [00:12:13]: Now also in the book, you talk a lot about how adversity can actually make children more resilient. Can you share some examples of how fathers can help their children to reframe difficult situations? And it could be something like it could be peer conflict, it could be academic struggles, it could be other aspects that they're going to run into. Dr. Tovah Klein [00:12:36]: So I think, you know, one of the biggies on the academic side is, you know, your child comes home, your daughter comes home from pick a grade and says, like, I'm just stupid. I can't do math. This is very stereotypical and yet happens all the time for girls, for adolescents and younger girls. I'm stupid. I can't do this. You know, and as a dad, you might think, oh, maybe maybe I shouldn't push her to take that harder math that she wanted to take. You know, maybe I should just say to her, oh, honey, you know, you don't have to take algebra, advanced, or whatever it is. Instead, you can say, like, yeah, that is hard, and learning is a hard process, and be there with them. Dr. Tovah Klein [00:13:15]: So some of it is listening. You know, we tend to want to problem solve. I know, there's all kinds of jokes about, you know, men and dads wanting to problem solve, but I always say, well, moms do that, too, you know, but, you know, that's sort of the stereotype of, of males. And what we don't do as parents well enough is listen. So it may be listening to your daughter really cry, scream, tear the paper up if they still have paper tests, and then say, yeah, this is there's no question this is hard. Maybe you recall a story from your own. Oh, yeah. I remember when I got to quadratic equations, and, woah, I thought I'm the dumbest person in the world, but I wasn't. Dr. Tovah Klein [00:13:54]: And it's holding them through that, allowing them to have all of those emotions, and then some sense of tomorrow might be better is what I call it. Right? So let's see how it goes tomorrow. Do you wanna talk to the teacher? Tomorrow, you're in the moment. It's like, no. You know? They just wanna vent, and you let them vent. But the next day when they go back to school, they may actually come back and say, hey. I got my test back, and I didn't do well, but I didn't do the worst. Or I got problems right. Dr. Tovah Klein [00:14:21]: I was sure I got wrong. You go, oh, really? What you learned from that? Oh, okay. And you have to have this, like, almost like a humorous distance. Right? You don't wanna say I told you so or I knew it, but you can say, yeah. You know? That's gotta feel great. So what are you thinking next time? Or if you wanna think through studying differently, let me know. And then the child builds on that. Oh, I actually didn't do as poorly on that test as I thought. Dr. Tovah Klein [00:14:48]: The dad wasn't there going, oh, it's only because you were tired. Like, we love to make excuses for our children. We either blame them, like I told you to go to bed earlier, or we make excuses. Oh, remember you weren't feeling so well. And all of that works against a child saying, I faced something. It was hard. I don't love my score in that test, but I'm actually proud of the things I did get right, and I'm gonna study a little differently next time. That's strength. Dr. Tovah Klein [00:15:14]: Fighting with friends, children do it all the time. And in fact, the data we have with younger children is that they fight more with the people they're closest to. So they don't really fight so much over, you know, building a block tower or how to organize the playground game if it's somebody they're not friends with because it's not worth their energy. But they can get into pretty heated fights with people that they're friends with or that they play with a lot, and then they come back together. Why? Because they want to. The motivation is I might have thrown you out and said I never wanna see you again or talk to you again yesterday, but today, you're my friend again. And it's even stronger because we've been through this conflict, and we've we've resolved it. And so I think as a father to know that it's not about the problem solving, but to to listen, to say, hey. Dr. Tovah Klein [00:16:09]: If you want my help, I'm here. But to recognize that you have to wait for the child to come in and say, I really do wanna play with her tomorrow. Oh, okay. Well, you know, do you want wanna think about what helped you last time with that friend and and to talk it through. And I see it all the time now with with social media and teenagers. You know, when I hear my kids or my college students, I teach at a women's college, so I have all these incredible young women. You know, that term ghosting, which was new to me in my generation probably shows, like, what? But with ghosting, it's almost like there's a brick wall. And so sometimes I say to a teenager, like, is there a way to take a step back and maybe try another day to reach that friend? Because it sounds like that really was a friend. Dr. Tovah Klein [00:16:55]: So it doesn't have to be the message is this doesn't have to be forever. And I think dads have to give that message when it's appropriate. Right? You're really heated now, but I'm wondering if in some time and initially, the the child goes, no way, but then they may come back to you and say, yeah, I was thinking about what you said. Dr. Christopher Lewis [00:17:11]: You know, one of the things I was thinking about, and it kinda goes into some of the things you wrote too, was the fact that more and more you hear today about the mental health concerns in young people and the rising concerns about mental health and the struggles that young people are having. What would you say to fathers about how they can contribute to create a supportive environment at home that fosters both emotional intelligence and emotional component. You know, I say it in my book, these 5 pillars, but the first is building trust, right? That's what every father is doing with their child. They're building trust in this relationship. Like, even when things go awry between us, I'm here for you. You know, putting your child to bed at night or going into check on your teenager really can be about, boy, we had some rough spots today, and you know, I'm sorry, and I still love you. All of those disconnections that get repaired, reconnecting are really core for our children and particularly, I'm gonna say, for our girls, because they need to know conflict is part of life. That's where you get this emotional attunement, which is, yeah, we were angry before, you were really mad at me, and now we're back together, and we're good. This is part of it. You're not, like, overlooking it. Dr. Tovah Klein [00:18:40]: But I think the other piece at home is that we tend to put a lot of pressure on our children, particularly firstborns. Not always, but particularly firstborns. Right? They're our first ones. They make us a parent. You know what I'm saying? Before that first one, there was no such thing as I'm a parent. Now I'm a daddy. You might have subsequent children, but the first ones are kind of our reflection. They go out in the world, we feel great when they're doing well, and we like smile. Dr. Tovah Klein [00:19:06]: And then when they're not doing well, we're like, we feel terrible, but also, we tend to blame them. Don't do it that way. So I think for dads to really think about, when am I too hard on my child or my children, and when am I putting too much pressure on them? Because we live in a very competitive world, you know, certainly academically and just there's all this messaging about mental health, which we should be concerned about. But there's equally messaging about, there's only one way to get to the top, or if you're not at the top, you won't succeed. And it's a total lie. It's just a lie. And I feel like if every per parent, every dad could say to their child, there's lots of ways to be okay in the world. You know, some people are really great at sports. Dr. Tovah Klein [00:19:50]: Some are really great at math. Some just enjoy it. Like, we've taken the joy out of learning or doing. So I think at home to really think about, can I bring the pressure down? Can I find moments of joy together? Like, you're much better off having a dance party, if that's what your children like to do, or have a backwards dinner. This is I grew up with backwards dinners occasionally, and they were just such a joy, or can we take a different path to get to where we're going today, and who wants to map it out? And even if you get lost on the way, that's funny. That's really funny, you know. So where can you have those moments of shared joy, and then I'm gonna get back to listening. We don't listen to children. Dr. Tovah Klein [00:20:29]: They're not busy people. Dads are busy. Maybe you have work or maybe home is work. You've got a couple of kids or you've got one who's got some special needs right now and you're trying to figure those out and you're taking them to different therapists. Whatever it is, we're busy. And what gets lost is what I call the space in between, which is like getting there. You know, maybe that's in the car or it's, you know, you walk to school or to a doctor's appointment or something. In those moments, there's a lot of time to connect and listen to your child. Dr. Tovah Klein [00:20:59]: And so putting more of that in or thinking, like, do I really wanna rush through bedtime with my 8 year old? Or can I slow it down and so they go to bed 10 minutes later? Anything at home that brings down the pressure and gets parents to exhale and the dads to say, just wanna connect with you. I don't really care what you eat for dinner. I'm gonna serve it. I'm not gonna take it personally if you don't need it, and I'm gonna listen to you today. So the lighter we are with children, the better. And it also opens them up to talk more. And we say, you know, we ask them questions, they shut down. They're like, I'm not answering you, daddy. Dr. Tovah Klein [00:21:32]: But when we sit down at dinner and say something funny that happened I I'm just thinking of my husband used to sit down and he'd go like, I'm gonna tell you the funniest thing that happened today. And it would just be this, like, beat fact of some kind. Then the children would start talking because nobody asked anything of them. Dr. Christopher Lewis [00:21:47]: Earlier, you talked about fathers trying to protect their kids. And I think that the word protect means different things for different men. But I guess one thing that I think that many men feel is that they need to protect their kids from hardships, from that they need to protect them from getting hurt. How can fathers reconcile that instinct with some of the approaches that you're talking about, about allowing kids to face adversity as a means of building resilience? Dr. Tovah Klein [00:22:20]: So much of this is about work on themselves. Right? Of course, we wanna protect our children. There's a part of any dad in particular because what's the function of a daddy to love a child and keep them safe? And to say, you're not gonna always be with them. You're not gonna always be there to protect them. So what can I do to help them deal with the little hurts and the smaller hurdles and the smaller adversities now is to back off and let the child deal with them? So, I'll give an example. You know, that term bully gets used a lot. Now, there are some children who really are victims to being bullied, but every child potentially is going to have meanness in their life from other children and from themselves, by the way. I think we do a disservice when we tell children that's mean, that's mean, that's mean because it scares the child. Dr. Tovah Klein [00:23:09]: Well, what if I don't like my friend today? And then am I a horrible person for telling them I don't like them? No. They're not horrible people. They may be standing up for themselves. So when we step back, and if a dad steps back and says, what's worrying me so much about my child getting hurt? Because every dad brings their full self to being a dad. And so it's really about saying, what's the really, what is the harm that I'm worried about? And usually, it's I remember how bad that was being left out, or I was terrible at athletics, which is takes in a whole other life for men than it does for women, right, because boys are supposed to be athletic. Right? So if you were that child who was left out or you were that kind of outsider peer who didn't really feel like you belonged, we then get more worried for our children, and we jump very quickly. So I think being aware of self, and that's what I call in my book, The You Factor, those are I have all these reflective questions there for dads, for moms, for anybody taking care of children. What is it that I bring? Because when we don't give children this opportunity to handle the smaller hurts, even when the child thinks they're big hurts you know, my friend wouldn't play with me today. Dr. Tovah Klein [00:24:22]: He starts young and goes all the way through adolescence and then becomes part of social media. But to say, yeah, that's really crummy. Sometimes that happens. And to have some empathic, but genuinely empathic, but also, I'm gonna sit by you, but I'm not gonna take this away. I'm not gonna march up to the school and speak to the teacher unless I hear it as a pattern and I'm really getting concerned. Or as I often say to to a parent, you know, to a dad, just check-in with the school and see what the school says, if it's a school that, you know, you're comfortable with or the counselor, you know, the the middle school or a high school counselor. But when we don't let children deal with these smaller stressors, hurts, you know, not doing as well as they wanted, not getting the teacher they wanted, but then they might actually find that teacher is not so bad. It actually strengthens children to say, hey. Dr. Tovah Klein [00:25:13]: I got through that. I figured that out, or I didn't like that teacher because she yelled more than I liked, but, actually, she was a really great teacher, and I learned to deal with the fact that she yelled a lot. That's where strength comes from, that children see people are complicated. And I think as dads, the role is to help them see, yeah, people are complicated. Maybe your friend had a bad day today. Doesn't mean she should've been like that with you, but maybe she had a bad day. Do you wanna see if tomorrow's better? Gives them a world view of, you could have a bad day, and I don't want people vilifying you, and other people also are sometimes hurtful. That doesn't mean they're hurtful all the time, and that strengthens children. Dr. Tovah Klein [00:25:53]: The other thing it does is it helps them use voice. If you never face adversity, you never have to say, hey. I don't agree with that, or you can't do that to me. And I actually think that this huge part of resilience, which is confidence and the ability to stand up for yourself, comes from learning to do it, and it starts off in smaller ways. I well, now I said I didn't wanna play basketball today, and then I basketball today, and then I finally walked away. I just said I'm not gonna play. It's a smaller way to use voice because when people are doing things to you that you don't like, we wanna be sure that our children, the daughters say, absolutely not. You can't do that to me, and not feel like I'm being a mean person. Dr. Tovah Klein [00:26:31]: We do give them double messages, particularly to girls. Be nice. Be nice. Now stand up for yourself. And I see girls getting confused with that. And it's like, well, actually, you can do both. You can be a kind, decent person, and that's not in opposition to saying no, or I don't like that, or can we talk about this. Dr. Christopher Lewis [00:26:50]: So what I'm hearing you say is that there really are a lot of tensions, a lot of things that can impact a child in many different ways, whether it be familial tensions, whether it could be tensions from outside the home, whether that that are impacting the child directly, or even world events that may be causing strife, and are impacting your child, whether you like it or not, as as you're thinking about that, or how can fathers take a proactive role in addressing those external those external stressors while still being able to maintain some sense of stability? Some some sense of some sense of stability at home? Dr. Tovah Klein [00:27:36]: Yeah. I mean, that's a big question, obviously. You know, what are those stressors? But I'll start with sort of the innermost or the most intimate, which is your personal stressors. And here's your first level of uncertainty. Like, we change. You know, dads change. You might be calm at some days and a little more frantic or a lot more frantic others. So part of that is being truly in tune with self as best you can and not being hard on yourself when you're not. Dr. Tovah Klein [00:28:06]: So, oh, I'm stressed. Why am I stressed? And then what can I change? Sometimes you can. Sometimes you can't. But I find that more often than not, a dad could change something. Yeah. You know what? I keep saying that I can't bring the work stress down, but I'm gonna have to, and I'm gonna find a way, or I am gonna help ask for help. If there's a group of people who probably don't ask for help enough, it's parents, and then dads on top of that. Right? They don't say, hey. Dr. Tovah Klein [00:28:33]: Can I ask my neighbor to take my child to the bus stop or pick my child up today or, you know, I'm gonna be late for my child's band concert? Could you let her know I'm still coming? Right? So any way to turn to others for help can help. But then there's the wider world, and that's a lot of self work. I mean, there's a lot going on in the world that is scary. There's no question. And with news being 247 in in our faces, I think it's up to us as the parents. So to the dads to say, okay. I'm a news junkie. I've gotta take some of these notifications off my phone. Dr. Tovah Klein [00:29:11]: I've gotta come up with a way that when I walk in the door and I've got children now to connect to, I've gotta find a place to put my phone. And by the way, that's modeling for when your children have their own phones. It's very hard to say to children, when we walk in, we put our phones here if the dad doesn't do it, because they just call they'll call you out right away. You don't do that. So it's becoming aware of what's stressing you, what's scaring you, and how can you shift in dealing with it. It's a very intentional process. How do I get my feet planted? How do I exhale? 1, I'm just thinking of a dad I worked with for years, and and the first time he called me, he said, you know, I manage this huge group of people. He's in construction, this huge group of people, and I tell them what to do. Dr. Tovah Klein [00:29:56]: And I'm, you know, in the car driving home telling, you know, putting out fires or whatever. And then I get home and no one listens to me, and I said, can you put the phone down, like, a mile away so that the last part of your drive, you're shifting focus? And then when you get to the door of your house, you exhale and say, I'm going in now, to 2 children who won't listen to me. So you're literally intentionally exhaling, switching modes, and getting some humor because that actually that calm or calmer it doesn't read perfect calm is felt by the children, and they feel they feel that dad walking in the door. They feel that dad who's stressed at the dinner table, and so it's really a very intentional process. And again, I think it's something that men in in particular are not raised with. Like, you are gonna be the emotional sustenance for your children, and you are. And so to take that in and say, wow, what a privilege, what a great thing, and wow, That means I have to be aware of myself because the more emotionally attuned a dad is, particularly for those daughters, the more they feel loved and respected. And in their worst moments, they really need to feel that. Dr. Tovah Klein [00:31:10]: Like, I really messed up. They wanna know that this is unconditional love. I still love you. Yeah. That was a mess up. We're in this together. I'm not gonna leave leave you or abandon you because you had a, you know, rotten day or set of events, And that's what bolsters mental health too. I'm loved even when I'm my worst self for the children. Dr. Christopher Lewis [00:31:30]: Well, Tovah, there's a ton to unpack here, and I really appreciate you coming and talking about all of this. And I know that, this book can definitely help so many fathers and mothers and parents in general to better connect with their kids, but also help their kids in a lot of ways. If people wanna find out more about the book itself, where's the best place for them to go? Dr. Tovah Klein [00:31:56]: Yeah. Well, the easiest place is to go to my website, Tovahkleen.com. That's Tovahkleen.com. And the book is sold wherever books are sold. So you can get online at your local book store. And if you go to my website, you've bought the book, you just put in your receipt, whatever receipt it is, and there's a free download for something that I call the UFACTOR journal. And that's all the reflective questions from the book and a place to either write out answers or just have the questions there to reflect on. And I will say I got an email this week from a couple who wrote to me and said that a mom and a dad couple, were doing the reflective questions together and then coming together and discussing them, and it's been good for our marriage. Dr. Tovah Klein [00:32:42]: So I thought, oh, that's really great. Because reflecting on self makes you a stronger person, which makes you a better dad. No question. And shedding vulnerability, because sometimes reflecting on yourself does not feel so great. Dr. Christopher Lewis [00:32:53]: So true. Well, I truly want to say thank you. Thank you for writing this and helping parents to connect with their kids in this better way, but also for sharing this with us today for being here and for challenging us to think about resilience in a different way as well. And I wish you all the best. Dr. Tovah Klein [00:33:14]: Yeah. Thank you for having me. Dr. Christopher Lewis [00:33:15]: If you've enjoyed today's episode of the Dads with Daughters podcast, we invite you to check out the fatherhood insider. The fatherhood insider is the essential resource for any dad that wants to be the best dad that he can be. We know that no child comes with an instruction manual and most dads are figuring it out as they go along, and the fatherhood insider is full of resources and information that will up your game on fatherhood. Through our extensive course library, interactive forum, step by step road maps, and more, you will engage and learn with experts, but more importantly, dads like you. So check it out at fatheringtogether.org. If you are a father of a daughter and have not yet joined the dads with daughters Facebook community, there's a link in the notes today. Dads with daughters is a program of fathering together. We look forward to having you back for another great guest next week all geared to helping you raise strong and powered daughters and be the best dad that you can be. Dr. Christopher Lewis [00:34:14]: We're all in the same boat, And it's full of tiny screaming passengers. We spend the time. We give the lessons. We make the meals. Dad you can be. You're the best dad you can be.

Prioritizing Presence Over Presents As we approach the holiday season, the hustle and bustle of gift-giving can often overshadow what truly matters—being present. Just a reminder to cherish moments with our children, whether that's through family traditions, snowy escapades, or heartfelt conversations. These memories are the true treasures that shape our daughters' lives. Taking a Meaningful Break We will be taking a short hiatus for the podcast and I encourage you to immerse yourselvef fully in the season's magic. This is definitely not the end of the podcast, but a chance to recharge and return with renewed energy and insights in the new year. Resources for Reflection and Growth To continue your growth as a dad even during the break, I suggest youo explore the Fatherhood Insider resource. This platform offers an extensive course library, interactive forums, and actionable roadmaps tailored for fathers navigating the complexities of parenthood. Join the Community Don't forget to connect with fellow dads by joining the Dads with Daughters Facebook community. It's a space to share experiences, seek advice, and find inspiration from other fathers who are equally committed to raising empowered daughters. Check the podcast notes for a direct link. Embrace the Joy of Fatherhood This holiday season, let's focus on the laughter and love that fill our homes. Appreciate the simple moments and remember that being a dad is a gift that keeps on giving. Happy holidays from the Dads with Daughters family to yours.   TRANSCRIPT Dr. Christopher Lewis [00:00:05]: Welcome to dads with daughters. In this show, we spotlight dads, resources, and more to help you be the best dad you can be. Dr. Christopher Lewis [00:00:15]: Hey, Hey, everyone. Welcome back to Dads with Daughters, where we bring you stories, tips, and inspiration for raising strong, independent women and helping you to be the best dads that you can be along the way. I just wanted to take a moment to connect with you as we approach the holiday season. It's such a special time of year. And if you're like me, it's also a time to reflect on what really matters, family, friends, and those precious moments we get to spend together. This season, I'm making it a priority to be present with my loved ones, and I want to encourage you to do the same. Whether it's watching holiday movies with your daughters, building a snowman, or just sitting down for a quiet conversation. These are the memories our kids will carry with them forever. Dr. Christopher Lewis [00:01:03]: To give myself and all of us a chance to really soak in the magic of the season, Dads with Daughters will be taking a short break over the next few weeks. Don't worry, we'll be back in the new year for more amazing guests, stories and insights to empower you in your fatherhood journey. Until then, I want to wish you and your family a truly joyful holiday season. May it be filled with laughter, love, and those simple moments that remind us why being a dad is the greatest gift of all. Thank you for being a part of this incredible community. Your support, your stories and your dedication to being present with your daughters inspire me every single day. Take care, be safe, and from all of us here at Dads with Daughters, happy holidays. If you've enjoyed today's episode of the Dads with Daughters podcast, we invite you to check out the fatherhood insider. Dr. Christopher Lewis [00:01:58]: The fatherhood insider is the essential resource for any dad that wants to be the best dad that he can be. We know that no child comes with an instruction manual and most dads are figuring it out as they go along, and the fatherhood insider is full of resources and information that will up your game on fatherhood. Through our extensive course library, interactive forum, step by step roadmaps, and more, you will engage and learn with experts, but more importantly, dads like you. So check it out at fathering together dot org. If you are a father of a daughter and have not yet joined the dads with daughters Facebook community, there's a link in the notes today. Dads with daughters is a program of fathering together. We look forward to having you back for another great guest next week, all geared to helping you raise strong and powered daughters and be the best dad that you can be. Dr. Christopher Lewis [00:02:50]: We're all in the same boat, And it's full of tiny screaming passengers. We spend the time. We give the lessons. We make the meals. We buy them presents and bring your a game. Because those kids are growing fast. The time goes by just like a dynamite blast, calling astronauts and firemen, carpenters, and musclemen. Get out and beat the world to them. Dr. Christopher Lewis [00:03:37]: Be the best dad you can be. Be the best dad you can be.

JCO PO authors Dr. Philippe Bedard (Staff Medical Oncologist at Princess Margaret Cancer Centre and Professor of Medicine at University of Toronto) and Dr. Alberto Hernando Calvo (Medical Oncologist at Vall d´Hebron University Hospital) share insights into their JCO PO article, “Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab,” one of the top downloaded articles of 2024. Host Dr. Rafeh Naqash and Drs. Bedard and Hernando Calvo discuss how combined transcriptome and ctDNA longitudinal analysis associates with pembrolizumab outcomes. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.  Today we are excited to be joined by Dr. Philippe Bedard, Staff Medical Oncologist at the Princess Margaret Cancer Center and Professor of Medicine at the University of Toronto, as well as by Dr. Alberto Hernando-Calvo, Medical Oncologist at the Vall d'Hebron University Hospital, both authors of the JCO Precision Oncology article titled, “Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in Advanced Solid Tumors Treated With Pembrolizumab.”  Thank you for joining us today. Phil and Alberto. Dr. Alberto Hernando-Calvo: Thank you. Dr. Philippe Bedard: Great to be with you. Thanks for having us.  Dr. Rafeh Naqash: One of the reasons we do this podcast, as some of the listeners who listen to this podcast regularly may know, is to bring in novel approaches and try to understand how the field is moving towards a space where we are understanding biomarkers better. So your manuscript that was published in JCO Precision Oncology fulfills many of those criteria. And interestingly enough, I was at a conference at the Society for Immunotherapy of Cancer last month earlier in November and a lot of excitement at SITC was revolving around novel transcriptomic biomarkers, proteomic biomarkers or imaging based biomarkers. So could you tell us a little bit about why you started looking at biomarkers? This is an extremely competitive field. Why did you think that looking at the transcriptome is somewhat different from or more interesting from tumor mutational burden PDL-1 than other biomarkers that we currently use? And that question is for you Alberto to start off.  Dr. Alberto Hernando-Calvo: So I think gene expression profiles may have a predictive performance as compared to already existing biomarkers and this was one of the points that we describe in our manuscript. The gene expression signature that we developed back in 2019 at Vall d'Hebron Institute of Oncology was initially developed based on over 45 different tumor types and tested in over 1000 patients treated with antiPD-1 and anti PDL-1. And back then and in this manuscript, we proved that for instance the gene expression signature VIGex that we developed has a potential complementary role to other predictive biomarkers. In this case, we observe this predictive power with ctDNA dynamics and we then see a correlation with other existing biomarkers such as tumor mutational burden. So I don't think we need to use one or the other, but rather they may have additive predictive power. So we need to better individualize predictive biomarkers based on tumor types and select the best combination possible to improve the performance.  Dr. Rafeh Naqash: I completely agree that one size does not fit all, especially in the landscape of immunotherapy. From your perspective, when you developed the original signature, how did you choose what genes to look at? I looked at the manuscript, on the methodology side, some of the signatures are pro-inflammatory STING interferon gamma based, so how did you try to identify that these are the 7 to 10 or whatever number of signatures on the transcriptome side? And then why did you try to combine it with ctDNA based changes?  Dr. Alberto Hernando-Calvo: Back in our initial manuscript, published in Med from Cell Press, we developed the VIGex gene expression signature, as I mentioned, with taking into consideration over 1000 tumor samples from FFPE that we can consider real world samples because they are from real patients coming from the clinic notes as part of real investigational protocol doing or performing biopsies on patients. We did observe after doing a VIGex research and doing different tests, we eventually collected these 12 different genes. Because there is a combination of both genes involved in the interferon gamma pathway, we have genes associated with Tregs as well as T cell memory cells. So it's not only looking at genes that are associated with T cell activation or CD8+ T cell infiltration, but also looking at genes that may be overactivated, overexpressed, an immunosuppressive tumor microenvironment. So it was both selecting genes, the minimum number of genes to do it more scalable and having the minimum dataset of genes and including in the signature genes that are already at targets for immune sequent inhibitors or are being tested in immunotherapy combinations.  Dr. Rafeh Naqash: Thank you. And Phil, for the sake of our listeners, could you elaborate upon this aspect of using ctDNA? So this was tumor-informed ctDNA from what I understood in the manuscript. You guys basically try to use it to understand changes in the ctDNA with treatment and then try to combine it with the transcriptome signature. How did the idea come up initially and how did you plan on combining this with an RNA-based signature? Because I have seen manuscripts and other data where people are either using one or the other, but not necessarily both together. So how did you guys come up with that idea? Dr. Philippe Bedard: Well, we thought that this was a great opportunity to look at the combination of the transcriptome as well as the ctDNA dynamics because we had run an investigator-initiated phase 2 clinical trial called INSPIRE at our institution at Princess Margaret from 2016 to 2018, where patients across five different tumor groups received single agent pembrolizumab. And we really did a deep dive on these patients where there were tumor biopsies before and while on treatment. We did exome sequencing, we did RNA sequencing to capture the transcriptome. And in a prior analysis, we had partnered with Natera to look at their Signatera assay, which is a bespoke ctDNA assay, to look at ctDNA dynamics using this test and the association with response outcomes as well as survival outcomes. So we thought that this was a really unique data set to try and address the question of whether or not there was complementarity in terms of looking at the transcriptome and transcriptome signatures of IO benefit together with the ctDNA dynamics. Dr. Rafeh Naqash: From a patient treatment standpoint, it sounded like you mostly tried to include individuals who were treated with pembrolizumab. Did this not include individuals who were treated with chemoimmunotherapy or chemotherapy with pembrolizumab? Just pembrolizumab alone? And if that's the case, some of the tumor types there included, from what I remember, ovarian cancer and some other unusual cancers that don't necessarily have approvals for single agent pembrolizumab, but perhaps in the TMB-high setting. So can you elaborate on the patient selection there for the study?  Dr. Philippe Bedard: Yeah, that's a great question. So at the time that the study was designed in 2015, this was really the early days of immune checkpoint inhibitor therapy, so we didn't have the approvals that we have now in specific tumor types for immunotherapy and chemotherapy combinations. So when the study was designed as an investigator initiated clinical trial, the idea was really to capture patients across different tumor types - so head and neck squamous cell carcinoma, malignant melanoma, ovarian cancer, triple negative breast cancer, and a kind of mixed histology solid tumor cohort, where we knew that there were some patients who were going to be immunotherapy responsive, where there was already approvals or evidence of single agent activity, and others where the responses were more anecdotal, to try and understand in a phase 2 clinical trial with kind of a deep dive, which patients benefited from treatment and which didn't. Dr. Rafeh Naqash: Interesting approach. Going to the results, Alberto, could you help us understand some of the important findings from these data? Because there's different sections of how you tried to look at the response rates, the survival, looking at the immune deconvolution, if you could explain that. Dr. Alberto Hernando-Calvo: So the first thing that we tried was to further confirm the external validation of this immune gene expression signature, VIGex in the INSPIRE asset. So what we observed at VIGex-Hot, the category defined by VIGex-Hot tumor microenvironment, was associated with better progression free survival. After including that in a multivariable analysis adjusted by other biomarkers such as TMB, PDL-1 or tumor type, this was also confirmed for overall survival. So then the next step was to really try to hypothesize if the addition of ctDNA dynamics, taking into consideration the ctDNA quantification at baseline as compared to cycle three, if those dynamics could further improve the predictive performance of VIGex categories taken in the baseline samples. What we did observe was that, for instance, VIGex-Hot tumors in baseline tumor samples that were having a ctDNA decrease, as I mentioned before on cycle three assessment as compared to baseline, were having both better progression free survival and better prognosis overall. Another important finding was the evaluation of response rate across tumor types considering both biomarkers. I would say the most important finding is that when we were considering a cold tumor microenvironment in baseline samples before pembrolizumab initiation plus an increase in ctDNA values, what we observed is that those patients were having a 0% response rate. So this may help as a future strategy either for intensification of immunotherapy regimens in a more individualized way or for an early stop to immunotherapy and try to avoid financial toxicities as well as toxicities for our patients. Dr. Rafeh Naqash: From the data that you showed, it seems that there was a strong correlation, as you sort of mentioned, between individuals that had ctDNA clearance and baseline immune pro-inflammatory signatures. So do you really need the transcriptome signature or could the ctDNA just serve as an easy quick surrogate? Because from a cost standpoint, doing whole transcriptome sequencing or more RNA sequencing or tissue standpoint, where tissue is often limited, can become a big issue. So do you think that validation of this may perhaps more revolve around using ctDNA as an easier metric or surrogate? Or am I overestimating the utility of ctDNA? Dr. Philippe Bedard: I think it's a really good question. In our data set which was relatively small, there were 10 patients who had ctDNA clearance, meaning ctDNA that was positive at baseline was not detected. And so 9 out of those 10 patients, as you alluded to, were VIGex-Hot. So the question is a good one, could you do the same with just ctDNA clearance alone, particularly in identifying these patients who really do well, who have long term disease control on immunotherapy? I think it's a tough question to answer because the field is also changing in terms of sensitivity of detection of ctDNA tests. So we know now that there are newer generations of tests which can detect even at logs down in terms of allele variants in the circulation. So I think we need more data to address the question. I think it is important as to what is the best test, what is the endpoint that we should be using from a drug development point of view in terms of really trying to push and understand which treatment regimens are the most effective and have early readouts in terms of activity. Because we all recognize in the clinic that radiographic response doesn't tell the whole story, especially early radiographic assessments using RECIST or other criteria that we apply in clinical trials. Dr. Rafeh Naqash: From a clinical trial standpoint, we often talk about validation of these studies. You may have heard of other tests where, for example, the NCI iMatch, which is incorporating transcriptome sequencing based approach to stratify patients as an integral biomarker for treatment stratification. Is that something that you guys are thinking of using, this approach where individuals who are signature highly inflamed perhaps get lesser therapies or there's a de-intensification of some sort similar to what people are trying to do with ctDNA-based approaches? Dr. Philippe Bedard: I think that's a great question. I think it makes a lot of sense. And certainly, with the new wave antibody drug conjugates in terms of identifying patients who have expression of targets for antibody drug conjugates, that's very attractive as an approach because we don't necessarily have IHC markers for all of the different targets of antibody drug conjugates. We don't necessarily have IHC markers to completely understand different contributions to the tumor microenvironment and whether or not tumors are inflamed. But it's also a challenging approach too because RNA-seq currently is not a routine clinical test. Sometimes there are issues, particularly in patients who have stored specimens that are formalin-fixed and paraffin-embedded in terms of the quality of the RNA for RNA sequencing. And it's not always feasible to get pre-treatment biopsies and turn them around in an approach. So I think it is an attractive approach for clinical trials, but it's a hypothesis that needs to be tested. It's not something that is ready for clinical prime time today in 2024. Dr. Rafeh Naqash: One of the other interesting observations that I came across in your manuscript was that tumor mutational burden, interestingly, did not correlate with signature high tumors. What is the explanation for that? Because generally you would expect a TMB high to perhaps also have an immune gene high signature. Could it have something to do with the tumor types because there was a heterogeneous mixture of tumor type? Or I'm not sure. What else could you possibly think of that you didn't see those correlations or just sample size limitations? Dr. Alberto Hernando-Calvo: Yes. So our findings are consistent with prior data suggesting for instance T cell inflamed gene expression profile was also not correlated with tumor mutational burden and both biomarkers in a prior publication. So to have additive predictive performance for identifying patients most likely to benefit from anti PD-1 regimen, so we somehow were expecting this observation, the fact that both biomarkers are not very correlated. Dr. Rafeh Naqash: So given the proof of concept findings from your study, Phil, what is the next interesting step that you guys are thinking of to expand this? Would you think that a nivolumab-ipilimumab treated cohort would have similar findings? Or is this a treatment specific single agent immunotherapy specific correlation that you found versus something else that you may find in a nivo-ipi cohort or a doublet immune checkpoint cohort?  Dr. Philippe Bedard: The findings are really hypothesis generating. They require additional validation. And you're quite right, there may be nuances in terms of specific tumor types, combinations with other immunotherapy or combinations with chemotherapy or other agents. So I think it would be great if there are other data sets that are collecting this type of information that have ctDNA dynamics and also have transcriptome and potentially exome or genome analysis to look at these types of questions because the field is moving quickly and we really need more data sets in order to understand some of the nuances and greater numbers to validate the signals that we see. Dr. Rafeh Naqash: And one thing, as you said, the field is definitely moving very quickly. I was meeting with a company an hour back and they have an imaging-based approach using fresh tissue to look at pharmacodynamic biomarkers. And I used to work in the NCI with a group that was very interested and they developed an immuno-oncology pharmacodynamic panel that has been used and published in a few clinical trials where they did phosphorylation status. So the final theme that comes out of most of these research based studies that are being done is that one size does not fit all. But the question that comes to my mind is how many things do you necessarily need to combine to get to a predictive biomarker that is useful, that is patient centric, and that perhaps is able to identify the right therapy for the right patient. What is your take on that, Phil?  Dr. Philippe Bedard: Yeah, that's a great question too. The challenge is it depends on the context in terms of what degree of positive predictive value do you need as well as the negative predictive value to drive clinical decisions. So I think in certain situations where you don't have other approved treatment options and with a therapy that is potentially low toxicity and low financial toxicity, then I think the bar is very high in terms of being able to really confidently identify that patients aren't going to benefit. I think the nuance and the challenge becomes when you move into earlier lines of therapy, or when you talk about combinations of agents, or trying to understand within the context of other available options, particularly with treatments that have significant side effect profiles as well as financial risks, then it becomes a much more nuanced question and you really need comparative studies to understand how it fits versus the existing treatment paradigm. So I'm not really answering your question with a specific number because I think it's hard to give you a number. Some of that we also need input from patients in terms of what kind of level of validation do you need and what kind of level of discrimination do you need in order to drive decisions that are meaningful for them. Dr. Rafeh Naqash: Definitely early days, as you pointed out. More and more work in this field will hopefully lead us in the direction that we all want to go in.  Now, going to a different aspect of this podcast, which is trying to understand the trajectories for both of you, Phil and Alberto. And as you mentioned, this project seemed to have started in 2015. So I'm guessing there's a history there between Princess Margaret and Vall d'Hebron. Could you highlight that a little bit? And then perhaps, Alberto, after that you could tell us a little bit about your career when you worked at Princess Margaret as a fellow and then now back at Vall d'Hebron. Phil, you as well. Dr. Philippe Bedard: So absolutely. We have a long history of collaborating with Vall d'Hebron in Barcelona. It's really a great cancer institution with a lot of like minded individuals. We have a formal partnership and we have a lot of informal links in terms of scientists and clinicians who we work with and who we collaborate with on early phase clinical trials, as well as through different investigator networks and other translational projects. So this was really how this collaboration came about and we were fortunate to have Alberto, who came to work with us for two years and brought this great idea of looking at this signature they had developed at Vall d'Hebron in their phase one group and applying it to a data set that we had through the INSPIRE clinical trial.  Dr. Rafeh Naqash: Sounds like a very successful academia-academic collaboration, which is very nice to see. So, Alberto, could you tell us a little bit about your career trajectory and how you ended up at Princess Margaret and then back at Vall d'Hebron and what you do currently? Dr. Alberto Hernando-Calvo: Yes. So I did my oncology residency at Vall d'Hebron in Barcelona, Spain. Then I decided to further specialize in early drug development as well as head and neck cancer oncology. So I decided to pursue a clinical research fellowship under the supervision of Phil Bedard, among others. And so we decided to further validate the signature that we had developed both in the cancer genomic lab at Vall d'Hebron Institute of Oncology and the phase one unit at Vall d'Hebron, and apply the signature that have been originally tested in patients receiving anti PD-1 or anti PDL-1 combinations in early phase clinical trials. In the phase 2 clinical trial of INSPIRE, where we also had ctDNA dynamics and allowed us to test both biomarkers and see that additive predictive power when we were using both. That was one of my research topics under the mentorship of Dr. Bedard and my fellowship at Princess Margaret. And this was one of the manuscripts describing all the findings of this collaboration between Vall d'Hebron and Princess Margaret Cancer Center. Dr. Rafeh Naqash: And then, Phil, if you could highlight some of the things that you've done over the course of your career and perhaps some advice for early career junior investigators and trainees.  Dr. Philippe Bedard: I finished my oncology, medical oncology training at the University of Toronto in 2008. And then I did a breast cancer fellowship in Brussels at Breast International Group. At the time, I was really intrigued because it was really kind of the early days of microarray and RNA signatures in terms of expressing signatures were being used as part of a clinical trial that BIG was running called the MINDACT Study. And so when I finished my fellowship, I came back to Princess Margaret, started on staff. I've been here now for 15 years. I was fortunate to work with the phase 1 group and kind of my career has sort of morphed in terms of early drug development as well as genomics. I've been involved with the American Association for Cancer Research project GENIE, where I'm the current chair. This is really an international data sharing project with panel based sequencing, which both Princess Margaret and Vall d'Hebron have contributed to. And I've been fortunate to work with a number of really talented early career investigators like Alberto, who spend time with us in our drug development program and launched transitional research projects that leverage some existing data sets at their own institutions and also bring together with different research groups at our institution to lead to publications like this one. Dr. Rafeh Naqash: Thank you so much. This was very exciting. Phil and Albert, thanks for joining us today and thank you for allowing us to discuss your interesting manuscript and hopefully we'll see more of this biomarker work from you guys in the near future, perhaps published in JCO Precision Oncology.   And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.     The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this week's Dads with Daughters podcast, we welcomed Katie Koestner, an influential activist and the executive director of the Take Back the Night Foundation, who shared powerful insights on teaching daughters about consent, autonomy, and resilience. Here are some key takeaways from their enlightening conversation. Understanding Consent and Autonomy Katie Koestner underscores the critical importance of educating daughters about consent and bodily autonomy. Consent is not a one-time agreement that cannot be retracted; it can be revoked at any moment. Katie emphasizes teaching daughters the difference between regret and rape, highlighting that a lack of initial resistance does not imply consent. This understanding is vital for fostering an environment where daughters feel empowered to assert their rights and boundaries. Healing from Trauma: A Collective Journey Healing from trauma is an arduous yet rewarding journey that necessitates patience and collective support. Katie reflects on her own experiences, noting that regaining power and control over one's life is a long-term commitment. It's essential for parents, especially fathers, to support their daughters through this process without taking away their agency. Fathers should help their daughters navigate decisions collaboratively, emphasizing that the journey and growth are more important than immediate outcomes. Mentorship and Community Involvement Community involvement and mentorship programs like Take Back the Night are instrumental in fostering resilience and support networks for young women. Katie encourages fathers to guide their daughters in engaging with empowering communities that can offer strength and solidarity. Participating in such programs helps build a sense of belonging and mutual support, which are critical for personal empowerment. Fostering Equal and Respectful Relationships To raise daughters who thrive in healthy, respectful relationships, fathers need to challenge archaic notions of women needing to be "taken care of." Katie advocates for teaching daughters the value of equality and collaboration within relationships. It's crucial for fathers to set an example by treating women with respect and equality in their own lives, reflecting these values in everyday interactions. Encourage daughters to seek partners who value collaboration, mutual respect, and independence rather than falling into roles dictated by outdated stereotypes. Practical Tools for Empowerment Katie offers practical advice for fathers wanting to empower their daughters. She suggests affirming their worth based on their talents, energy, and intellect, rather than appearance. Role-playing challenging scenarios can also help daughters prepare for difficult situations and build the confidence to handle them independently. Katie's conversation with Dr. Lewis reiterates the significance of dads actively contributing to their daughter's self-respect and ability to navigate the world confidently. Take Back the Night and Advocacy Katie remains a staunch advocate against sexual assault through her work with the Take Back the Night Foundation, which organizes events to raise awareness and support survivors. She encourages community involvement in various forms, such as bike races, walks, and vigils, to promote solidarity and resilience. Fathers can support this cause by participating with their daughters, fostering a shared commitment to ending sexual violence. In conclusion, the episode with Katie Koestner on the "Dads with Daughters" podcast provides valuable insights into raising empowered, resilient daughters. Through understanding consent, supporting the healing process, fostering respectful relationships, and active community involvement, fathers can profoundly impact their daughters' lives, guiding them toward independence and confidence. TRANSCRIPT Dr. Christopher Lewis [00:00:05]: Welcome to dads with daughters. In this show, we spotlight dads, resources, and more to help you be the best dad you can be. Dr. Christopher Lewis [00:00:16]: Welcome back to the Dads with Daughters podcast where we bring you guests to be active participants in your daughters' lives, raising them to be strong, independent women. Really excited to have you back again this week. And, you know, every week, I love being able to sit down, talk to you, and work with you as you're walking through this journey that you're on to be the best dad that you want to be, and working with your daughters to be those strong, independent women that you want them to be as well. That's why every week we have this opportunity to be able to sit down, talk, and to be able to learn and grow from each other, but also from the people that come on to our show. And it is really important that we're open to learning and growing and being able to truly hear what people have to say and to be able to take that in, internalize it, and turn it into something tangible that we can then use to be those dads that we want to be. And that's why every week I love being able to bring you different guests, different people with different experiences that can help you on this journey. And today, we've got another great guest with us. Katie Kessler is with us today. Dr. Christopher Lewis [00:01:22]: And Katie is a activist on sexual assault. She has worked for many years in the Take Back the Night Foundation. She is the current director of the Take Back the Night Foundation. She has a a story that we all should be here to be able to see what we can do to be able to assist our own daughters in having healthy relationships, but also to be safe in their lives as they get older. And I'm really excited to be able to have her here and to be able to have her share her story and also to provide you with some some things to think about as we're moving forward in our own parenting journey. Katie, thanks so much for being here today. Katie Koestner [00:02:07]: Absolutely. Chris, thank you for having me. Dr. Christopher Lewis [00:02:09]: It is my pleasure having you here today. I'm really excited to be able to share your story because it's not an easy story. And definitely, it's not I'm sure it's not been an easy journey as you have become the advocate that you've become in sexual assault. And I I know that not everyone has heard your name before and not everyone knows that story, but only you can tell that story in your way. Can you tell tell me a little bit more? Can you share your story with us and what led you to being the activist that you are today on sexual assault? Katie Koestner [00:02:43]: Absolutely. I am delighted to do so. So I think for all the dads out there, importantly, I am the daughter of an FBI agent and a homemaking mom. I grew up outside of Atlanta, Georgia, and then my dad was transferred to Harrisburg, Pennsylvania when I was in middle school, and I had a younger sister. I was pretty darn ambitious in every way, and, loved, I would say, everything from softball and swimming and field hockey to clarinet and trying to miss none on the SAT. I won a scholarship and lived in Japan when I was 16 on to 17 in high school. I was adventurous in every sort of the word. I decided to go up to college and went to the College William and Mary in Virginia as I double majored in Japanese and chemistry. Katie Koestner [00:03:34]: And the orientation was a whirlwind whirlwind experience, and I met a very handsome he could speak 3 languages, wanted to be a brain surgeon, played a great game of soccer, incredible, potential prince charming and well beyond what I had encountered in my life so far and quickly, you know, went out and hung out with him. And he asked me out to dinner probably the 3rd weekend and to the fanciest, most expensive French restaurant in town. And any of you who don't know my story, I'm not gonna share all of it here because it's on TED Talks, and I've only lectured at 5,000 schools, and I'm sure there's clips here and there. I've been on open Good Morning, American, CNN, NBC News, lectured in front of a quarter of a 1000000 people on the mall in DC, at the United Nations, at the Pentagon, just a few places along the way. But the end of the story is I simply trusted this guy. He paid for a very expensive dinner, and I thought he would respect my being a virgin and waiting till I was married. I wasn't drunk at dinner nor that night. And I simply told this guy no. Katie Koestner [00:04:39]: And for historic purposes, I'm sure I am older than many of the dads, who are listening. I might be younger than a few, but I was 18, and this was 1990. And I am the first woman in history to speak out nationally and publicly as the victim of date rape and appeared on the cover of Time Magazine at age 18. So I I stopped there just for a second because I think any dad listening is wondering now, when I already alluded to the fact my dad was an FBI agent, whether this, perpetrator was going to live to see another day when I knew exactly where he lived and could talk tell my dad. But, unfortunately, back then, my dad said I shouldn't have had the boy to my room and it wouldn't have happened. And while I think he probably had mixed emotions, and I don't wanna oversimplify, I do want to say that he was very traditional and very protective and very conservative, which means in high school, if a boy came to get me, he would probably fingerprint the guy's the front doorknob. He would wear his arsenal strapped on the outside as he answered the door. He would usher the potential boyfriend to the family room with the dead animals hanging on the wall and then motion to the back of the house where the targets for bows and arrows were set up. Katie Koestner [00:05:59]: He was easily intimidating to most guys. So before I go on, I I would say that my dad's never heard me speak in all my life, which is hard, and it's one of my motivations for coming on your show, Chris, because I have two main themes that I would get across, and then we can delve into the details. But I'm gonna start with the end first because this is way too important to me. My father told me what to do in regard to boys. He was very protective, and I never I never had a bad boyfriend in high school. Maybe that's because my dad was looming in the backdrop at all times, But I will also say to all the dads, protecting your daughter does not serve her. She's gonna have to do it herself at some point. And if not in high school, then when? So if she can learn how to fend for herself and navigate situations on her own, you are gonna have a much stronger, resilient, confident daughter who will be able to suss out when things are not safe by herself and calling you for help is not what you want to have happen. Katie Koestner [00:07:11]: You want her to navigate the hard situation, to come home that night or next morning at breakfast, and to say, dad, I did it all by myself. Sensed this one comment he made. I was around his friends who were making fun of women, and I knew better that this was not what I wanted, and I'm deserving of more. Do you want her to say that when what I wanted, and I'm deserving of more. You want her to say that when she's 14, when she's 16, and then you'll know when she goes off into the world, she's gonna do it better on her own because she had you to fall back on if she had to. But I would send her out on every date saying, you've got this. You deserve respect. It's not about your appearance. Katie Koestner [00:07:58]: It's about your amazing talent, your energy, your grace, and your brilliance. If you compliment her just on her appearance, you're gonna teach a frail daughter. I don't care how pretty she is, but you've got to compliment her on something other than that. So I start with, dads, don't protect your daughters. Let them teach themselves how to protect themselves. And the second thing I would say is be mindful of how you talk about women at all times. Be mindful of what you watch, what screens you're on, how you do or don't comment on women in movies, women in television, women in the media, women in politics, women in your work workforce. What do you say about women that's the same or different from men? And the more you treat all genders the same in terms of your analysis and your accolades or your criticisms, the better off your daughter is gonna learn how to navigate the world through equity and respect. Katie Koestner [00:08:57]: And then lastly, even if you're separated from the birth mother of your daughter, even if she is the worst person you've ever met, God forbid, always hold your hate inside and treat everyone even when they're wrongfully treating you, even if they're a train wreck of a human, it's really important that you teach your daughter that denigration is always wrong even when somebody else is wrong. So sorry that was a mouthful, Chris, but, like, I wanted to get those things out on the table and get dads really thinking about them because those two important things are probably the most helpful I can be. And I I would also footnote that I do have children now of my own. I have 16 year old twins. They're not girls. They're boys. And so I I'm on the flip side of your your equation. I'm a mom of boys, not a dad of a daughter, but I think we could talk about that later on is, like, how do you parent all your kids and how when your daughters are out on dates, if they if they actually like boys, who knows? What does that look like? Because I'm raising my sons. Katie Koestner [00:10:02]: I think they're both into girls, maybe not quite so much yet, but I I think that's the track they're on. I'm not too judgy. People are people, but I definitely want them to be somebody's best date and best memory even if they're not in men. I want them to be good, humble, respectful young men, and that's what you should be asking your daughters to look for if they're into men into boys. So and don't look me up if your daughter wants a date. Like, my boys are not once, like, ready for, like, full time studying and the other one's too much on his games to be even intriguing to a girl yet. So don't look me up for dates for your daughter. Dr. Christopher Lewis [00:10:40]: I love what you shared right there. And I think and I have to say, I'm sorry that you had that experience with your own father and but I appreciate what you had to say and the advice that you gave to fathers because I think it is so important for us as men and as fathers to be able to support our daughters in many different ways. And you talked about the fact that for you, one of the the first things that you mentioned was to treat your daughter to fend for herself, to be able to navigate situations by herself. I want you to think back to your own father and what could he have done for you that would have allowed you or made you feel that he was giving you the ability to fend for yourself? And what can other dads do tangibly to be able to start on that path with their own daughters? Katie Koestner [00:11:29]: Yeah. Fantastic question, Chris. And this is called, I would say, one of those conversations of courage. And not every human is wired to have this kind of conversation. And, I mean, I'm gonna be honest. A lot of people aren't comfortable with their own sexualities, their own relationships, and and men and women both. And I'll footnote it with this. If you're a dad and wants to have what I'm about to describe with your daughter, And you're like, oh, crap. Katie Koestner [00:11:55]: I totally can't do that. I don't have that vocabulary. I couldn't come up with that sentence structure. This makes me feel awkward. I I could look I'd be, like, so nervous. Like, that's totally okay. Not everybody has to be you know, not everyone's a brain surgeon. Not everyone's a psychologist. Katie Koestner [00:12:10]: Not everyone's into like, you everybody has different skill sets. What I want to have happen right now is for the dads listening to hear me model it and then say, if I don't think I can say this, I should at least tell my daughter. There's a few things I'm really awkward at saying that I want you to hear and then listen to this podcast. Push play, like, right here. Like, oh, I've listened to this woman, Katie, once, and she was trying to say it. I I can't do it the same way, but pretend it's my voice and I'm your dad. And, like, seriously, I don't I don't care. You it takes a team of, like, 8 or 9 people to raise a a great kid, and you have to have a lot of role models and a lot and all that matters to me at the end of the day is is intent and try. Katie Koestner [00:12:54]: I intend to do this. I tried to do this. I might not be great at it. People will see your intent and that you tried. So here's kind of what I would say. You said, how could my dad have done it? And it's very simple. You'd you say, like, she's really interested in a guy or somebody, a date, a prospect. She's going out to a party. Katie Koestner [00:13:11]: She's going to her first homecoming. She's going to the think of any number of potential social situations. The best thing you can say is, darling, sweetie, whatever you say. Jenny, Susie, you know, Aloysius, whatever her name is. You say, I know tonight's really important. I don't know how many of these kind of social things you've done, but what's really important to me is that you know you are that good. You know you deserve respect. You know what your morals, your values are. Katie Koestner [00:13:40]: You know what you want to to have happen tonight. Keep that in mind throughout the whole time. You wanna walk away from tonight feeling positive, respected. You wanna come home and feel like tomorrow's gonna be a great day. And if someone treats you at all with disrespect, you know that you don't have to take it. You don't have to stay in that environment. There's never an okay reason where someone should say anything that's degrading. No one should touch you in a way that makes you uncomfortable, and you can navigate a way out. Katie Koestner [00:14:12]: If you want to, we can role play some of the ways you could do that tonight. If you think you're all set, I'm here a phone call away, a text away if you need me. That's all. You just just remind her she's worth it. Put her eye on the prize, which is, like, at the end of the night, she wants to come home safe, respected, and tomorrow is gonna be a great day. And that's it. You don't have to go into the nitty gritty. You don't have to say, like, what if he tries to like, girls might feel awkward about that. Katie Koestner [00:14:40]: That could be a different class. Like, if somebody tried to touch you, how are you gonna if she wants to go there. But if you're just on square one, that's all you have to say. It's like, you've got this. Not like go, oh, you look so pretty, sweetie. You don't need don't say her dress is great, her skirt's cute, her hair looks great. That's fine, But, really, more important than how she looks is being being confident in how she should be treated all all night or all day. Like, whatever the event is, focus more on how she should feel and end up being respected. Katie Koestner [00:15:12]: Not like I mean, do logistics. How's she gonna get home? Who's driving? What happens? You could do some logistics. But if you just constantly say you deserve respect, you're amazing, you're talented, how do you want this night to end? Just focus on the the finish line all the time. I mean, what do athletes do? What it what's anyone who wants to a date is nothing more than an event where you wanna succeed. And succeed is, like, be safe and not be assaulted and have fun. Dr. Christopher Lewis [00:15:38]: Now one of the things you talked about in your story, you talked at the beginning that you met the gentleman at college, kind of the prince charming effect in many different ways. And then you talked about the importance of really as you're parenting and as you're working, not in in our situation here, in my situation, working with my daughters to identify and try to figure out what to look for in a relationship, whether it be with a man, with a woman, whatever it might be. I guess as you think back to your experiences and the experiences of others that you've spoken to on your podcast, Dear Katie, survivor stories or in your experience in speaking in so many different places. What advice would you give to fathers that are listening that could help them with their daughters to be able to navigate those relationships and help them to provide them with the tools that they should be looking for in those healthy relationships. Katie Koestner [00:16:41]: A healthy relationship, you're gonna hear a lot of working together, collaboration. It's not me, me, me, me. The partner or guy who's all about himself and constantly boasting or bragging, he's actually frail. Like, frail in his ego in that he might need to also eventually use his partner as part of his power play. And anyone who simply talks about themselves, their achievements, it's fine to be a high achiever. That's great. It's fine to be talented and smart, but it's really important to find a partner who's also equally interested in having a partner who is also talented, also brilliant, also smart, and wants to, like, do things collaboratively, not for. You know, old school men are like, I'll do this for you. Katie Koestner [00:17:30]: I'll take care of you. That language is dead. Nobody should be taken care of anymore. We're not in the dark ages. So I think the woman today needs to dad to say, you've got this on your own, and the best thing you can hope for is a collaborator, not a take care of her because no one's gonna be able to take care of anyone else unless you're being purchased, essentially. Being taken care of means you have less power, less equality, less confidence. No one needs to be taken care of. I think that this is not to say, and I wanna nuance this, you can have 2 totally different lanes. Katie Koestner [00:18:08]: And I'll even go so far as to say it's fine if one is a full time stay at home parent, and all they want to be is a, maybe, full time mom. I wanna have 5 kids. I wanna bake cookies. I wanna clean the house. I wanna be the PTA. I wanna do all I wanna volunteer. That's all fine as long as it's a pure choice. So, I mean, the gender roles, who cares? But the idea is, is there respect and valuation that's equitable between the partners? And that's a lot that's thinking way ahead. Katie Koestner [00:18:40]: But at the root of a relationship, when you start out, you can get your daughter thinking about how how does this partner value what I do? How does he or they see what I do? And if she's being taught and trained that she needs someone to be taking care of her, that's gonna only cripple her long term safety and success. Dr. Christopher Lewis [00:19:02]: I appreciate that as well because I think you're right. I mean, I know in my own situation with my own daughters, I don't want them to feel crippled by to their success as you just mentioned. I want them to be able to have those healthy relationships. And Katie Koestner [00:19:15]: Yeah. I think what I'd like to say, Chris, is it's gloriously amazing to be the power couple. Seriously, who wouldn't want that? You see you see a few that are still, like, kept wise and, you know, people kind of pity them now. Nobody's like, oh, what a glorious, fabulous relationship you have because all you do is dress up like a Barbie doll, hence the movie. But I think it's an age of glorious and we went through some individual like, you might go back. We're so old, Chris. Like, the eighties, you know, we had all the, like, me, me, me's. Then we had you know, the decades are interesting when we look back at them, but I think we're we're hopefully going into an age of this amazing it's the combination of individuality that blends together into cooperation to build something even more beautiful. Katie Koestner [00:20:08]: And I do think, you know, partnerships and relationships can be that good. It's really there's no such thing as a renaissance person anymore. Like, it's impossible. We have micro slices of everything in the world. So the best thing we can hope for is 2 really dedicated, kind, amazing, committed people who say, like, things are gonna get hard. That's I actually, that brings me to a really good point. Fights are good. Disagreements because you know why? The moment she comes your daughter comes home and is like, oh my god. Katie Koestner [00:20:39]: He made me so mad. You that's good. That's like, okay. Well, how did how did you resolve it? Because if you can't work together and not that's the tell. That's like the next level tell. If you have to think about the first date tells, like, where he makes some random joke or he can't pay look you in the eye if he's checking his phone every second. If he's asking you who your follow these are warning signs. Is he gonna say, why are you following him? What do you see? Like, jealousy is a really bad one. Katie Koestner [00:21:08]: Telling, like, why you why you not not allowing your daughter to have other male friends. That's a big red flag. Like, if a guy goes out with you and I mean, hello. It's it's 2024. Like, if you can't have male friends I remember I was in the chess club in 6th grade, and I was, like, the only girl. So I only hung out with boys, and I was not dating the entire chess club. Let me just tell you. No. Katie Koestner [00:21:34]: It was not like that. I was just like, these are the cool, smart guys. Like, I know. And luckily, back then, I had male friends, but I think you've gotta have a male partner who's good. You can talk to a guy and not be jealous. Like, even if he's cuter than you. Even if he's better at soccer than you. Like, who cares? Like, a secure guy is what you want. Katie Koestner [00:21:56]: He's not constantly jealous because he's ultimately gonna be manipulative and and doing power plays. That I would say that's another one. I'm thinking small things. I don't care about, like, send you flowers and open the door. Who cares? Sometimes people get hung up on, like, oh my god. I can't see the guy who holds the door. I'm like, give it up. Like, he's just trying to be nice. Katie Koestner [00:22:16]: Hold the door for him. If he sends you flowers, send him flowers. I think you break all the rules. And if he spies into silly stuff like guys can't get flowers, what's wrong with you? Again, it's 2024. I mean, maybe you don't wanna paint your nails blue as a guy, but that's fine. But if they buy into too many rigid stereotypes, there's going to be a problem down the road. And I think building in that, like, wow, creativity is helpful because later in life, the more open minded and creative someone is by the time they get to our age, Chris, you bet they're gonna get really dry and boring if they don't have a creative open mind. You wanna see all of those awesome traits. Katie Koestner [00:22:56]: I guess I last thing is do pay attention. I hate to say this, but many rapists, we didn't talk about this, many rapists themselves were also victimized. So do pay attention. No. It's a little bit let's say a few stats. Like, 1 in 4 women or girls is raped sexually assaulted in her lifetime. About 1 in 6 to 1 in 8 men the same. Now the difference is the 1 in 6 to 8 men often go on to become perpetrators. Katie Koestner [00:23:22]: And the 1 in 4 women, a lot of them go on to be victimized again because once you've had it happen once, there's such a huge blow to your confidence and ego as a woman. Many women turn that against themselves, their shame and blame, and many men turn it outward as anger. So a young man's own experience with relationships and and or abuse is really important to find. I mean, you don't wanna, like, quiz him on the first date and give him an interview, but you do wanna find out and see how do they if they have a mother, how do they treat their mother? If they have a father, how do they treat their father? How do they do they fight constantly? Is there a lot of tension? I hate to say it. It's not what they what do your parents look like? Because then I'll know how you look when you look old. Okay. That's fine. If the girl's like, I wanna see your dad. Katie Koestner [00:24:10]: Is he bald to know if he'll be bald? No offense taken. But, like, I think that's so not important. I mean, it is more important to see how they interact, though, with their siblings and with their parents. That part's really important. Dr. Christopher Lewis [00:24:26]: You know, those numbers are really staggering. And, you know, when I think of 1 in 4 girls experiencing this type of trauma, I guess one question that I would ask of you is thinking about that stat, how can fathers support their daughters if they come to them and say, I've experienced this trauma? Katie Koestner [00:24:46]: Okay. Two best sentences ever. Ready? 1 is well, 3. 1st is, I'm so glad you trusted me enough to tell me. 2nd is, I'm so sorry this happened to you. And thirdly is, what can I do to help you right now? That's it. And then everything else you're gonna have to figure out as you go because everyone's gonna be different. The situation might be urgent. Katie Koestner [00:25:08]: It might be immediate danger. It might be and I'll just nutshell it this way. There's 3 things to think about all the time. First one and I'll do them in order of expiration date. If it's recent, medical attention is paramount. Medical attention also means collecting evidence. You have 3 to 5 days after a sexual assault or rape to get evidence collected. It's free. Katie Koestner [00:25:29]: It's done at usually a hospital rape crisis center. It can be held evidence can be held for up to 2 years. There's no pressing immediacy to to go forward with the district attorney. But if you don't get the evidence, it can't be used later. And that's important because what many of the dads thinking about right now, it may not make sense. 84% of sexual assaults involve someone the victim knows. Trust, likes, not a stranger off the street. So if you get your thinking evidence collected, well, we already know who it is. Katie Koestner [00:25:57]: Even microscopic patterns of bruising and tearing on the victim can prove what her body position was in, whether she was asleep, passed out, if she was up against a wall. Like, all of it now is so great and scientifically proven that can help sway a jury if there was ever a trial about the likelihood of consent. So medical, medical, medical. And then, of course, pregnancy, STIs, all potential and have them looked at immediately. And, obviously, we've got a shape shifting goings on about what to do about unwanted pregnancies, including through rape across the country. So you'll have to think about what state you're in and what your okay. So that's first. And second after medical is reporting options. Katie Koestner [00:26:39]: If it's within 8 years, most states will take a rape case for criminal prosecution. If a girl is a minor when this happens, it might even be longer. But mindfully, let's nuance this a little bit. Let's say she's 14 and her boyfriend's 17. That could be statutory rape in most states, even if it's her boyfriend. So if your daughter is 14 having sex with her 17 or 18 year old boyfriend, that technically could be rape in most every state in the country. I'm not sure you wanna prosecute her boyfriend if she really likes him, if you find out they had sex, but I'm just letting you know. If indeed it was an adult, let's say it was her 30 year old soccer coach, that's definitely gonna be sexual abuse of a minor, and the statute of limitations on that can be much longer. Katie Koestner [00:27:25]: It can be entirely a whole lifetime. So the age does matter and the state does matter for how long you have to criminally prosecute. Luckily, luckily, Take Back the Night, the foundation has started. The, the Take Back the Night predates me by a lot. It's over 50 years old as a movement around the world to end sexual violence and support survivors. But over 20 years ago, I corralled all the event holders and created the foundation. But we, about 4 years ago, also put together something called the sexual assaults victims legal support hotline. So that is so important. Katie Koestner [00:28:02]: It's 1567 shatter for any dad listening. That's free. It's confidential, and it puts you through to an attorney who's steeped in this kind of information who can go over your rights and options. I just put that out there in case someone's all of a sudden interested. But that that's criminal. Then you also we have 2 more systems of reporting of justice. So I think of them as the 3 c's. We have the criminal system, then secondly, we have the civil system. Katie Koestner [00:28:30]: Civil is where let's say your daughter was assaulted by the soccer coach at school. She could potentially sue the school. You you know, you all could because of sexual assault of a minor and failure to protect her and all kinds of things. A civil suit, you usually just have 2 years. Again, there's some exceptions. The third one, though, is the campus reporting system. If it's a college, you have as long as the perpetrators affiliated with the college, you can report it and have some sort of adjudication. If it was your high school or elementary school or middle school, same deal. Katie Koestner [00:29:05]: There's also a school campus system. So remember, criminal, civil, and campus are three areas where you can report. And that legal support hotline I just mentioned, 567 shatter, is a great option to learn about any and all. The third thing so we did first is medical attention. 2nd is reporting. The third thing to tell her is emotional or long term support and healing. There's no expiration date. Obviously, that can be done anytime. Katie Koestner [00:29:33]: There's no one size fits all. It could be their rabbi. It could be their priest. It could be a professional rape crisis counselor. It could be online BetterHelp. It could be there's a million different ways to get emotional support, but it takes more than one person to heal. Meaning, the victim by themselves almost always benefits from having someone else to talk to. And sometimes the parent needs also support and counseling. Katie Koestner [00:29:57]: You're a secondary trauma victim. You're trying to help your daughter, and it can feel exhausting. So don't hesitate to do good self care for you and your partner along the way or your other children. You know, it can be so devastating and frustrating, and the spin out can include everything from drug addiction, alcohol addiction, suicide, eating disorders, like metal, all kinds of depression, it can be really rough. Bodily trauma of a sexual nature is just really hard to process. Dr. Christopher Lewis [00:30:28]: One of the things that I guess from what you 2 were talking about is that education is important. And especially health and wellness education when it comes to our children's bodies and helping them to understand that. What would you say are some practical steps that fathers can take to educate their daughters about consent and what they should know for themselves as they go out into the world? Katie Koestner [00:30:53]: Well, some schools do a really good job of consent education. Many do not. But essentially, that was the whole if anyone researches back into my case, when I was raped at William and Mary, the entire country and William and Mary's policy had sexual assault and rape as only happening to women by definition because only women were property and rape was a crime of property. That's the history of it. You know, when you hear the phrase damaged goods, damaged goods basically meant a woman was no longer a virgin. She'd be more expensive to marry off, and that's where that phrase came from. And I was the one who came along at 30 3 years ago, Chris, and said, I'm not damaged goods. And if a man doesn't wanna marry me, I don't wanna marry him. Katie Koestner [00:31:37]: And why is rape the only crime where force is required? If I reached out and said, give me your money and you had your wallet in your hand and I just took it, I wouldn't have to you wouldn't have to say, well, she punched me to take it. If I took your wallet, I stole from you. Like, whether or not you, like, had a very nice gold watch on, you could be, you know, wearing expensive clothes. No one could say, oh, you must give away lots of money and be rich. Why would you miss your wallet? You were asking for it. But I go back to consent because I helped rewrite the law to say it should be simply the lack of consent, not the action of resistance. And dads, dads, dads, that's critical. Your daughter doesn't have to fight off her attacker, and she doesn't even have to say no even though that would be great, I'm sure, in your minds. Katie Koestner [00:32:26]: But if she freezes up and doesn't feel like she can do anything and just lays there, that's still not consent. So it's really important for you to validate. Like, don't rank how she responded. Like, if only you had been, like, superwoman and had out your gold braces and your golden whip and, like, your steel belt, you know, and gotten the guy. Like, who cares? It's over. It was still wrong. It's not, like, more wrong or less wrong. It's just wrong wrong. Katie Koestner [00:32:53]: So all rape is wrong wrong. There's not like, oh my gosh. I here's a fun story, Chris. In all the education I do, one time I was talking to some boys in high school, and one was like, but, you know, what if she leads me on? And I just get it's I'm I'm at the point in a return. And I said, oh my gosh. That's so that sounds so interesting. Like so let's just run this through. Like, imagine you're over at your girlfriend's house and you're making out on the sofa because her parents are gone out for the weekend or out of town, like, for dinner or something. Katie Koestner [00:33:22]: They're out out, and you 2 were just going at it, and you're at this point, you know, return. And then all of a sudden, at the back door, you hear the jingling of the keys. The parents are unexpectedly home. I said, young man, I know exactly what you would do. You'd holler out, like, mister and missus Smith, you think you could just wait outside for a couple of minutes? I'm almost done with your daughter, and it's the point of no return for me, and I just can't stop right now. You know, like, the absurdity. Right? Like, any there's no such thing. We're not animals. Katie Koestner [00:33:50]: We can totally stop. Even if it's uncomfortable, awkward, embarrassing, horrible, there's no such thing as we're not out of our mind and body having sex. So I think it's really important to tell your daughter, like, if all of a sudden it's hurting, if it doesn't feel good, whatever her I don't know what the values of your dads are, but whatever they are, she should know. There's no point at which it's too late to say no. I say when someone said to me, Chris, once, they said, when is rape regret? And I said regret is when you change your mind afterwards. Rape is when you change your mind in the middle and they don't stop. If you change your mind after after and say, I shouldn't have done that, that's regret. It's not rape. Katie Koestner [00:34:31]: If you change your mind, 5 minutes in, if they keep going, it's still rape. So I think those are those are nuanced things for dads to hear, but I think if they can talk to their daughter, and that sounds like a way awkward conversation for most dads, but just put the podcast on again. This is sex ed consent ed 101. Dr. Christopher Lewis [00:34:49]: You know, the other thing you just talked about was the fact that healing takes time, and it takes effort. And it's it's, something that's going to be a multi year entire life situation. So talk to me about the process that you had to go through, but also that what you tell to other survivors in regards to what it looks like to regaining power, regaining your life, but also are there things that dads can do to be able to support their daughters on that journey? Katie Koestner [00:35:21]: I'll start with the last part of your question first. Things dads should not do is take away agency. Meaning, here's the difference and nuance there. Taking away agency, it means not doing everything for them or telling them what to do. Taking weight, that's taking away agency. Giving agency means let's make a list together and let's do the research. If you're up for it, help me do the research. If not, I'm the dad. Katie Koestner [00:35:47]: I I'll take this on. I'll make the whole list of options that I can find. Then I'll review them. Let's think about them together. The best thing a dad can do or anyone could do is start to collaborate and build more control and power and agency back into the victim. The more you here here's a good small point. If they really want to try if you wanna put the guy in jail, let let's say the traditional dad reaction, we need to put him in jail. You know what? The average rapist rapes 12 to 17 times before going to jail. Katie Koestner [00:36:19]: The conviction rape on sexual violence is the lowest of any crime. This is the tough reality. It's fine. So jail time is not likely. However, the entire process of seeking power and control and some sort of I tried is that in and of itself has to be honored. And so often, I think I hate to ever stereotype men, but men sometimes get caught up on the outcome instead of the process. Men sometimes wanna come up with the answer instead of talk it through. You know, that's a total stereotype. Katie Koestner [00:36:52]: Women are like, I just wanna talk to you about this. I don't need an answer, and I wanna get men better at like, I'm very outcome driven, Chris. Like, seriously, like, I'm just one on the SAT. I'm a math girl. I'm a science girl. I like the data. I like to crunch the numbers. I like to win. Katie Koestner [00:37:09]: I like to be successful. I like to speak in front of a quarter of a 1000000 people. You know, I'm very, very driven. So but I also like the process because what I did helped. So I'll go back now to the other part of your question. So dads should sit with the process. Don't take away the agency. Don't provide the outcome. Katie Koestner [00:37:27]: Don't get to the finish line. Let your daughter run the marathon herself. She's got to. However, what happened in my world was a little unique because there was no name for what happened to me. So I literally had to research everything old school before the Internet, go to the library, get some books, read law books at the law school at William and Mary. I did what I could because I was confident enough in every aspect of my life that I could do this. And I got there in high school and in middle school. Like, I had already felt like the one good thing I will say my parents did is they they're like, do everything. Katie Koestner [00:38:04]: They always said you're never good enough, but they were they were also like, do everything. They never limited what I could do except for going to MIT. I wanted to go to MIT. Sorry. Well, they said we don't have enough money for MIT, and there's not enough girls there. That's what my mom said. Anyway, that aside, I think what helped me so much was I learned and I taught and I sat in it and I did everything. I changed laws. Katie Koestner [00:38:27]: I tested on in Capitol Hill. If you read that Time Magazine, you'll see me testifying on Capitol Hill when I'm only 18 years old. I made a movie with HBO about my story. No one helped me. I just did it. I went to New York City to get that picture taken. I I I debated the vice president of my my college on Larry King Live when he was alive. I stunk at it. Katie Koestner [00:38:47]: I was a terrible debater. I went and I did and I flew and I tried and I talked to other survivors. I became a rape crisis counselor. I answered that hotline from 11 to 7 AM while I was in college. I immersed myself in the pain of myself and others by full immersion, and I won't say I deleted everything else. I'm very lucky. I still was getting a's and still going to classes and still am doing everything else. But I think that by burying things, we hurt more. Katie Koestner [00:39:17]: The wound does not heal with a patch. The wound heals when we put it in full sunlight and we we just go with it. And who cares? Like, that's a great scar. You got through it. You survived, and you went on. For a while, I wanna go back one thing. Your daughter might go through a phase. Why in the blank did this have to happen to me? Is there something wrong with me? And you've simply gotta tell her it happens to a lot of people. Katie Koestner [00:39:42]: It's not you. You're unfortunately, my dear, you're not special. It happens to 25% of women. So it's just you were one of those, but let's makes it had to happen for you. Let's why? Let's do something with this. Let's make it into something more. Let's make it part of who you are in a positive way. And and and I would and here's a way that I think about that. Katie Koestner [00:40:02]: If someone you care a lot about in your life dies, like your grandmother, your auntie, you don't say when are you gonna get over it. That pain, that horrible gap in your heart, no one says, when are you gonna stop missing your grandma? That's wrong. Big losses in life, you're like, how do you honor her? Big losses, we honor them if we're on the right path. We figure out what's glorious about that, about her, about that experience, and what goes forward. That's the way to to spin anything. And and and and even for the dads who fortunately, hopefully, don't have daughters in distress, start teaching her how to spin everything that's bad into positive as fast as possible. Get over it. It's not you. Katie Koestner [00:40:43]: It's them. How do I navigate a different path? If I don't like what I'm on, how do I change the lanes? That is resiliency. I'll say, like now I'll also say this for any dad who's still listening to me. Your daughter's I have a 14 year old intern on my team. She is magnificent. She helps with my podcast, and I mentor, if you have a daughter who wants to kick butt in the world, join the Take Back the Night team. We have volunteers across even all the way to Kenya. We have Benter who does our like, it's so cool and amazing. Katie Koestner [00:41:15]: We empower every single woman, and and we teach them business skills. And if your daughter can't like, how about flourishing with fabulous, like, international global women, young women? Like, we have amazing women. I would our 14 year old is the youngest volunteer, but my gosh, we have a team of, like, 50. They're so we put them on teams. Like, your daughter should be around, like, if she's on into sports. Like, what team is she on? Don't let her isolate. Don't let her find her heart just in one boy. Like, put her around amazing people who are gonna push her, help her thrive. Katie Koestner [00:41:57]: That's gonna make her really amazing. So I'm just plugging, like, I don't care if it's Take Back the Night. I do care if it's something. Just find some way to put around, not just singing. I know. Not pooh poohing singing. I can't sing at all. I can't do singing. Katie Koestner [00:42:15]: I can't do car wheels. But I I think, you know, it's putting around people who will push her in a positive way. Honor her spirit, push her enough to be ready to take criticism in a positive way. Like, all of the things you want. Right? Like, those are all great things. They're very idealistic. If you can't tell, I'm very positive that the glass is always almost full. Dr. Christopher Lewis [00:42:40]: Well, Katie, I just wanna say thank you for sharing your journey, but sharing all of this amazing insight today. If people wanna find out more about you, your story, your organization, where should they go to find out more? Katie Koestner [00:42:53]: Love, love that. First of all, believe it or not, I still go around the country and speak. I just got back from speaking in Nantucket. How fun was that? I took a ferry to my speech. That's the first time I could say that. But I think I love speaking, but I also have a team of speakers. So if you want more education in your community, that is either Google Katie Koestner, my name, or you can go right to campus outreach services, and that's education and awareness. There's tons of ideas there. Katie Koestner [00:43:23]: 2nd idea, take back the night. We are always eager to have more volunteers, more financial support. Go read about the hotline and coolness. You could even plan a take back the night event in your own community. We have a whole team who will help you. It's just a one day event of awareness. You could do a bike race. You can do a walk. Katie Koestner [00:43:42]: You can do a vigil. You can have it at your church. You can have it at your school. You can have it at your business, but an event is a way of honoring and bringing awareness. So I encourage everybody to do that as well. But thank you, Chris. This is fabulous. This is so much fun. Dr. Christopher Lewis [00:43:58]: Well, I truly appreciate you being here today. Thank you for all the work that you're doing to support so many across the globe, and I wish you all the best. Katie Koestner [00:44:06]: Absolutely. Take care. Dr. Christopher Lewis [00:44:08]: If you've enjoyed today's episode of the dads with daughters podcast, we invite you to check out the fatherhood insider. The fatherhood insider is the essential resource for any dad that wants to be the best dad that he can be. We know that no child comes with an instruction manual, and most dads are figuring it out as they go along. And the fatherhood insider is full of resources and information that will up your game on fatherhood. Through our extensive course library, interactive forum, step by step roadmaps, and more, you will engage and learn with experts, but more importantly, dads like you. So check it out at fatheringtogether.org. If you are a father of a daughter and have not yet joined the dads with daughters Facebook community, there's a link in the notes today. Dads with Daughters is a program of fathering together. Dr. Christopher Lewis [00:44:57]: We look forward to having you back for another great guest next week, all geared to helping you raise strong empowered daughters and be the best dad that you can be. Dr. Christopher Lewis [00:45:06]: We're all in the same boat, and it's full of tiny screaming passengers. We spend the time, We give the lessons. We make the meals. We buy them presents and bring your a game. Because those kids are growing fast. The time goes by just like a dynamite blast. Calling astronauts and firemen, carpenters, and muscle men Get out and be the world to them. Be the best dad you can be. Dr. Christopher Lewis [00:45:59]: Be the best dad you can be.

An Educational Journey Turned Parenting Mission Jen Lumanlan's shift from a sustainability consulting career to a focus on parenting wasn't incidental. After grappling with the challenges of raising her own daughter, she realized that academic research on child development could serve as a guiding light. This led her to pursue master's degrees in psychology and education, and subsequently, to the creation of her podcast and book. Her primary goal? To leverage her learnings to support other parents facing similar challenges. Challenging Conventional Discipline Understanding the Power Dynamics at Play At the heart of Jen's approach is the critique of conventional discipline methods such as timeouts and consequences. According to Jen, these methods often perpetuate harmful power dynamics. They emphasize a power-over relationship, where the authority figure (the parent) uses their power to correct or control the child. These traditional methods can breed resentment and a lack of genuine understanding. Exploring Alternative Strategies The Shift From Control to Collaboration So, what can parents do instead? Jen advocates for strategies that satisfy both the parent's and the child's needs, fostering a power-sharing relationship. For example, during conflict, she suggests addressing the situation outside of the moment of crisis. Proactive discussions about recurring issues like tooth brushing or bedtime can pave the way for more harmonious solutions. By understanding and meeting each other's needs, both parties can find agreeable strategies, reducing resistance and conflict. Identifying and Meeting Needs The Two-Way Street of Parenting Needs Parents often neglect their own needs in the face of their child's demands, but Jen emphasizes that both parent and child have valid needs. Strategies should aim to fulfill both. She introduces the concept of "cherry needs" — the most critical needs that recur for both parents and children. For instance, a child's need for autonomy can be met with choices that do not compromise the parent's essential needs, such as brushing teeth in a different room. Problem-Solving in Real-Time Navigating Tantrums and Meltdowns Tantrums and meltdowns are common challenges, and Jen offers peace and empathy as the best tools. Understanding the underlying needs that prompt such behaviors and addressing them proactively or with empathetic responses in the heat of the moment can defuse tension. Validating the child's feelings and needs even during a meltdown can lead to quicker resolutions and more trust. Shifting Dynamics with Teens It's Never Too Late to Transform Relationships Parents of older children might assume it's too late for change, but Jen underscores that it's never too late. Even with tweens and teens, shifting from a power-over to a power-sharing dynamic can salvage and improve the relationship. She proposes using phrases like “I'm worried that…” to express needs and concerns, fostering mutual respect and understanding. Healing From Our Own Childhood Breaking Cycles Through Self-Reflection Many of our parenting triggers stem from our own childhood experiences. By unpacking and healing these old traumas, parents can become more conscious and connected. This self-awareness prevents past negative patterns from repeating, helping parents respond more thoughtfully rather than reacting on impulse. Broader Societal Change Raising Children Who Challenge Injustice Jen believes that by fostering power-sharing relationships at home, we can equip children to challenge systemic injustices. When children learn to view all individuals' needs as equally important, they carry this perspective into broader societal contexts, questioning and challenging systems of domination and inequality. Jen Lumanlan's insights offer valuable guidance in our quest to raise empathetic, empowered children. By shifting from control to collaboration and addressing the deeper needs within our family dynamics, we not only nurture healthier relationships but also contribute to a more just world. Tune into this enlightening episode of Dads with Daughters for more practical wisdom on transformative parenting. Connect with Jen and deepen your understanding of parenting dynamics at Your Parenting Mojo. TRANSCRIPT Dr.Christopher Lewis [00:00:05]: Welcome to Dads with Daughters. In this show, we spotlight dads, resources, and more to help you be the best dad you can be. Dr. Christopher Lewis [00:00:16]: Welcome back to the Dads with Daughters podcast where we bring you guests to be active participants in your daughters' lives, raising them to be strong, independent women. Really excited to have you back again this week. As always, every week, you and I are on a journey together. I love being on this journey with you where we have an opportunity to be able to learn together about what it takes to be that dad that we wanna be. And all of us wanna be that those engaged dads, those dads that are there for our kids. And it takes work. It takes time. It takes effort to be a quality parent, and it takes resources. Dr. Christopher Lewis [00:00:55]: And that's why this podcast exists. Every week, I love being able to bring you different guests, different people with different experiences that can bring different resources to you, different different opportunities for you to learn and grow. The the biggest thing is that you're open to learning. And that's what I hope for me for you every week when we're talking. This week, we got another great guest with us. Jen Loominlan is with us today. And Jen hosts the Your Parenting Mojo podcast, which was named the best research parenting podcast by Lifehacker. It's been downloaded over 3,000,000 times. Dr. Christopher Lewis [00:01:33]: After attending Berkeley and Yale and following a traditional career path in sustainability consulting, Jen found that parenting was her toughest challenge yet. She went back to school for a master's degree in psychology focused on child development and another in education and trained as a coactive coach to share what she learned with other parents. She's an author of the book Parenting Beyond Power, How to Use Connection and Collaboration to Transform Your Family and the world. And today, we're gonna be talking with her about her own experiences and these experiences with the book and some of the things that you can take out of this book to help you to be that parent that you wanna be. Jen, thanks so much for being here today.  Jen Lumanlan [00:02:16]: Thanks for having me. Dr. Christopher Lewis [00:02:16]: It is my pleasure. I mentioned the fact that you've got this book that you've put out into the world. As an author myself, I know how much time, effort, passion has to go into putting a book out into the world. And it is a lot of time and effort, and you have to have a passion for it to be able to get to that end point. So tell me the story. What what was it about? You know, I introduced you. You you had this career, but you said, you know what? I wanna go back and I want to do do more work on education, work with parents. But what made you decide that you wanted to put all this into a book that was gonna help others? What drew you to that final point? Jen Lumanlan I think I started the podcast because, you know, I had no idea how to parent. And I didn't have the most amazing parenting role models myself either, and so I realized I could look to academic research to help me understand how to go about raising my daughter. And so I kind of figured, you know, I I should get some education on this so that I can put some kind of guardrails around it and know I'm not missing anything huge, and that's what led to the master's degrees. And and then I was kinda thinking, well, it's kinda silly to do all this learning for myself and not share it. So I created the podcast to share that with other people. And then I over the course of of sort of exploring a lot of topics on the podcast that we have over 200 episodes now that are all research based. And I think, you know, it became really clear that I was hearing similar challenges from parents over and over again. And and they're kind of variations on the phrase, how do I get my child to Right? How do I get my kid to put their shoes on in the morning, to eat their breakfast, to stay at the dinner table, to get in the bath, to stay in bed at the end of the night? You know? And that's just the toddler set. Jen Lumanlan [00:03:59]: The challenges expand from there. So, what I realized was the the tools that I had learned from others and kind of adapted with putting my own spin on them were really helping parents to kind of address those challenges, those daily challenges on a day to day basis. And at the same time, they also help us to address some of the big challenges that we face out in the world that are related to kind of being in power over relationships. And it turns out that our kids learn a lot about power from our relationships with them and when we're using our power to get them to because it seems like that's the only thing we can do. Right? We just wanna get through the day. It's not we want to use our our power over our kids. We're just trying to get through the day. And we use our power because it seems like that's the only option we have because that's what was modeled for us when we were kids. Jen Lumanlan [00:04:50]: And if we can instead see how to be in a power sharing relationship with our kids, then our kids stop resisting us because you don't resist when your needs are met and when, you know, when you're not being sort of dominated by somebody else. And and also that will help us to address some of the social challenges we face that have their origins in these power based relationships. Dr. Christopher Lewis [00:05:11]: So let's talk a little bit about power because in your book, you do talk about the that that power dynamic, and you challenge conventional discipline methods like timeouts and consequences. And you suggest that they perpetuate harmful power dynamics like you just were mentioning. So what are some other alternative strategies that parents can use when they feel overwhelmed, or when they feel that their child's behavior is especially difficult? Jen Lumanlan [00:05:38]: So the I mean, firstly, the challenge with those conventional discipline methods. I mean, if you ever put a child in time out, right, do they come out of time out kind of contrite and ready to apologize for the thing that they did wrong and they never do it again? Right? No. They usually kinda resent being in time out. They come out of it kinda pissed at you, and they do it again. Right? They do the same thing over again. Same with consequences. We can we can withdraw a privilege of some kind. We can punish a child in some way, and we can call it a, quote, unquote, logical consequence because it seems like the punishment is sort of related to the thing they did wrong. Jen Lumanlan [00:06:12]: But, essentially, it is a punishment. It is us using our power to say your behavior is not acceptable to me. And until that changes, I'm going to withdraw this thing that you care about. Right? We are using our power to to make both of those things happen. And so what what I want to make sure that that your listeners understand is that I am not advocating that we parents suddenly say, okay. Whatever you want. Totally fine. Totally cool. Jen Lumanlan [00:06:32]: Right? I'm just here to exist to enable you to live your best life. No. What I'm saying is that both parent and child have needs. And the way that we use the word need in our culture is a little bit odd. Right? Like, I might say, I can't play with you right now. I need to make dinner. And needing to make dinner is not actually a need. That's a strategy that I'm using to meet my need for food, for nourishment. Jen Lumanlan [00:07:01]: Right? And there are a 100 other strategies we could use. I could toss a pizza in the oven. We could go out and get dinner. I could ask someone to bring us dinner. We could have cereal for dinner. So many different strategies we could use to meet that need. And so what I'm saying is that you, parents, are a whole person with needs, and you deserve to get those needs met. And your child is a whole person with needs, and your child deserves to get those needs met. Jen Lumanlan [00:07:26]: And the vast majority of the time, preferably if we're not dealing with it in the moment. Right? We're not we're not waiting in for this thing that our kid does over and over and over again, and we're not waiting for that to happen. Then, okay, needs? What what am I supposed to do? Right? Instead, we can actually address that outside of that difficult moment. We can say, hey. I noticed we've been having a hard time with tooth brushing lately. Can we have a chat about that? Because I'd really like for that to be different. I'd like for our evenings to be different. Would you like for our evenings to be different? Chances are the kid probably does. Jen Lumanlan [00:07:53]: Because if this is a big deal to you, then, you know, there have been time outs and all kinds of stress around toothbrushing. And then, okay, so we're we're trying to understand how each person is feeling. We're trying to understand what each person needs. And what the need is determines the strategy that we can use to help them meet the need. So I'm happy to dig further into that if you'd like, but I'm curious if you have any questions about that aspect. Dr. Christopher Lewis [00:08:14]: No. I'd love to delve a little bit deeper into needs because I know that in the book, you do talk about the importance of meeting both the parents and the child's needs, like you were talking about to reduce that conflict. So how can parents begin to identify and prioritize their own needs without feeling guilty or neglecting their children's? Jen Lumanlan [00:08:32]: So it's super common for the parents that I work with to say to me, before I started working with you, I didn't even know that I had needs. Because we didn't learn this when we were kids. Right? And so just to be clear on what I'm talking about related to needs, I'm talking about things like rest, like self care, like respect, which is not necessarily having everybody do everything you say. Right? It can be, like, holding someone in esteem and high regard. And we all want respect, and our kids want respect too. It's things like ease. And we just want parenting to be a little bit easier for collaboration, for harmony with our kids. Right? These are the kinds of things I'm talking about related to needs. Jen Lumanlan [00:09:10]: And so if we take tooth brushing as an example, right, could imagine if tooth brushing has been stressful because my kid has been resisting it. Let's say my kid is a toddler. My kid's actually 10 by now. But let's say it's a toddler, and I might think, okay. What is my need in this? Right? I might I might have been saying to my child, I need you to brush your teeth. That's not actually my need. My need is for protection of her health and safety. It is for a little bit of ease and collaboration and harmony in the evenings at the end of a long day. Jen Lumanlan [00:09:39]: And if you're wanting to, like, explore what needs are, there's a a list of needs in the back of of the book. And there's also a quiz that I offer at your parentingmojo.com, which allows you to go through it's your parentingmojo.comforward/ quiz, and you can answer some simple questions about your child's behavior and get to your child's most important needs that come up over and over and over again. And you may well find that some of those are coming up in tooth brushing. So if your child has what we call a cherry need, right, there's the cherry on top of the cupcake, which is the 3 to 5 needs that are coming up over and over and over again. For many toddlers, autonomy is right up there at the top. They want to be able to have some kind of say over something that feels important to them. Underneath that, we have the frosting needs, which is the next 3 to 5 most important. Underneath that is kind of all of the other needs. Jen Lumanlan [00:10:26]: And so we're always firstly looking at what are those cherry needs, and that quiz is gonna help you to understand what your child's cherry needs are. And so even if your child isn't speaking yet, right, if your child is too young to speak, if your child doesn't speak, if you've done this quiz, you can say, okay. What is it an autonomy? Is it possible the child wants to have some kind of say over what's happening here? How can I make that happen? Right? You're not giving the child necessarily the choice, do you want to brush teeth or not? But what kind of toothpaste do you wanna use? What kind of toothbrush do you wanna use? For us, oh my goodness. It it turned out to be I my daughter wanted to decide where we brushed. For a solid 6 months, we brushed in the living room. And so I might initially think, no. She should have brushed her teeth in the in the bathroom. That's where teeth are brushed. Jen Lumanlan [00:11:10]: Right? But if I can find the cognitive flexibility to say, alright. What are my needs? Her health and safety, peace, ease, harmony. Does brushing teeth in the living room meet my needs? Yes. It does. Does brushing teeth in the living room meet her need for autonomy? Yes. It does. Then is there a reason why we can't brush teeth in the living room? No. There is not. Jen Lumanlan [00:11:28]: And so that's what we did. And so the critical, critical piece here is that when it's a need for autonomy, right, it's not it's not the brushing teeth in the living room. It's some magical solution that will work for every child. If your child has a need for comfort, right, if you've been holding them down and forcing the toothbrush in their mouth, saying, let's brush in the living room is not gonna address that. And so we have to know what is the child's need, and then we find strategies to meet their need. And it feels good to have our needs met, and everybody wants to have it happen. And so that's how it helps us to get both of our needs met. Dr. Christopher Lewis [00:11:59]: So another thing that your books talk about, and really what you just kind of framed seems to fit in with it, is one of the key concepts you talk about is your problem solving approach, and it it basically what you just described. Are there other parts though of that approach that you could walk us through that would allow for someone to get a better sense of what the approach kind of how an adult would frame that approach, and also how a parent might then apply it to other challenges like tantrums or other situations like that. Jen Lumanlan [00:12:34]: What I want to have parents see is that very, very often, these are not isolated instances. When your child is having tantrums, chances are it's kind of about the same thing over and over and over again. And so that represents a huge opportunity because you don't have to wait for the next tooth brushing session to address this. You can address this beforehand while everybody's calm, everybody's rested, everybody's fed, nobody's at the end of their rope. Right? That's the time ideally we want to address this. And that allows us to have more of a conversation. And even if your kid isn't talking yet, kids sense the difference between, you're gonna brush your teeth because I said so, because because I want what's good for you, and you have to brush your teeth so you don't get cavities, and all the reasons that we give them. And, oh my gosh, I really wish that this could be easier for both of us. Jen Lumanlan [00:13:22]: I'm trying to figure out how do we meet both of our needs here. Right? Kids know the difference between those two things. And even if you can't fully understand the child's need, they are often willing to come towards you because you're trying. But I also wanna give you an example of, like, in the moment the kid is already melting down. And so I'm thinking of a parent that I coached a while ago whose child was having this meltdown, and it was coming up because the child and the parent were having 1 on 1 playtime in the afternoon, and it's coming time to go and pick the older child up from school. And so the kid has, like, a you know, the kid the the younger child who's at home with the parent is having a fallout on the floor, wailing, hitting, biting, all the rest of it meltdown that's happening. And the parent is trying to reason with the child. Right? Come on. Jen Lumanlan [00:14:06]: It's time to go. We do this every day. Why is this so hard? We already had playtime. Let's go. And if you've ever had a meltdown yourself with your partner, with anyone else who's in your life, if you imagine your partner coming back and saying, but I told you a 100 times, this is how we do it. We can sort of get a sense for what it might be like to receive that from our parent. And what do we want instead? What we really want is someone to try to see it from our perspective. And so what I asked that parent to do and what she ended up doing was when the next time the child had the the the meltdown because they didn't have a chance to kinda talk about it beforehand, the parent kinda went in with, oh my goodness. Jen Lumanlan [00:14:46]: I hear you. It's so hard to transition out of playtime with me. Right? Because it's so much fun, and you love it so much. And now we're going to pick up your sibling, and for the rest of the afternoon, you're gonna have to share me. You're gonna have to wait. You can't just have the thing that you want right at the moment that you want it. Is that what's going on for you? And the kid is like, yes. And we're done. Jen Lumanlan [00:15:05]: And there's no more hitting, and there's no more biting, and there's no more flailing on the floor because the child was heard. And so I'm not saying this magically fixes every tantrum in your child's life, but I can tell you that when you see these things coming, when you see, okay. Yeah. Every day at this time, my kid has a tantrum. Why is that? What need are they trying to meet? Can I help them meet that need? That takes care of, like, a massive chunk of them up front, so you never even get into the tantrum in the first place. And then once you're in it, then the empathy the okay. What's really going on for you? Can I sit with you in this hard time that you're having? And that's where you find the real beauty of, yes. I just wanted to be heard. Jen Lumanlan [00:15:45]: I just wanted somebody to acknowledge that it's hard for me to to stop playing with you and have to share you for the rest of the evening. Dr. Christopher Lewis [00:15:51]: So a lot of the examples you gave were of younger children. And in a perfect world, I would have loved to have had this book when my kids were really young. So if someone is hearing this and they're saying, I've got a tween, I've got a teen, and our relationship's not the best, we're in this fighting, we were fighting together, we're not seen eye to eye, you know, we're, you know, we're isolated, you know, we're we're not where we need to be. Are there things that they can do with this problem solving approach that they can start putting in place even though their children are not at that young age that they can start using right away? Jen Lumanlan [00:16:28]: Yes. It's never ever, ever too late to do this. I mentioned that my parenting role models were not the best, and I've thought about this a lot actually. And, you know, what would have happened I guess I do wanna be clear. You know, they were doing the best they could with the tools that they had. And if one of them had learned these tools and had tried to make some kind of shift, even in my late teenage years, would that have made a difference? Yes. It absolutely would have. And so where I would try to start with this kind of thing is to to try to kind of back off where you see that you're using power to get your child to change their behavior. Jen Lumanlan [00:17:04]: Not back off completely, but try to use a simple phrase. And that phrase is, I'm worried that dot dot dot. So if your, you know, your your kid is asking to do something, they wanna go out with friends, they whatever whatever is the thing that you're thinking about saying no to. That previously would you would have used your power, you would have made sure that they didn't do the thing that you that they're asking to do, that they really want do, that you don't want them to do. And so instead of of doing that, we can say, I'm worried that you're not gonna be safe. Right? I'm worried that this specific thing is going to happen. How can we make sure this thing doesn't happen? Because what what what the I'm worried that does is it helps me to articulate my need. I am worried for your safety. Jen Lumanlan [00:17:46]: If I can know that certain parameters are in place that mean that I think you're gonna be safe, then, yeah, I'm willing to say yes to this thing. Then I don't have to use my power over you to try and get you to change your behavior. I think that what what parents you're describing or seeing is I get actually reading for the first time doctor Thomas Gordon's book on, parent effectiveness training, and he talks about power and influence. And when we've used power over our children for a long time, we tend to find we have less influence as they get older because people don't like being influenced by people who have used power over them. And so if we want to have influence over our children as they get older and and they realize, you know what? You don't you actually don't have any power over me anymore. I'm getting bigger to the point where you can't physically intimidate me, and once I have the car keys, right, I'm done. I'm out of here. You can't control me anymore. Jen Lumanlan [00:18:37]: And if we still want to be able to influence our children at that point, we have to be willing to give up some of that power, and I'm worried that is a great place to start with that. Dr. Christopher Lewis [00:18:47]: One of the other things that you talk about in the book is that many of the triggers, the triggers that all of us have internally, the things that set us off in our own parenting journey with our kids stem from how we were raised. How can parents begin to unpack and heal from their own childhood experiences to become more conscious, connected parents? Jen Lumanlan [00:19:09]: Well, that could be another episode by itself. So, I mean, there's a lot there. And what parents that I work with tend to find is that they are most triggered by their child's behavior when they when their child gets to an age where they were having a hard time with their parents. So there's, you know, all the typical toddler stuff that is just hard when the toddler is resisting for the first time, and we used to resist as well. Right? We didn't like it either, being told what to do and that my way is the only way and that even if we try and kind of be nice about it, that ultimately, the kid's gonna do things the way that we want them to do. We didn't like that either. We pushed back against it. And, eventually, we learned there's no point in pushing back because the parent's gonna win eventually. Jen Lumanlan [00:19:50]: And so you know, most people find that stage difficult for that reason. And then as we go through life, there was probably an age where we kinda butted up against our parents for for whatever reason. And then when our child gets to that age, then we remember all those struggles. It's like they're they're right here again. They're right here with us, and they remind us of the hard time that we had, the ways that we were dominated by our parents. And I think this, it's especially difficult actually for parents who have done a little bit of work, who are trying to do things differently with their child. Because when their child is doing something the parent finds difficult, there's this kind of tug of war happening in their heads. There's this, I know what my values are. Jen Lumanlan [00:20:31]: I know how I want to raise you. I want to be in this power sharing relationship with you, but I would have been punished for doing the thing you just did. If I never spoken to my parent like that, right, they would have hit me. And so it's like there's this this massive, you know, you can imagine this tug of war literally happening inside of our heads. And and it's happening in this moment when our kid is doing something we told them not to do. And the amount of mental capacity it takes to be able to navigate that and also be calm for your child and show up for your child is is overwhelming, and so we snap. And so that's why I teach a whole 10 week workshop called taming your triggers on where does this stuff come from, really digging deep and to start healing those things so that we don't have to carry around the weight of that hurt every day. And, also, really digging deep into the the tools that I've been mentioning that are described in the book and, like, how do we actually use them when I'm feeling triggered? Right? How do I how do I create a pause? Because that's that's the critical phase for especially for people who are triggered, is creating that pause between the thing my child does and my reaction. Jen Lumanlan [00:21:42]: And once you have that pause, then you have a moment to be able to say, okay. What are my values here? What's really important to me? What is my need? Okay. This is it. And so the thing that's gonna come out of my mouth is gonna be x rather than, you know, whatever it is that currently flies out in the moment that our child does this thing right now. Jen Lumanlan [00:22:00]: And so many times, it is that latter aspect. Jen Lumanlan [00:22:03]: And so often, it's your parents' voice that comes out. You're like, where did that come from? Yes. Because our parents raised us using these tools. They they dominated us. Even if they didn't mean to, even if they were doing the best that they could, they dominated us. And so when we're in these stressed moments, the thing that comes out is the thing that was modeled for us. Dr. Christopher Lewis [00:22:22]: You know, the final thing that I think that I'd mentioned is that in your book, you really talk about transforming the family dynamic and that you say that through transforming this dynamic within our own homes, we can contribute to what you call a broader societal change. So how do you envision parents using these parenting tools to raise children who are capable of challenging system systematic injustices in the world around them? Jen Lumanlan [00:22:48]: Yeah. I mean, I see it happening already in the parents that I work with. And there's an example in the book of a parent who parent Maria and her her daughter, Isabelle. And, you know, Isabelle is one of those kids who, from the get go, knew exactly what she wanted and would scream if you held her the wrong way and would refuse to put her shoes on as a toddler. Right? Even even to go to a a nice outing. Right? The parents are like, okay. Put your shoes on. Well, no. Jen Lumanlan [00:23:13]: You told me to do it. No. I'm not doing it. And they stand there and stand off for half an hour, and the kid's not doing anything, and and they never make it out. And so Maria very quickly realized that using these power over tools was just gonna result in endless repetitions of that situation and started using these power sharing tools. And the transformation in their own relationship has been really profound. I mean, this is a kid who, I think Maria actually sprained her ankle in the house one day, and Isabelle stepped over her and said, you know, what? What's for lunch? No empathy, no compassion, no nothing. And within a period of months, right, we see empathy, we see compassion start coming out. Jen Lumanlan [00:23:57]: We see the kids all around the table, and some of the kids are teasing mom. And and Isabelle says, I'm looking at mom, and it seems like she's not up for being teased right now. Right? Reading mom's cues and being able to say, you know what? I'm not seeing that that mom's really into this. And so that's just within the family. And then we look outside the family, and Isabel sees that there's a kid in the school who has ADHD and is being bullied by the peer group that Isabelle is a part of, and Isabelle says, you know what? No. I'm not I'm not gonna do that. I'm not gonna be part of this group and goes over and makes friends with a kid with ADHD. So that's, you know, that's a super small example. Jen Lumanlan [00:24:32]: And then we start to extrapolate that out to other systems in the world. Right? If we think about things like racism, it's ultimately a power over system. It's me saying, my right to exist as a white person, to be comfortable as a white person is more important than people of color's right to exist in their whole selves. And what if we were to say, you know what? Your needs are just as important as my needs. I don't believe that these systems of domination out in the world can exist when we all perceive each other's needs to be equally as important as our own. And so, yes, it's gonna take some time. Right? This can't be the only way we go about doing these things. Parents are not responsible in themselves by, you know, just alone for solving these societal challenges. Jen Lumanlan [00:25:16]: We also need lots of other work as well. But I truly believe that seeing each other's needs as as important as our own is a critical piece of making the world a place where everybody can thrive. Jen Lumanlan [00:25:30]: I really appreciate you sharing everything that you've been sharing today. And if people want to find out more about you, your podcast, your book, where's the best place for them to go? Jen Lumanlan [00:25:40]: So everything I do flows through your parentingmojo.com. I would definitely advise parents to go check out the quiz at your parentingmojo.comforward/quiz. Because once you know your child's needs, everything just gets so much easier. Because as soon as you see resistance, you can say, okay. Where is this coming from? Is it a need? Oh, yes. It's autonomy. It's connection. It's, you know, whatever that cherry need is. Jen Lumanlan [00:26:03]: And then you can very quickly find the strategies that meet their need instead of having to look through the list of 50 needs and say, oh, which one is it? So I would definitely recommend that. I am on Facebook and Instagram. I don't use them super much, but I am there as well. And so, yeah, subscribe to podcast episodes as well, through the through the website. And the book is at Parenting Beyond Power. Dr. Christopher Lewis [00:26:25]: Well, I really appreciate you sharing all of this today for what you're putting out into the world and what you're doing to help parents be better parents, and I wish you all the best. Jen Lumanlan [00:26:32]: Thanks so much, Chris. It was great to be with you. Dr. Christopher Lewis [00:26:34]: If you've enjoyed today's episode of the Dads with Daughters podcast, we invite you to check out the Fatherhood Insider. The fatherhood insider is the essential resource for any dad that wants to be the best dad that he can be. We know that no child comes with an instruction manual and most dads are figuring it out as they go along, and the fatherhood insider is full of resources and information that will up your game on fatherhood. Through our extensive course library, interactive forum, step by step roadmaps, and more, you will engage and learn with experts, but more importantly, dads like you. So check it out at fatheringtogether.org. If you are a father of a daughter and have not yet joined the dads with daughters Facebook community, there's a link in the notes today. Dads with daughters is a program of fathering together. We look forward to having you back for another great guest next week, all geared to helping you raise strong, empowered daughters and be the best dad that you can be. Dr. Christopher Lewis [00:27:32]: We're all in the same boat, And it's full of tiny screaming passengers. We spend the time. We give the lessons. We make the meals. We buy them presents and bring your a game. Because those kids are growing fast. The time goes by just like a  

Dr. Nathan Pennell and Dr. John Sweetenham discuss the evolving landscape of oncology in 2025 and the challenges oncologists will be facing, including the impact of Medicare drug price negotiations, ongoing drug shortages, and the promising role of AI and telehealth in improving patient outcomes and access to clinical trials. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. 2025 promises to be a year of continued progress in drug development, patient care, and technological innovations that will shape the future of cancer care. Oncologists will also be grappling with some familiar challenges in oncology practice and probably face a few new ones as well. I'm delighted to be joined today by Dr. Nathan Pennell to discuss some of these challenges. Dr. Pennell is the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research at the Taussig Cancer Center. He also serves as the editor-in-chief of the ASCO Educational Book.  You'll find our full disclosures in the transcript of this episode.  Nate, it's great to have you on the podcast today. Dr. Nathan Pennell: Thanks for inviting me, John. I'm excited to be here. Dr. John Sweetenham: Thanks. So, Nate, we've been hearing a lot recently about implementation science in oncology particularly. This has been the case, I would say, over the past decade and of course the goal is to how do we figure out the best way to integrate evidence-based practice into oncology care? There's been a lot of very good guidance from organizations like ASCO and every year we're reminded of the need for clinical decision support for practicing oncologists at the point of care. Although I think we all agree it is the right thing to do, and this has been a matter of discussion for probably more than 10 years, for the most part, I don't think we've really got there. Some big practices probably have a truly well-integrated clinical decision support tool, but for many of us this is still lacking in the field. I wonder whether we do need some kind of global clinical decision support tool. What do you think about the future of clinical decision support at the point of care? And do you think this is going to continue to be a need? Dr. Nathan Pennell: I think that's a fantastic question and it absolutely is something we're going to continue to work towards. We're in an incredibly exciting time in oncology. We've got all these exciting predictive biomarkers, effective treatments that are working better than anything we've had in our careers up to this point. But when we actually look to see who is benefiting from them, what we find is that outside of clinical trial populations, many of our patients aren't actually accessing these. And so publications that look at real-world use of these, one that jumps to mind for me is a publication looking at biomarker testing for driver oncogenes in lung cancer showed that while everyone who treats lung cancer says, “Absolutely, we need to test for biomarkers such as EGFR mutations,” in the real world, probably only slightly over a third of people ever access these drugs because there are so many different gaps in care that fall through the cracks. And so decision support is absolutely critical.  You mentioned this has been going on for a decade. Actually, the Institute of Medicine in 2013 recommended that with the uptake of electronic medical records, that we move forward with building these true learning health care systems that would improve quality and use every patient's information to help inform their care. And in 2023, as a representative of ASCO, I was able to look back at the last decade, and the uniform conclusion was that we had failed to build this learning health care system. So, what can we do going forward? The good news is there are improvements in technology. There are, for better or for worse, some consolidation of electronic medical records that has allowed larger numbers of patients to sort of have data sets shared. ASCO started CancerLinQ to try to improve quality, which is now part of OpenAI, and is still working on technology solutions to help provide decision support as we are better able to access patient data. And I think we're going to talk a little bit later about some of the technological advances that are going on in artificial intelligence that are really going to help improve this. So I think this is very close to impacting patient care and improving quality of care. I think for, as you'd mentioned, large health care systems and users of the major EMRs, this is going to be extremely close. Dr. John Sweetenham: Thanks, Nate. And just to extend the conversation into another area, one of the constant, I think, pain points for practicing oncologists has been the issue of prior authorization and the amount of time and energy it takes to deal with insurance denials in cancer care. And I think in a way, these two things are linked in as much as if we had clinical decision support tools at the point of care which were truly functional, then hopefully there would be a more facile way for an oncologist to be able to determine whether the patient in front of him or her is actually covered for the treatment that the oncologist wants to prescribe. But nevertheless, we're really not there yet, although, I think we're on the way to being there. But it does remain, like I said, a real pain point for oncologists.  I wonder if you have any thoughts on the issue of prior authorization and whether you see in the coming year anything which is going to help practicing oncologists to overcome the time and effort that they spend in this space. Dr. Nathan Pennell: I think many oncologists would have to list this among, if not the least favorite aspects of our job these days is dealing with insurance, dealing with prior authorizations. We understand that health care is incredibly expensive. We understand that oncology drugs and tests are even more expensive, probably among, if not the most rapidly growing costs to the health care system in the U.S., which is already at about 20% of our GDP every year. And so I understand the concern that costs are potentially unsustainable in the long term. Unfortunately, the major efforts to contain these costs seem to have fallen on the group that we would least like to be in charge of that, which are the payers and insurance companies, through use of prior authorization. And this is good in concept, utilization review, making sure that things are appropriate, not overutilizing our expensive treatments, that makes perfect sense. Unfortunately, it's moved beyond expensive treatments that have limited utility to more or less everything, no matter how inexpensive or standard. And there's now multiple publications suggesting that this is taking on massive amounts of time. Some even estimated that for each physician it's a full 40-hour work week per physician from someone to manage prior authorizations, which costs billions of dollars for practices every year. And so this is definitely a major pain point.  It is, however, an area where I'm kind of optimistic, maybe not necessarily in 2025, but in the coming several years with some of the technology solutions that are coming out, as we've talked about, with things like clinical pathways and whatnot, where the insurance company approvals can be tied directly to some of these guideline concordance pathway tools. So the recent publication at the ASCO Quality [Care] Symposium looking at a radiation oncology practice that had a guideline concordant prior auth tool that showed there was massive decrease in denials by using this. And as this gets rolled out more broadly, I think that this can increase the concept of gold carding, where if practices follow these clinical guidelines to a certain extent, they may be even exempt from prior authorization. I think I can envision that this is very close to potentially removing this as a major problem. I know that ASCO certainly has advocated on the national level for changes to this through, for example, advocating for the Improving Seniors Timely Access to Care Act. But I think, unfortunately, the recent election, I'm not sure how much progress will be made on the national level for progress in this. So I think that the market solutions with some of the technology interventions may be the best hope. Dr. John Sweetenham: Yeah, thanks. You raised a couple of other important points in that answer, Nate, which I'll pick up on now. You mentioned drug prices, and of course, during 2025, we're going to see Medicare negotiating drug prices. And we've already seen, I think, early effects from that. But I think it's going to be really interesting to see how this rolls out for our cancer patients in 2025. And of course, the thing that we can't really tell at the moment that you've alluded to is how all this is going to evolve with the new administration of President Trump. I understand, of course, that none of us really knows at this point; it's too early to know what the new administration will do. But would you care to comment on this in any way and about your concerns and hopes for Medicare specifically and what the administration will do to cancer care in general? Dr. Nathan Pennell: I think all of us are naturally a little bit anxious about what's going to happen under the new administration. The good news, if there's good news, is that under the first Trump administration, the National Cancer Institute and cancer care in general was pretty broadly supported both in Congress and by the administration. And if we look at specifically negotiating drug prices by Medicare, you can envision that having a businessman president who prides himself in negotiations might be something that would be supported and perhaps even expanded under the incoming Trump administration. So I think that's not too hard to imagine, although we don't really know. On the other hand, there are very valid concerns about what's going to happen with the Affordable Care Act, with Medicaid expansion, with protections for preexisting conditions, which impact our patients with cancer. And obviously there are potential people in the new administration who perhaps lack trust in traditional evidence-based medicine, vaccines, things like that, which we're not sure where they're going to fall in terms of the health care landscape, but certainly something we'll have to watch out for. Dr. John Sweetenham: Yeah. Certainly, when we regroup to record next year's podcast, we may have a clearer picture of how that's going to play out. Dr. Nathan Pennell: I mean, if there's anything good from this, it's that cancer has always been a bipartisan issue that people support. And so I don't want to be too negative about this. I do think that public support for cancer is likely to continue. And so overall, I think we'll probably be okay. Dr. John Sweetenham: Yeah, I agree with that. And I think one of the things that's important to remember, I do remember that one of the institutions I've worked at previously that there from time to time was some discussion about politics and cancer care. And the quote that I always remember is “We all belong to the cancer party,” and that's what's really important. So let's just keep our eye on the board. I hope that we can do that.  I'm going to switch gears just a little bit now because another issue which has been quite prominent in 2024 and in a few years before that has been supply chain issues and drug shortages. We've seen this over many years now, but obviously the problems have apparently been exacerbated in recent years, particularly by climate events. But certainly ASCO has published some recommendations in terms of quality care delivery for patients with cancer. Can you tell us a little bit about how you think this will go in the coming year and what we can do to address some of the concerns that are there over drug shortages? Dr. Nathan Pennell: Yeah. This continues to be, I think, a surprising issue for many oncologists because it has been going on for a long time, but really hasn't been in the public eye. The general problem is that once drugs go off patent and become generic, they often have limited manufacturers that are often outside the U.S. sometimes even a single manufacturer, which leaves them extremely vulnerable to supply chain disruption issues or regulatory issues. So situations where the FDA inspects and decides that they're not manufacturing things up to snuff and suddenly the only manufacturer is temporarily shut down. And then as you mentioned, things like extreme weather events where we had Hurricane Maria hit Puerto Rico and suddenly we have no bags of saline for several months. And so these are major issues which I think have benefited from being in the public eye.  ASCO, on the one hand, has, I think, done an excellent job leading on what to do in scenarios where there are shortages. But I think more importantly, we need more attention on a national level to policy changes that would help prevent this in the future. Some suggestions have been to increase some of the oversight of the FDA into supply chain issues and generic drugs, perhaps forming more of an early warning system to anticipate shortages so that we can find workarounds, find alternative suppliers that perhaps aren't currently being widely utilized. We can advocate for our legislators to pass legislation to support drug production for vital agents through things like long term contracts or even guaranteed pricing that might also even encourage U.S. manufacturers to take back up generic drugs if they were able to make it profitable. And then finally, I think just more of a national coordinated approach rather than the piecemeal approach we've done in the past. I remember when we had a platinum [drug] shortage last year. Our institution, with massive resources in our pharmacy, really did an excellent job of making sure that we always had enough supply. We never actually saw that shortage in real time, but I know a lot of places did not have those resources and therefore were really struggling. And so I think more of a coordinated approach with communication and awareness so that we can try to prevent this from happening. Dr. John Sweetenham: Thanks, Nate. And you raised the issue of major weather events, and I'd like to pick up on that for just a moment to talk about climate change. We now know that there is a growing body of evidence showing that climate change impacts cancer care. And it does it in a lot of ways. I mean, the most obvious is disrupting care delivery during one of these major events. But there are also issues about increased exposure to carcinogens, reduced access to food, reduced access to cancer screenings during these major disasters. And the recent hurricanes, of course, have highlighted the need for cancer centers to have robust disaster preparedness plans. In addition to that, obviously there are questions about greenhouse gas emissions and how cancer centers and health care organizations handle that.  But what do you see for 2025 in this regard? And what's your thinking about how well we're prepared as deliverers of cancer care to deal with these climate change issues? Dr. Nathan Pennell: Yeah, that is sobering to look at some of the things that have happened with climate change in recent years. I would love to say that I think that from a national level, we will see these changes and proactively work to reduce greenhouse emissions so that we can reduce these issues in the future. I'm not sure what we're going to see from the incoming administration and current government in terms of national policy on changes for fossil fuel use and climate change. I worry that there's a chance that we may see less done on the national level. I know the NCI certainly has policies in place to try to study climate change impact on cancer. It's possible that even that policy could be impacted by the incoming administration. So we'll have to see.  So, unfortunately, I worry that we may be still dealing in a reactive way to the impacts of this. So, obviously, wildfires causing carcinogens, pollution leading to increased cancer incidence, obviously, major weather events leading to physical disruptions, where cancer centers definitely have to have plans in place to help people maintain their treatment during those periods. As an individual, we can certainly make our impact on climate change. There are certainly organizations like Oncologists United for Climate and Health, or so-called OUCH, led by Dr. Joan Schiller, a friend of mine in the lung cancer world, where oncologists are advocating for policies to reduce use of fossil fuels. But I don't know, John, I don't know if I'm hopeful that there's going to be major policy changes on this in the coming year. Dr. John Sweetenham: I suspect you're right about that, although I think on the positive side, I think the issue as a whole is getting a lot more attention than it was maybe even two or three years ago. So that has to be a good thing that there's more advocacy and more attention out there now.  Nate, before we go on to the last question, because I do want to finish on a positive note, I just wanted to mention briefly that there are a couple of ongoing issues which, when we do this podcast each year, we normally address, and they certainly haven't gone away. But we know that burnout and workforce issues in oncology will continue to be a big challenge. The workforce issues may or may not be exacerbated by whatever the new administration's approach to immigration is going to be, because that could easily significantly affect the workforce in oncology. So that's one issue around workforce and burnout that we are not addressing in detail this year. But I wanted to raise it just because it certainly hasn't gone away and is going to continue to challenge us in 2025.  And then the other one, which I kind of put in the same category, is that of disparities. We continue to see ethnic and racial disparities of care. We continue to see disparities in rural areas. And I certainly wouldn't want to minimize the challenges that these are likely to continue to present in 2025. I wonder if you just have any brief comments you'd like to make and whether you think we're headed in the right direction with those issues. Dr. Nathan Pennell: Well, I'm somewhat optimistic in some ways about burnout. And I think when we get to our final topic, I think some of that may help. There may be some technology changes that may help reduce some of the influences of burnout. Disparities in care, obviously, I think similarly to some of the other issues we talked about have really benefited from just a lot of attention being cast on that. But again, I actually am optimistic that there are some technology changes that are going to help reduce some disparities in care. Dr. John Sweetenham: It's always great to finish one of these conversations on a positive note, and I think there is a lot to be very positive about. As you mentioned right at the beginning of the podcast, we continue to see quite extraordinary advances, remarkable advances in all fields of oncology in the therapeutic area, with just a massive expansion in not only our understanding, but also resulting from that improved understanding of the biology of the disease, the treatment advances that have come along. And so I think undoubtedly, we're going to see continued progress during 2025. And I know that there are technology solutions that you've mentioned already that you're very excited about. So, I'd really like to finish today by asking you if you could tell us a little about those and in particular what you're excited about for 2025. Dr. Nathan Pennell: Yeah. It's always dangerous to ask me to nerd out a little bit about some of these technology things, but I don't think that we can end any conversation about technology and not discuss the potential for artificial intelligence (AI) in health care and oncology. AI is sort of everywhere in the media and sort of already worked its way into our lives in our phones and apps that we're using and whatnot. But some of what I am seeing in tools that are probably going to be here very soon and, in some cases, already arriving, are pretty remarkable.  So some of the advances in natural language processing, or NLP, which in the past has been a barrier to really mining the vast amounts of patient information in the electronic medical record, is so much better now. So now, we can actually use technology to read doctor's notes, to read through scanned PDFs in our EMRs. And we can imagine that it's going to become very soon, much harder to miss abnormal labs, going to be much harder to miss findings on scans such as pulmonary nodules that get picked up incidentally. It's going to be much easier to keep up with new developments as clinical guidelines get worked in and decision support tools start reminding patients and physicians about evidence-based, high-quality recommendations. Being able to identify patients who are eligible for clinical trials is going to become much more easy.  And that leads me to the second thing, which is, throughout the pandemic we have greatly increased our use of telehealth, and this really has the potential to reduce disparities in care by reaching patients basically wherever they are. This is going to disproportionately allow us to access rural patients, patients that are currently underrepresented in clinical trials and whatnot, being able to present patients for clinical trials. In the recent “State of Cancer Care in America” report from ASCO, more than 60% of patients in the U.S. did not have access to clinical trials. And now we have the technology to screen them, identify them and reach out to and potentially enroll them in trials through use of decentralized elements for clinical trials. And so I'm very optimistic that not just good quality standard cancer care, but also clinical research is going to be greatly expanded with the use of AI and telehealth. Dr. John Sweetenham: Really encouraging to hear that. Nate, it's been a real pleasure speaking with you today and I want to thank you for taking the time to share your insights with us on the ASCO Daily News Podcast.  Dr. Nathan Pennell: Thanks, John. Dr. John Sweetenham: I also want to say thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers: Dr. Nathan Pennell @n8pennell   Dr. John Sweetenham   Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. John Sweetenham:   Consulting or Advisory Role: EMA Wellness   Dr. Nathan Pennell:     Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron    Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi  

Exploring the Role of Fathers in Pregnancy and Beyond In a heartwarming and insightful episode of the "Dads with Daughters" podcast, host Dr. Christopher Lewis chats with Matthew Morris, who shares his unique journey into fatherhood. Through experiences that span 15 countries, Morris does more than recount personal stories; he advocates for systemic changes in how fathers are supported during the pregnancy journey. Here's a deeper dive into the profound topics discussed in this enriching episode. The Discovery of Parenthood Matthew Morris and his wife Shannon found out they were expecting their first child in the most memorable way. Following an offhand Mother's Day comment, a series of pregnancy tests confirmed the joyous news. As fate would have it, the couple discovered they were having a girl at a family gathering through a creative, heartwarming gender reveal—Matthew dyed his hair pink to share the news. A Journey Across Continents Before settling into parenthood, the adventurous couple decided to travel to 15 countries, immersing themselves in different cultures and learning global perspectives on pregnancy and childbirth. They planned their destinations whimsically; Brazil if a boy, Thailand if a girl, turning every step into an adventure. Their travel decisions were also influenced by significant life changes, including job losses and leaving active military duty. These pivotal moments pushed them forward into the next chapter of their lives. Navigating Healthcare and Birth The Morris's initial plan was to have their baby in Denmark, attracted by the progressive and cost-effective healthcare system. However, visa issues forced them back to the U.S. at 35 weeks pregnant. Matthew expressed strong critiques of the U.S. healthcare system's support for childbirth, and particularly its lack of resources for fathers. Ultimately, Shannon opted for a home birth in their Chicago apartment, supported by a midwife and a doula. This experience emphasized the importance of having a birthing team that values the father's role—Matthew even got to "catch" his daughter when she was born on February 2nd, 2024. Advocacy for Doulas and Progressive Paternity Leave From their global travels, Matthew observed how other countries treat pregnancy as a natural life event rather than a medical condition. He strongly advocates for the inclusion of doulas and midwives in insurance coverage, given their essential role in supporting both parents. His experiences highlighted the stark differences in parental leave policies worldwide, with some countries offering up to 24 months of government-supported leave—a far cry from the limited options in the U.S. The Birth of a Book Inspired by their journey, Matthew authored "The Partner's Purpose During Pregnancy." This practical guide offers straightforward, actionable steps to help expectant fathers get involved early and remain supportive throughout the pregnancy. Matthew's insights are geared towards making the transition into fatherhood less daunting, emphasizing the importance of preparation and involvement. Matthew Morris's journey into fatherhood is a testament to the importance of an involved and supportive parenting partner. His stories and insights underscore the need for systemic changes in how we support fatherhood and childbirth in the U.S. For fathers looking to connect and learn, resources like the "Dads with Daughters" podcast and the "Fatherhood Insider" offer invaluable support. For more from Matthew Morris, visit his website at www.thepartnerspurpose.com and follow him on Instagram at @thepartnerspurpose. TRANSCRIPT Dr. Christopher Lewis [00:00:05]: Welcome to dads with daughters. In this show, we spotlight dads, resources, and more to help you be the best dad you can be. Christopher Lewis [00:00:16]: Welcome back to the Dads with Daughters podcast where we bring you guests to be active participants in your daughters' lives, raising them to be strong, independent women. Really excited to have you back again this week. As always, every week, you and I are on this journey together. You know, I've got 2 daughters, you've got daughters, and we are all rolling in the same direction. We're all working to raise those strong, independent women that we want for our daughters to become. And hopefully, by now, after 250 episodes that we've had of this podcast, you know that we cannot do this alone. You and I cannot do this alone. We have to be able to rely on others. Christopher Lewis [00:00:55]: We have to be able to rely on working with one another to be able to lift each other up, to be able to learn and grow from each other, to be able to be the dads that we want to be. None of us have all of the tools, have all of the understanding. None of us have the perfect manual to follow to be that great dad that you want to be. But this podcast is here to be able to give you some, some hints, some tips, some things that you can do to be able to be that father that you want to be. So every week I bring you different guests, different people, people with different experiences, fathers, mothers, other people with resources that can help you to be able to see fatherhood in a little bit different way, provide you some tools for your toolbox, and help you to be able to become that father that you want to be. This week, we got another great guest with us today. Matthew Morris is with us today. Really excited to have him here. Christopher Lewis [00:01:49]: And we're gonna be talking about his own journey in becoming a father. And prior to becoming a father, he and his wife traveled to 15 countries to learn about parenthood and preparation for the birth of their daughter this past February. And, as he says, it's been a wild ride. And I think for every father, it's a wild ride when you lead up to to to fatherhood. And and once your daughter's here, it becomes an even greater ride, and it continues to go on throughout their lives. So I'm really excited to have him here today to talk about fatherhood, talk about his own journey and a little bit more, and to introduce him to you. Matthew, thanks so much for being here today. Matthew Morris [00:02:28]: Thank you, Christopher. Glad to be here. Christopher Lewis [00:02:29]: It is my pleasure having you here today. Glad that you and I were able to connect and be able to have you talk about your own journey. And one of the first things that I always love to do is turn the clock back in time. So I wanna go back to that first moment that you found out that you were going to be a father to a daughter. What was going through your head? Matthew Morris [00:02:46]: My wife was standing at the top of the staircase, and I had just walked in the door, and I heard her scream. And my wife is a hardcore former United States Navy veteran, and she just, like, even keel all the time. Things do not rile her. And when I heard, bat, yeah, from the top of the staircase, I thought one of 2 things has happened. I said, okay. The house is being breached, and we are about to go on the defense, or she's pregnant. And sure enough, I look up, and she has 3 pregnancy tests in her hands like Wolverine. And I am I book it up the stairs, and she looks at me, and she's like, can you see the pink line? Can you see it? And mind you, my eyes aren't what they used to be. Matthew Morris [00:03:41]: I'm looking. I'm like, may maybe. I think so. And she goes, okay. You pee on 1, and then we'll know. And so shortly that was right after Mother's Day last year. And we were coming back from a wedding, and a woman had wished Shannon. She said happy Mother's Day. Matthew Morris [00:04:02]: And Shannon was like, I'm not a mom, and and we were walking away. And she kinda elbowed me and was like, wouldn't it be funny if and so I found out initially that that she was pregnant and went in a few weeks later to to verify everything. And then then we knew she was pregnant. Obviously, didn't know it was gonna be a little girl until a few months later. And the way that we found out that it was gonna be a little girl was we were we were at a family reunion with Shannon's family. It was a birthday party. And she gets an email, and we're we're sitting all sitting around kinda talking, talking. And, again, Shannon Shannon does not get super excited or super emotional about anything. Matthew Morris [00:04:50]: She's so just level headed. And and she puts her phone down. She looks at me and goes, we gotta go. And I said, why? What was going on? She goes, I know what we're gonna have. And I said, you mean for dinner? She goes, no. For the rest of our lives. And I said, okay. So we say goodbyes, and we go to the haircare store, and she buys a bottle of blue hair dye and a bottle of pink hair dye. Matthew Morris [00:05:22]: And we go to her parents' house, and we said, here's Matthew what we're gonna do. I'm gonna blindfold you. I'm gonna dye your hair one color or the other, and that is how we are going to do the gender reveal. And I have a very proud mohawk. And so if you go on her Instagram, there's a hilarious video of me blindfolded and Shannon with bright pink hair dye, and I take the blindfold off. And as soon as she hands me in the mirror, well, the sun's behind me, so I look in the mirror, and it just blinds me. So I can't even say I can't even tell what I'm looking at myself. And finally, I look around and I see it's pink, and then that's that's how we found out. Matthew Morris [00:06:04]: So that was kind of the the spark to our international journey. And now so we're in fast forward. That was a little over a year ago. We come back to now. Shannon and I made a bet. We have a little boy, we're going to Brazil. And if we have a little girl, we're gonna go to Thailand. And so right now, as we are wrapping up our adventure in Chicago, we are prepping to set sail for title. Matthew Morris [00:06:31]: And so that in between everywhere that we went from the beginning of 2023 to now. And we had to work through our personal endeavors. So January, February of 2023, Shannon was the tech layoff, and then we found out Shannon was pregnant in April of 2023, and then my separation from the marine corps came in June of 2023. And so we went from dual income, no kids, to dual unemployed with a baby on the way. And there is nothing that is a better catalyst for it's time to grab life by the horns than realizing, hey. We gotta figure out somehow to eat. And with that, and this comes into the fatherhood aspect, in our study of how childbirth and the medical system of childbirth in the United States is so far behind the rest of the world, unfortunately, we actually made the decision that we didn't wanna have the baby in the States. And that was a big part of why we left the country. Matthew Morris [00:07:45]: So our original plan was to have Maven in Denmark because Denmark, Sweden, that region has a extremely progressive and much safer approach to childbirth, and it's also significantly cheaper. Even with the cost of flying over there, living temporarily, and paying for the birth out of pocket, all of that would still have been cheaper than going through an uninsured birth in a US medical system. And the big challenge for us was coming off of active duty where almost all of your medical is paid for. When that came to an end, we didn't have health insurance for childbirth. And so what is normally nothing out of pocket with your insurance policy is between $3,025 total to have a baby in the United States. And in addition to that, the restrictions that are put on expecting moms when they are going through, the tests that are mandatory, the lack of education for dads and partners or birthing partners or whoever that person is that is supporting mom through her pregnancy. It's such an afterthought in the United States, which is what set us off on putting the information together for the partner's purpose during pregnancy. So fast forward a few months, our visas were not processed properly, and so we had to come back to the United States when Shannon was 35 weeks pregnant. Matthew Morris [00:09:31]: Well, the FAA won't let you travel at 36 weeks. So it was either be considered an illegal immigrant in a foreign country where we were having a baby or hightail it back to the United States and try and get connected with a midwife and doula team here, which fortunately, we did. So Shannon made the decision that she wanted to have a midwife and doula guided home birth. And so in our apartment in Lincoln Park, Chicago on February 2nd, 2024 at about 1:45 AM. She gave birth with no meds, no anesthesia, just the raw power of being the woman that she is to our daughter. And our birth team coached me through, and I actually got to catch my daughter. I was the quarterback before the hike and had her in my arms and then passed her to the midwife to do all of the immediate post birth things. And baby is healthy and just a a little tornado right now.   Matthew Morris [00:12:56]: And that divide and conquer team, I stand beside and advocate for work on it. And part of what we're also trying to advocate for is the use of doulas and midwives to be covered by general insurance. Because that is a big reason why so many people don't use them is because it's not considered a necessary medical expense. Well, my advocation to that is it is. It is just as important for the birthing or the pregnancy for me to have someone that I can ask questions of, that I can go to, that has experience so that Shannon didn't have to in dealing with with pregnancy brain or brain fog or exhaustion or all of the stress that your body and mind undergo during pregnancy, I had a person that I could ask these questions of, get the answers for so that she could focus on her health and the health of the baby. Christopher Lewis [00:13:57]: So I guess one of the questions that I would ask, with that whole journey is you took a number of months while she was going through that pregnancy, as you said, to be able to learn more about pregnancy, learn more about what happens in other countries to be able to create this book that you've created. And I know that you were out for, I think it was 41 weeks, you said you went to 15 countries. And I guess let's talk on the high level. What are some of the biggest things that you learned in going to those different countries, seeing what other countries do in comparison to what happens in the United States? Matthew Morris [00:14:38]: So saying we were mostly in Sangin. And by and large, there is a different mindset in the way that pregnancy and pregnant people are viewed. My biggest lesson, my biggest learning point was that pregnancy is not a disease. In the United States, we treat pregnancy as a disease. A pregnant mom is looked at as having symptoms. Well, symptoms are the byproduct of illness as opposed to what I viewed there was pregnancy is just part of life. It's the natural progression of all things culminating in birth, and because it's treated so much differently, you have significantly lower rates of things like postpartum depression, you have a lower infant mortality rate, you have a lower maternal mortality rate. The other piece is the recovery time. Matthew Morris [00:15:45]: So commonly referred to as maternity leave, paternity leave, and what's referred to as nesting leave. Now in the United States, all of your leave comes from the company. In these areas, the leave is partially compensated by a government organization. So if you take the longest that we saw was 24 months of total family leave, and that leave could be used by either parent, either during or after the pregnancy, and and there was no expiration date. So imagine in the states, you can't even fathom that. The longest publicly traded company that we have found in the United States is 18 weeks. And that's good. That's better for our area. Matthew Morris [00:16:44]: But the question that we continue to ask is if you are trying to advocate for employees to come back and remain loyal, what are the things that you're doing to incentivize them? And what stands out more than anything is companies that that advocate for more family recovery time. And that's the biggest difference that we've seen from overseas to the states.   Christopher Lewis [00:17:08]: I appreciate you sharing that. And now that you I have transitioned into being a dad, a dad of a daughter, I talk to a lot of dads that step into fatherhood. And fatherhoods can be scary just in its own right in being able to step into that new persona and being able to be there for your child. I hear from a lot of dads with daughters that there's a particular fear of being a father to a daughter. And I guess for you, what's your biggest fear in being a father to a daughter? Matthew Morris [00:17:38]: That when she comes of age, she will come to me and say, father, I am not prepared to go out on my own. And that encompasses a lot. And when I say come of age, there's not a number that's associated with it. She might be ready to set out on her own at 13. She might not be ready to set out on her own until she's 20. Her development is going to happen on its own timeline. My responsibility as a dad is to hold her hand until it's time to let go. And when it's time to let go, I have to have given her every ounce of me so that she's ready. Matthew Morris [00:18:20]: Does that mean that it's gonna be smooth sailing and she's gonna have no trials of her own, and she's never gonna be in a situation where she has to fight for herself or for the other people that she loves and believes in? Absolutely not. But when it's time for her to fight, she is ready. Christopher Lewis [00:18:37]: That's fair. Now as I mentioned, you have put together this book, this book that you're putting out into the world to be able to help other dads, the partner's purpose during pregnancy. Talk to me about that and why you decided that you wanted to take the time to be able to put all of this learning into this, and what are you hoping that people are gonna take out of it? Matthew Morris [00:18:57]: Joshua Sharfstein (zero zero four:fifty seven): I put the partner's purpose during pregnancy together. Number 1, it was my personal way of processing. So on the fortunate side of being unemployed for that period of time, it gave me the head space to sit down and start asking really hard questions, to start reading the books. Right? I read all of them. I read what to expect when you're expecting, the birth partner, bumpin', misconceptions, the Mayo Clinic's guide to pregnancy. Oh, boy. Let me tell you. If, if you're looking for a captivating read, sit down and and pop that 600 pager open. Matthew Morris [00:19:35]: But the reason that I did was I treated Shannon's pregnancy and the birth of my daughter as my new mission. When we would fly in the marine corps, you would prep for sometimes weeks for one specific mission. And you would begin building that knowledge base of the operating area, the weapon systems that you were going to employ, the teammates that you were going to be fighting with and supporting, and the enemy that had a say in every action that you made, well, this was my new mission. And for me to process the intensity of watching Shannon's body change, watching her mindset on things change, I had to have an outlet. And my outlet was putting a pen to paper because when I was asking some of these questions from the point of view of an expecting dad, there were no answers. And fortunately, there is now a culture shift in the United States away from the way that our dads were were kinda forced into it. And what I mean by that is I have a very loving and supportive father. Shannon has a very loving and supporting father, but there was no such thing as dad being there after the baby was born. Matthew Morris [00:21:00]: Took mom to the hospital, baby was born, and 2, 3 days later, dad's back at work. And that's just the way it was. Well, now one of the positives from COVID is the acknowledgment of remote work and the fact that so many jobs can be done from home, which allows you the opportunity to be in proximity to your kids for a longer period of time. And with Partner's Purpose, our mission is to show that you can have a faster postpartum recovery period. You can reduce postpartum depression and other maternal mental health situations if you start being involved and educated way before baby comes. And the other piece is the books that I listed, they have a place on my bookshelves, and I'm not saying that if you are in this phase of birth not to go study them. Go. Do it. Matthew Morris [00:22:42]: And it's practical. It's not theoretical. It's not big universe things. It's tangible. It's make your birth plan together. It's read out loud to your baby before you go to sleep. It's make her a sandwich. It's let her cry. Matthew Morris [00:23:00]: It's these things that when you're in a stressful situation or sorry. When you're in a a calm situation, it's like, oh, yeah. That makes sense. But pregnancy is stressful for both parties involved. And so when we can lay out, do this, do this, do this, I am taking that thought out and replacing it with very basic, simple muscle memory. It's just like training. Marine Corps, you do rifle training. You learn every single in and out aspect of your weapon so that when you are in an extremely high stress environment, you don't have to stop and think, wait, hang on. Matthew Morris [00:23:40]: How do I take it off safety? How do I aim? No. You can be running on 36 hours of no sleep and half a stale piece of bread, and you still know how to make your weapon function when you need it to function. Maybe not that extreme in the average American pregnancy, but the concepts are the same. If I can lay your steps out for you, if I can show you ways to be involved, then all you have to do is pick it up, open it to any page and say, I know how to filter your feed. It's one of the other notes. I know how to invest in our education so that we can develop informed opinions, so that we can build our birth team together. So that if the doctor or the midwife or the doula or the nurse practitioner tells us we have to do something, we know what that means, and we can ask questions on if we really do have to do that or, and this is my favorite, we've always done it that way, so that's why we do it. Well, just because something has always been done does not necessarily mean it's the right way. Christopher Lewis [00:24:49]: Now we always finish our interviews with what I like to call our fatherhood 5 where I ask you 5 more questions to delve deeper into you as a dad. Are you ready? Matthew Morris [00:24:56]: Yes, sir. Let's do it. Christopher Lewis [00:24:57]: In one word, what is fatherhood? Matthew Morris [00:24:59]: Exciting. Christopher Lewis [00:25:00]: Let's think down the road, 18, 20 years. If I was to talk to your daughter, how would you want her to describe you? Matthew Morris [00:25:06]: Empowering and encouraging. I want her to, at no point, ever question if I have her back. I also acknowledge that probably is going to mean there are going to be moments where she is pissed at the decisions that I make. But if I've set her up for success to take on the world whatever way she chooses to take it on, then good. I have done my job. Christopher Lewis [00:25:31]: Who inspires you to be a better dad? Matthew Morris [00:25:33]: My wife holds me accountable for being a better dad. My daughter inspires me to be a better dad. Christopher Lewis [00:25:40]: Now you've given a bunch of pieces of advice today, things that you've learned so far. You've got more to learn as well as your daughter gets older. But as we finish up today, what's one piece of advice you'd wanna give to every dad? Matthew Morris [00:25:51]: Don't ever let your kindness be mistaken for weakness. You have now entered into a world where you have something that is precious, especially if you have a daughter. And my baby is only 6 months old and I see this with strangers. They will come up to her and she is beautiful, and cute, and bubbly, and engaging, and interacting. And the first thing they wanna do is reach out and squeeze her. That is not an acceptable course of action for anyone to attempt to physically touch my infant daughter without my express consent. Basically, if I don't give you permission to give her a hug, to grab her arm, to grab her cheek, you doing that is a violation of her personal space, and you might get smacked. If I don't get you, her mom will. Matthew Morris [00:26:50]: And as a dad, it does not matter what your culture is. It does not matter what your background is. It does not matter what other people tell you. You protect what is yours the best way that you believe it to be. And don't ever doubt yourself for doing the thing that you believe is in the best interest of your daughter. Christopher Lewis [00:27:14]: Now if people wanna find out more about you, your book, and more about what you're doing next, where's the best place for them to go? Christopher Lewis [00:28:04]: If you've enjoyed today's episode of the dads with daughters podcast, we invite you to check out the fatherhood insider. The fatherhood insider is the essential resource for any dad that wants to be the best dad that he can be. We know that no child comes with an instruction manual and most dads are figuring it out as they go along, and the fatherhood insider is full of resources and information that will up your game on fatherhood. Through our extensive course library, interactive forum, step by step roadmaps, and more, you will engage and learn with experts, but more importantly, dads like you. So check it out at fatheringtogether.org. If you are a father of a daughter and have not yet joined the dads with daughters Facebook community, there's a link in the notes today. Dads with daughters is a program of fathering together. We look forward to having you back for another great guest next week all geared to helping you raise strong and powered daughters and be the best dad that you can be. We're all in the same boat, And it's full of tiny screaming passengers. We spend the time. We give the lessons. We make the meals. We buy them presents and bring your a game. Because those kids are growing fast. The time goes by just like a dynamite blast. Calling astronauts and firemen, carpenters, and musclemen. Get out and be the world to them.

In a recent episode of the Dads with Daughters podcast, hosted by Dr. Christopher Lewis, the special guest Markus Wolf opened up about his experiences as a father to two daughters. Markus shared valuable insights into the multi-faceted journey of fatherhood, touching on themes ranging from emotional intelligence to the importance of male connections. Here, we delve deeper into the key topics from their enlightening conversation. The Joy and Fear of Knowing You'll be a Dad The Initial Ecstasy When Markus found out he was going to be a father, the joy was immediate. "I was ecstatic," he said, reflecting on that transformative moment. Unlike some men who may be taken by surprise or even ambivalence at the prospect of fatherhood, Markus had known from a young age that he wanted to be a dad. He even felt that having daughters was a form of karmic balance, avoiding the potential rebelliousness he feared from having a son. The Inherent Fears Despite his enthusiasm, Markus admitted that the journey of fatherhood comes with its own set of anxieties. One of his biggest concerns has always been about maintaining open lines of communication. He emphasized that building a home where his daughters feel safe to express themselves emotionally is crucial, yet challenging. This desire for transparent communication stemmed from his own struggles with emotional intelligence, something he recognized needed constant work. Crafting Unique Relationships with Each Child Individual Awareness One of the critical parenting strategies Markus highlighted was the importance of recognizing the distinct personalities of each child. For example, his daughter Madison is a "fireball," prone to expressing herself loudly, while Sienna tends to close off and become quiet. Understanding these differences has allowed Markus to tailor his parenting approach, ensuring that he meets each daughter's emotional needs effectively. Skill Development Through Coaching Techniques Drawing from his career as a fitness coach, Markus has seamlessly integrated coaching principles into his parenting. He speaks of a "confidence model" where he gradually builds his daughters' skill sets in a manner that empowers them. Much like his clients who increasingly master fitness routines, his children too are slowly being endowed with various life skills. Whether it's making breakfast or picking up their toys, these seemingly mundane tasks are steps toward building a well-rounded individual. Balancing Emotions and Strengthening Connections Managing Temperaments Markus is candid about one of his personal challenges—being a bit of a "hothead." He regularly finds himself working on temper control to avoid alienating his daughters. For Markus, being in a better emotional state often involves engaging in physical activity and maintaining connections with other men. These practices help him manage stress better, creating a more harmonious home environment. The Role of Male Connections The COVID-19 pandemic brought to light an essential aspect of Markus's life—male interaction. Prior to the outbreak, he found much-needed camaraderie in his daily interactions with clients and friends. The pandemic made him realize how vital these connections were for his mental well-being. According to Markus, this communication acts as a stress-relief mechanism, enabling him to return home balanced and prepared for fatherhood duties. The Mentor and Coach Pivot Incorporating Coaching into Parenting Markus describes his approach as "Miyagi-ing" his kids, reminiscent of the lessons from "The Karate Kid." By embedding valuable life skills subtly into daily routines, he's preparing his daughters for the real world without them even realizing it. This stealth approach to skill-building enables Markus to parent effectively, ensuring his daughters are ready for life's challenges while maintaining a supportive relationship. Role Models and Inspirations He also spoke about the crucial need for every man to retain some level of selfishness, not in a negative sense, but in terms of self-care. By maintaining his own well-being, Markus not only becomes a better father but also a better role model. The "loneliness epidemic" among men is something Markus is keenly aware of, actively working to combat it through his practice of connecting with other fathers and men. The Imperfect Yet Rewarding Journey of Fatherhood Markus Wolf's journey through fatherhood is not about being perfect; it's about being present and continuously striving for improvement. He emphasizes that fatherhood is a blessing that requires a balanced approach—recognizing individual needs, maintaining personal well-being, and building strong, open relationships. Markus's story serves as a powerful reminder that fatherhood, with all its challenges, is an evolving adventure, filled with moments of joy, learning, and profound love. For more insights and advice on fatherhood, join the "Dads with Daughters" community and explore resources that could make your parenting journey a little smoother.   TRANSCRIPT Dr. Christopher Lewis [00:00:05]: Welcome to dads with daughters. In this show, we spotlight dads, resources, and more to help you be the best dad you can be. Dr. Christopher Lewis [00:00:16]: Welcome back to the Dads with Daughters podcast where we bring you guests to be active participants in your daughters' lives, raising them to be strong, independent women. Really excited to have you back again this week. Every week, I love being able to have these conversations with you where we are walking on this path together, where you and I are working to raise our daughters in the best way that we know how. And the most important thing that everyone needs to understand, no matter if you have 1 daughter, 2 daughters, 7 daughters, doesn't matter, is that we don't have to do this alone. And every week I love being able to have a conversation with you, to walk with you as we are walking down this path together, as I said, But knowing that, we don't all know everything. There is not the there is not one right way to father, and there's not one playbook to follow. So it is important for us to be able to learn from others, find other resources, find more tools for our toolbox that we can pull from to be able to be the best dads that we want to be that will help our daughters to be the women that they want to be in the future. That's why every week I bring you different guests, different people that have different experiences, that are walking this path alongside of you and are doing things maybe in a little bit different way. Dr. Christopher Lewis [00:01:38]: But that's okay because we can learn and grow from all of their experiences as well. And this week, we have another great guest with us today. Markus Wolf is with us today. And Markus is a father of 2 daughters, and I'm really excited to have him here and for him to share his experiences with us. Markus, thanks so much for being here today. Markus Wolf [00:01:56]: Thanks for having me, Chris. Dr. Christopher Lewis [00:01:57]: It is my pleasure. Love having you here today. 1st and foremost, question I always start off with. I love being able to have the power to turn the clock back in time. I know you have 2 daughters. So So I wanna go back to that first moment. That first moment that you found out that you were gonna be a dad to a daughter. What was going through your head? Markus Wolf [00:02:13]: I was ecstatic. I really was. I knew I wanted to be a dad since I was very young, which some dads never expect to have a child. Some of them never even wanted to have a child and I knew it. I knew it since I was in grade school. I was like, it was part of the vision. I'm going to be a father. So when it happened, it was just kind of I knew I was with the right woman. Markus Wolf [00:02:32]: I knew everything was just pieced together perfectly. So I was really, really excited, especially girl for some reason. I think, I was pretty tough as a son, and I just didn't want the payback that my father got. So it was kinda nice to just know that I was like, okay. Great. I only have to deal with a a daughter and then I got a second one. So that was like, okay. Never gonna deal with a son. Markus Wolf [00:02:51]: Nothing wrong with having sons, of course. Dr. Christopher Lewis [00:02:53]: So you said you always knew that you wanted to be a father. Talk to me about that. What was it about being a father that really, I'm gonna say intrigued you or made you want to be a father yourself? You know, Markus Wolf [00:03:06]: Chris, it's kinda hard to explain. Right? It just some kids grow up and they wanna be firefighters. They wanna be doctors. And then some of them fulfill that that vision. And it was just part of the process of, like, what I pictured myself. I said to myself, I wanted the white picket fence house. I wanted kids. I wanted that lifestyle. Markus Wolf [00:03:23]: So I'm not really sure how to even explain it. It was just something that I knew that I desired. Dr. Christopher Lewis [00:03:27]: I talked to a lot of different dads. A lot of different dads tell me that walking into fatherhood is a bit scary. There's some fear that goes along with being a dad. A lot of it comes back to the fact that there's no playbook to really follow that outside of the mentoring or what you've seen in your life. As you look at the experiences that you've had thus far as a father, what's been your biggest fear in raising daughters? Markus Wolf [00:03:50]: Communication is something you really want. It's one of the hardest things when it comes to parenting. And the the again, part of what I always pictured was my children were gonna always be able to come to me for support and to open up emotionally. And then I realized really quickly, and I think kids do this, relationships do this as well. They expose what you haven't been working on. And I wasn't working on my emotional intelligence. I mean, God bless my wife, Lindsay, for even, like, always just putting up with my, you know, I'm very like, you could call it passionate, but I usually just call it hot tempered. And when you have children again, they're not going to want to come to a human being who just doesn't know how to sit there and and, you know, understand where they're coming from and really be able to just not try to, you know, do the manly thing of just fixing their scenario. Markus Wolf [00:04:38]: So that's the one thing I'm always afraid of. I just want them to not feel like they're ever afraid to come to me to be, I need support with X, Y, and Z. And then, because perhaps I'm not showing the greatest of light, they don't come to me. That'd be the, the, probably the worst thing because they, I don't know. I mean, I feel like I've always valued having mentors and I don't need to be their top mentor, but I would like to be someone that could come to. Markus Wolf [00:04:59]: And I'm definitely gonna be following back up with that on the mentorship piece because I think that that's something that you are incorporating into your fatherhood and I wanna delve a little bit deeper into that. But before I do, I wanna ask you a little bit about when you raise children, it's not always easy. There are ups, downs, sideways, everything in between. And there are good days, there are bad days, there are you know what I mean. So, what has been the hardest part for you in being a father to a daughter? Markus Wolf [00:05:29]: I mean, you kind of said it. I'm very regimented. It's just the way I can handle the toughness of life, if you want to say. And things have to be put in place so perfectly. And that's not parenting. And that's even different when you have 2 different children that have different requirements, different skill sets. I've tried with one of them will work on a Monday and then it won't work on a Tuesday and it's incredibly frustrating. And then again, yeah, it's a constant roller coaster. Markus Wolf [00:05:53]: That's probably the toughest part because it would be so great if they just did exactly what I asked them to do all the time, but they don't. So it's probably that constant battle I have to have with myself to just slow it down and not desire so much. It's just, like, let it go type of thing. Dr. Christopher Lewis [00:06:11]: Now you talk just talked about the fact that what works with one child may not work with the other. And every child is is different and the personalities are different. So talk to me about what you've had to do to be able to build those unique relationships with each of your daughters that may be different from each other. Oh, I Markus Wolf [00:06:28]: mean, first, yeah, you have to almost understand what their qualities are, right? I mean, I have my oldest daughter Madison, who she's just a fireball. So she'll rather yell, she'll scream. So she'll still voice her and she'll still communicate with words. And then you obviously have to, you know, deal with that. You just have to try to, like, bring the person bring Madison down a little bit. With my other daughter, Sienna, she just closes off. Like, she doesn't use words. She gets really quiet. Markus Wolf [00:06:52]: So then you're always just trying to figure out, well, now I know that this one is up and you gotta bring this one down to balance and the other one's a little bit down and you gotta bring it down. So that's been the first one. It's just being aware of how they respond to certain type of emotions. And then when you understand it, then you're like, okay, cool. Now what do I have in my tool belt to to bring one down and bring the other one up? Dr. Christopher Lewis [00:07:12]: Now you talked about that sometimes you can be a little bit of a hothead and you have to temper that. As you said, you don't want your children to be afraid to come to you because of that. How have you had to work on that to be able to get to a point where either you're in the right space or that you've had to had those conversations with your daughters, and you might not have had to have them yet with them so that they understand. But how have you been able to realign yourself in being a father and knowing that your emotions may be a little bit more heated and you have to be able to adjust for that. Markus Wolf [00:07:50]: I'm in fitness. I'm in health. And for me, I believe it's always about putting yourself into like a better state. So if you're like energetic, the stress is relieved. So usually, I think most dads can agree that the milk spilled on the floor is not why you had this huge yelling outburst or the TV not being shut off when you asked for it to be shut off is not really why you're you're yelling. Because if you really put things into perspective, you're like, okay. Am I really gonna get mad at this at a child for not shutting off the TV? Or am I mad because there's a whole bunch of other things I'm incredibly stressed out about that I hadn't just, you know, worked through. So for me, I have to always put myself into a state. Markus Wolf [00:08:26]: And one of them that I've really worked on for the last 2 years is I have to have a male connection at least once a week. That is like a mandatory and it's worked fabulously because once I do it, I come back and I'm I could recognize myself being like, oh, okay. So I think it was just because I needed a little bit of like stress relief. So I mean, obviously stress stress relief can look different for so many other men, but that has been the one that just brings me to the state that I need to be for parenting, if that makes sense. Dr. Christopher Lewis [00:08:52]: It does. And now you talked about the fact that you are a mentor, but you're also a coach. You are and you're incorporating some of those things that you've been doing in your own business as a fitness coach, as a coach in general into your parenting. So talk to me about how you've been able to pivot that in being able to do what you're doing with clients and trying to incorporate that into the work that you're doing in trying to be the father that you want to be? Markus Wolf [00:09:29]: I stumbled upon this. It must have been just almost like an epiphany. I was just obviously I was coaching a lot of men and parenting every single day. And then I started to realize there's something there where the ultimate goal, I believe this is my parent and style. I don't know if this is all fathers is my job is to set them up for the world, right? And the more skill sets I give them, the more, like, you know, let's say even like the emotional intelligence skills around the house. All these like little things are foundational tools that you do for clients. Like clients, they need to have foundational tools to get food prepared so they could eat healthier meals. They could go outside and prioritize themselves. Markus Wolf [00:10:08]: So there's there's very much I tried to work in. What is the process number 1 for this child? I mean, where are we at? Like, you know, at 3 years old, they could barely pick up many things. But at 4 years old, they can empty the dishes. At 5 years old, they can make their own breakfast, things like that. So I started to realize that my coaching style was always like that. It's kind of like a, I call it the confidence model where you take someone and you just, what is the one thing that could boost their confidence? But it's a very easy thing that they can do. And then each time you have to recognize what is the next thing they need to do to again move towards those skill sets that you were speaking of. So I've been doing it with my children. Markus Wolf [00:10:42]: They're excellent at things around the house now without realizing that it wasn't, I'm asking, like, you know, it's not doesn't feel like a chore, I guess, I suppose you're saying. Because, again, I'm gonna use this great reference because I've been watching Cobra Kai for those past couple weeks, which is I Miyagi then. You know, it's mean I just and I do that with my clients. I Miyagi them to just suddenly have these skill sets and now they're like, oh my goodness. Now I'm like equipped for the world and I'm like, yes. I did what I needed to do. Dr. Christopher Lewis [00:11:05]: Now even in Cobra Kai and Karate Kid, Daniel san ends up figuring out that he's getting Miyagi ed. So your kids are going to figure it out sometime. And they're probably going to be like, what the heck, dad? Why are you doing this? How are you gonna react? Markus Wolf [00:11:19]: I might even just do what I just did right now. I might smile a little and just said, you know, this is this is what I'm I'm trying my best. I'm like, I'm trying my best. I have good intentions and I think sometimes that's, like, at least gives you half the pass. But, yeah, if I get exposed, I will get back to you and I'll let you know how I handle it. Dr. Christopher Lewis [00:11:34]: So talk to me about you talked earlier about the fact that you found within your own life that you need to have those connections with other men, other fathers, other individuals, so important for you. I don't like referencing COVID too much, just because there's, so important for you. Markus Wolf [00:11:55]: I don't like referencing covid too much just because this feels like something you just want to put behind you. But it made me recognize that what I had in the past was like a third home. I had a place to go out and when I would personal trained before covid, I was interacting with 5, 10 people a day. And then when you go from 5, 10 to 0, you start to realize that that was something that was a requirement for you. You like being heard, you like hearing other people's stories. And then when you eliminate that, I started to replace my wife for that. So really, it was just get back that same outlets. And then then again, I I can't explain why it feels so good, but it was it was exactly what I just needed. Markus Wolf [00:12:32]: I just need to talk to others and hear others and just get out and about. Dr. Christopher Lewis [00:12:35]: You know, I've come to find that some men are for some men, that is not an easy thing to do, to reconnect, to make those connections, to make those friendships, especially once we become adults. Don't seem to have problems usually when we're growing up. We make those connections. We have friendships. But as we get into our adulthood and we start focusing on family, profession, other things, the push for maintaining friendships, building friendships goes away. As someone that mentors others, that coaches others, why do you think that happens? And what have you done to be able to try to help other men to reconnect like you are? Markus Wolf [00:13:16]: That's a really great point. You made me remember what it was like being with my father or being raised with my father and he had 0 friends. So I think that was already a glaring sign. And the first things that I feel like I recognize was I talk about that a lot with clients, even sometimes the very first interaction. I say to them that when we were younger, when we were men, it was 95% of our time were with other men. Locker room banter, playing video games, going outside, and you're pretty much just hanging out with men your whole entire life up until the point when you're dating the person that you're eventually gonna have children with and then get married. So for me, I personally just started to use I'm a meathead at heart, Chris, to be honest. So I just work out with men because it just seems to be a 2 birds with 1 stone type of scenario. Markus Wolf [00:14:05]: And I think a lot of men can can connect with that. Maybe it's not working out. Maybe it's, hey. I'm gonna go join a softball team, and that might even just be enough to do the thing. Markus Wolf [00:14:14]: No, it does. And I think that it's important to understand that. That's one of the reasons why in fathering together, we develop the online communities that we have, but we also have in person opportunities for dads to connect with other dads and be able to open up opportunities for men to be able to connect, connect with their kids, connect with each other because connection is so important. But we, as I said, sometimes forget about that and focus so much on other aspects that leads to the prevalence of loneliness. And you'll see lots of studies that are out there right now that talk about the pervasiveness of loneliness in malehood right now. And most men don't wanna talk about it, and they just wanna kind of push it down and keep pushing forward because that's what we do. We push through, right? So it's not an easy thing to deal with, but it's also important to for us to deal with because if we don't, our kids are watching and our kids will also identify and see what's happening. So one of the questions that I have, I guess, is this because you work with a lot of dads and men in the coaching that you do through fitness, through life. Dr. Christopher Lewis [00:15:32]: What are some of the biggest challenges that some of these men that are coming to you, working with you right now are dealing with? And are you seeing commonalities amongst them? Markus Wolf [00:15:41]: 100%. I feel like at this point, because I've worked with 100 and it's just patterns. And usually the one pattern that I'm noticing a lot is the values they have are outside of themselves. So it's never a bad thing to provide. That's one of a very important role you're supposed to do as a parent, as an adult. But I couldn't understand that because I'll admit it, I was quite selfish in my twenties, which kind of prepared me for how to, you know, be successful in fitness. But their line in what it does, it prioritizes self, it prioritizes if your energy is not where you want it to be, you prioritize it. If your stress management is not where you want it to be, you prioritize it. Markus Wolf [00:16:21]: And most of the men I work with, and this is what I fear for my kids, is, like, they don't prioritize themselves. They prioritize appeasing work, their boss, wife. You gotta keep your wife happy, but she's in control of her own happiness. In my personal opinion, that if you're not in control of yours, that's probably a big, big issue. Dr. Christopher Lewis [00:16:40]: For those men that you're working with that have a hard time identifying those priorities, because sometimes men do. Sometimes they are floundering a bit and there are individuals that are listening right now that may be thinking, I just don't know where to start. Where should they start? Markus Wolf [00:16:55]: Using that same model that I spoke about, it's usually the easiest route is the first route. So even if it's just going for a walk and listening to an audiobook you've been wanting to listen to forever, It's probably a larger sense of accomplishment to some men than you would even believe. To others, it would be that's just a typical Monday morning. I go for a walk on the beach and I listen to an audiobook or something. But for them, some of these men, they they they just keep saying that they're going to do something. And that's that action, I believe, is already enough for them to, put forward towards where they need to go. And if you're already doing that again, what is the the thing that you keep holding off at? Because that's likely the thing that's gonna push you forward. Dr. Christopher Lewis [00:17:33]: I appreciate you sharing that as well. Now, we always finish our interviews with what I like to call our fatherhood 5 where I ask you 5 more questions to delve deeper into you as a dad. Are you ready? Ready. In one word, what is fatherhood? Markus Wolf [00:17:43]: It's a blessing. Dr. Christopher Lewis [00:17:43]: When was the time that you finally felt like you succeeded at being a father to a daughter? Markus Wolf [00:17:47]: I take my girls on a on a monthly date. And usually, on days where they finish school, you have to drag them out of the playground just to leave to go home. But on our monthly dates, they will run and they cannot wait to to join me. And I feel like that's they're looking forward to it. That's already a good sign. Dr. Christopher Lewis [00:18:03]: Now your kids are still young, so they might not have a lot of answers for this. But if I was to talk to your kids, how would they describe you as a dad? Markus Wolf [00:18:09]: I think they totally answer it with, I'm the fun guy who tends to yell a lot. Dr. Christopher Lewis [00:18:14]: Now let's go at this point maybe 15 years down the road. What do you want them to say then? Markus Wolf [00:18:19]: As long as they could say something, that's the man I trust, That's the man I I look up to. That's the man that I am looking to get him a partner like. Dr. Christopher Lewis [00:18:26]: Who inspires you to be a better dad? Markus Wolf [00:18:27]: Ben, 100%. Dr. Christopher Lewis [00:18:28]: Now you've given a lot of piece of advice today, things that you've learned along the way. What's one piece of advice you'd wanna give to every dad? Markus Wolf [00:18:34]: Choose your battles. If you're like me, you want like, I just told you, I I wanna add skill sets to them. I want them to have things to be better in the world, but it's not gonna happen overnight. So just sometimes let it go. Dr. Christopher Lewis [00:18:46]: And that's definitely not always easy. Markus Wolf [00:18:48]: No. It's probably the toughest thing I've ever done in my life. Dr. Christopher Lewis [00:18:51]: Now, if people wanna find out more about you and what you're up to, where should they go? Markus Wolf [00:18:55]: They can find me on Instagram, coach Markus Wolf, m a r k u s, Wolf, and drop a whole bunch of knowledge bombs if they want anything. And also just, again, resonance. So if you're a father and you're just looking to resonate with someone who's been holding on to healthy habits even with 2 children, just give me a call. Dr. Christopher Lewis [00:19:10]: Well, Markus, I just wanna say thank you. Thank you for being here today, for sharing what you've learned thus far, and I wish you all the best. Markus Wolf [00:19:17]: Appreciate you, Chris. This was a pleasure. Dr. Christopher Lewis [00:19:19]: If you've enjoyed today's episode of the dads with daughters podcast, we invite you to check out the fatherhood insider. The fatherhood insider is the essential resource for any dad that wants to be the best dad that he can be. We know that no child comes with an instruction manual and most dads are figuring it out as they go along, and the fatherhood insider is full of resources and information that will up your game on fatherhood. Through our extensive course library, interactive forum, step by step roadmaps, and more, you will engage and learn with experts, but more importantly dads like you. So check it out at fatheringtogether.org. If you are a father of a daughter and have not yet joined the dads with daughters Facebook community, there's a link in the notes today. Dads with daughters is a program of fathering together. We look forward to having you back for another great guest next week all geared to helping you raise strong and powered daughters and be the best dad that you can be. Dr. Christopher Lewis [00:20:17]: We're all in the same boat, And it's full of tiny screaming passengers. We spend the time, we give the lessons, we make the meals, we buy them presents and bring your a game. Because those kids are growing fast, the time goes by just like a dynamite blast, be the best dad you can be. Be the best dad you can be.

Dr. Linda Duska and Dr. Domenica Lorusso discuss the practice-changing results of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, which evaluated pembrolizumab plus chemoradiotherapy as treatment for previously untreated, high-risk, locally advanced cervical cancer. TRANSCRIPT  Dr. Linda Duska: Hello, I'm Linda Duska, your guest host of the ASCO Daily News Podcast today. I'm a professor of obstetrics and gynecology and serve as the associate dean for clinical research at the University of Virginia School of Medicine. On today's episode, we'll be discussing a new standard of care for previously untreated, high- risk locally advanced cervical cancer. This follows the ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, which I will be referring to as KEYNOTE-A18 for the rest of this podcast, which demonstrated that pembrolizumab plus chemoradiotherapy improved both progression-free and overall survival compared to chemoradiotherapy alone. I was a co-author of this study, and I'm delighted to be joined today by the study's lead investigator, Dr. Domenica Lorusso, for today's discussion. She is also a professor of obstetrics and gynecology. She's at Humanitas University Rosano and the director of the Gynecologic Oncology Unit at the Humanitas Hospital San Pio in Milan, Italy. Our full disclosures are available in the transcript of this episode. Dr. Lorusso, it's great to be speaking with you today. Dr. Domenica Lorusso: Thank you, Linda. It's a great pleasure to be here. Thank you. Dr. Linda Duska: So I was hoping you could start us out with some context on the challenges associated with treating patients with high-risk, locally advanced cervical cancer. Dr. Domenica Lorusso: Yes. I have to make a disclosure because in my experience as a gynecologist, cervical cancer patients are the most difficult patients to treat. This is a tumor that involves young patients [who often have] small kids. This is a very symptomatic tumor. More than 50% of patients report pain. Sometimes the pain is difficult to control because there is an infiltration of the pelvic nerves and also a kind of vaginal discharge, so it's very difficult to treat the tumor. Since more than 25 years, we have the publication of 5 randomized trials that demonstrate that when we combine platinum chemotherapy to radiation treatment, we increase overall survival by 6%. This is the new standard of care – concurrent chemoradiation plus brachytherapy. This is a good standard of care because particularly modern, image-guided radiotherapy has reported to increase local control. And local control in cervical cancer translates to better overall survival. So modern radiotherapy actually is able to cure about 75% of patients. This is what we expect with chemoradiation right now. Dr. Linda Duska: So what are the key takeaways of A18? This is a really exciting trial, and you've presented it a couple of times. Tell us what are the key takeaways that you want our listeners to know. Dr. Domenica Lorusso: Linda, this is our trial. This is a trial that we did together. And you gave me the inspiration because you were running a randomized phase 2 trial exploring if the combination of pembrolizumab to concurrent chemoradiation was able to give signals of efficacy, but also was feasible in terms of toxicity. There were several clinical data suggesting that when we combine immunotherapy to radiotherapy, we can potentially increase the benefit of radiotherapy because there is a kind of synergistic effect between the two strategies. Radiotherapy works as a primer and immunotherapy works better. And you demonstrated that it was feasible to combine immunotherapy to concurrent chemoradiation. And KEYNOTE-A18 was based on this preliminary data. We randomized about 1,060 patients to receive concurrent chemoradiation and brachytherapy or concurrent chemoradiation and brachytherapy in combination with pembrolizumab followed by pembrolizumab for about two years. Why two years? Because in more than 80% of cases, recurrence in this patient population occurred during the first two years. So the duration of treatment was based on the idea to provide protection to the patient during the maximum time of risk. And the trial had the two primary endpoints, progression free and overall survival, and met both the endpoints, a significant 30% reduction in the risk of progression that was confirmed. At the 3-year follow up, the observation was even better, 0.68. So 32% reduction in the risk of progression. And more importantly, because this is a curative setting, 33% reduction in the risk of death was reported in the experimental arm when pembro was combined with chemoradiation. Dr. Linda Duska: That's amazing. I wanted to ask you, a prior similar study called CALLA was negative. Why do you think A18 was positive? Dr. Domenica Lorusso: Linda, there are several discussions about that. I had the possibility to discuss several times with the PI of CALLA, Brad Monk. The idea of Brad is that CALLA was negative because of using durvalumab instead of PD-1 inhibitor, which is pembrolizumab. I do not have exactly the same impression. My idea is that it's the kind of patient population enrolled. The patient population enrolled in KEYNOTE-A18 was really a high-risk population; 85% of that patient were node positive, where the definition of node positivity was at least 2 lymph nodes in the pelvis with a short diameter of 1.5. So, we are very confident this patient was node-positive, 55% at the grade 3 and 4 diseases. So this is really a high-risk population. I remember at the first presentation of CALLA, I was honored to discuss the CALLA trial when it was first presented at IGCS a few years ago. And when I received the forest plot of Calla, it was evident to me that in patients with stage III and node positive there was a signal of efficacy. And we have a huge number of patients with node positive. So in my opinion this is the reason why KEYNOTE-A18 is positive. Dr. Linda Duska: Yeah, I agree with you. I've thought about it a lot and I think you're right about that. The INTERLACE trial results were recently published. How should we interpret these results in the context of A18? Dr. Domenica Lorusso: So it's very difficult to compare the 2 trials. First of all, in terms of population. The population enrolled in INTERLACE is a low-risk, locally advanced but low risk population; 76% were stage II, 10% were stage I, 60% were node-negative patients. So, first of all, the population is completely different. Second is the type of radiotherapy that was provided. INTERLACE is a 10-year long trial, but in 10 years the quality and the technique of radiotherapy completely changed. Only 30% of patients in INTERLACE received what we call the modern image-guided brachytherapy, which is important because it provides local control and local control increases overall survival. And third, we read the paper. I'm not a methodologist, but there are some methodological biases in the paper. All the statistical design of the trial was based on PFS, but PFS was evaluated at physician description. And honestly, I never saw a trial that had no pre-specified timeline for radiological evaluation. It's very difficult to evaluate progression in cervical cancer because the fibrosis related to radiotherapy changes the anatomy in the pelvis. And I think that the radiological evaluation is important to address if the patient is progressing or not. Particularly, because the conclusion of CALLA is that the PFS was mainly in favor of distant metastasis. So really, it's difficult for me to understand how distant metastasis may be evaluated with the vagina visit. So really, it's very difficult to compare the two trials, but I have some concerns. And also because of toxicity in the study, unfortunately 30% of patients did not complete concurrent chemoradiation because of residual toxicity due to induction chemotherapy. So I wanted to be sure in the context of modern radiotherapy, if really induction chemo adds something to modern radiotherapy. Dr. Linda Duska: Well, I have two more questions for you. As we move immunotherapy into the front line, at least for these high risk locally advanced cervical cancer patients that were eligible for A18, what does that mean then for hopefully those few that develop recurrence in terms of second line therapy? Dr. Domenica Lorusso: Well, Linda, this is a very important question. We do not have data about immuno after immuno, but I would not completely exclude this hypothesis because in KEYNOTE-A18, the patient received treatment for a well-defined time period. And for those patients not progressing during immunotherapy, I really guess if there is a space for the reintroduction of immunotherapy at the time of recurrence. In this moment we have 30% of patients in KEYNOTE-A18 in the control arm that receive immunotherapy after progression, but still we have 11% of patients that receive immunotherapy in combination with concurrent chemoradiation and then receive, again, immunotherapy in later line of therapy. I think we need to collect these data to capture some signals and for sure we have the new drug. We have antibody drug conjugate. The trials are ongoing exploring the role of antibody drug conjugate, particularly in immune pretreated patients. So I think this is a very interesting strategy. Dr. Linda Duska: I was going to ask you, “What are the next steps,” but I think you already answered that question. You talked about the second line. If you were going to redesign a study in the frontline, what would it look like? Dr. Domenica Lorusso: Probably one question that I would like to answer – there are two questions in my opinion in KEYNOTE-A18 – one is induction immunotherapy. Linda, correct me if I'm wrong, you reported very interesting data about the immune landscape change when you use induction immunotherapy. And I think this is something that we need to explore in the future. And the second question is the duration of maintenance. Because, again, we decided for two years based only on the epidemiology of recurrence, but I guess if one year may be enough. Dr. Linda Duska: I think this sequencing question is really important, that the induction immunotherapy was actually GY017. I can't take credit for that, but I think you're right. I think the sequencing question is really important. Whether you need the concurrent IO or not is an important question. And then to your point about the 2 years, the length of the need for maintenance therapy is a question that we don't know the answer to. So there are lots of really important questions we can continue to ask. I want to thank you so much for sharing your valuable insights with us on the podcast today. You're always so thoughtful about this particular study and cervix cancer in general and also for your great work to advance the care for patients with GYN cancers. Dr. Domenica Lorusso: Thank you, Linda. It's our work - we progress together. Dr. Linda Duska: Yes. And we thank the patients as well. The over 1,000 patients that went on this trial during a pandemic. Right? Dr. Domenica Lorusso: Absolutely. Without their generosity and their trust, we would not be able to do this trial. Dr. Linda Duska: So we're very grateful to them and we thank our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you all.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.   Follow today's speakers:  Dr. Linda Duska @Lduska Dr. Domenica Lorusso   Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures:   Dr. Linda Duska: Consulting or Advisory Role: Regeneron, Inovio Pharmaceuticals, Merck, Ellipses Pharma Research Funding (Inst.): GlaxoSmithKline, Millenium, Bristol-Myers Squibb, Aeterna Zentaris, Novartis, Abbvie, Tesaro, Cerulean Pharma, Aduro Biotech, Advaxis, Ludwig Institute for Cancer Research, Leap Therapeutics Patents, Royalties, Other Intellectual Property: UptToDate, Editor, British Journal of Ob/Gyn Dr. Domenica Lorusso: Consulting or Advisory Role: PharmaMar, AstraZeneca, Clovis Oncology, GSK, MSD, Genmab, Seagen, Immunogen, Oncoinvest, Corcept, Sutro Biopharma, Novartis, Novocure, Daiichi Sankyo/Lilly Speakers' Bureau: AstraZeneca, Clovis, GSK, MSD, ImmunoGen, Seagen Research Funding (Inst.): PharmMar, Clovis, GSK, MSD, AstraZeneca, Clovis Oncology, Genmab, Seagen, Immunogen, Incyte, Roche, Pharma&, Corcept Therapeutics, Alkermes Travel, Accommodations, Expenses: AstraZeneca, Clovis, GSK, Menarini  

JCO PO author Dr. Michael J. Hall, Professor of Medicine, Chairman of the Department of Clinical Genetics, and Co-Leader of the Cancer Prevention and Control Program at Fox Chase Cancer Center in Philadelphia, PA, shares insights into the JCO PO article, “Uptake of aspirin chemoprevention in patients with Lynch Syndrome.” Host Dr. Rafeh Naqash and Dr. Hall discuss the finding that only about 1 in 3 patients with Lynch Syndrome use aspirin for cancer chemoprevention. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash podcast editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, I'm excited to be joined by Dr. Michael J. Hall, Professor of Medicine, Chairman of the Department of Clinical Genetics and co-leader of the Cancer Prevention and Control Program at the Fox Chase Cancer Center in Philadelphia, and also the lead author of the JCO Precision Oncology article entitled, “Uptake of Aspirin Chemo Prevention in Patients with Lynch Syndrome.” At the time of this recording, our guest disclosures will be linked in the transcript. Dr. Hall, welcome to the podcast and thank you for joining us today to explain and help the listeners understand your interesting research that was just published in JCO Precision Oncology. Dr. Michael J. Hall: Thank you so much for having me and really thanks for the interest in our work. I think it's an important subject and I hope people will also find it as interesting as we do. Dr. Rafeh Naqash: Absolutely. I think your research touches upon a few things. One, obviously, touches upon Lynch syndrome germline assessments of individuals. It also touches upon chemo prevention, prevention in general, and it also touches upon the knowledge and understanding of chemo prevention aspects. So to start off, I would like to ask you, for the sake of our listeners, many of whom who may not necessarily fully understand the length and breadth of Lynch syndrome, maybe perhaps some residents or trainees out there, could you tell us what Lynch syndrome is, what some of the mutations are, what the implications are, and then we can try to go and delve more into the research topic. Dr. Michael J. Hall: Sure, I'd be happy to. Lynch syndrome is probably, in the hereditary cancer genetics world, one of the most common hereditary risk syndromes we encounter. Recent estimates are that probably roughly about 1 in every 280 individuals in the population is a carrier of a pathogenic variant, one of the Lynch syndrome genes, there are roughly four. There's sort of a fifth gene that is also involved with Lynch syndrome, but really, we largely think about four genes in Lynch syndrome, MLH1, MSH2, MSH6, and PMS2. Over time we've begun to learn, and I'll say that the guidelines that we develop have become more specialized for each of those genes. They are not sort of all the same in the cancers they cause and the way they behave. But roughly, what is Lynch syndrome? It's a syndrome of DNA mismatch repair. So, individuals who have Lynch syndrome have some degree of deficiency in their ability to repair DNA via the mismatch repair system. Depending on the pathogenic variant that is within a family, that may be related to a more severe deficiency of mismatch repair, repair, editing, or for instance, with the PMS2 gene, we've learned over time that actually the degree of DNA repair deficiency is actually a milder phenotype. These individuals over a lifetime are at risk of a variety of different kinds of cancers, the most common being colon cancer. And the risk of that is variable by gene. With MLH1 and MSH2, it's close to 50% over a lifetime. With MSH6 and PMS2, somewhat lower. There are also risks of endometrial cancer, gastric cancer, ovarian cancer, pancreas cancer, a number of other ones. But they're all related again to the same underlying molecular deficiency, and that's this deficiency of being able to repair mistakes made in the DNA accurately. And so, mutations accumulate in the genome of cells in various tissues of the body. Dr. Rafeh Naqash: Thank you for that very simplified version of a very complicated topic otherwise. So, as you mentioned, these different genes have different implications. Perhaps some have higher risks for colorectal cancer than others. What are some of the current standardized approaches for screening or following these individuals over the course of their journey until perhaps either get detected with cancer or while they're being monitored? Dr. Michael J. Hall: Sure. It's a great question, because this is very much a moving target in this disease. I'm going to give you a quick second of history that up until maybe about six or seven years ago, we had uniform guidelines, really, that any Lynch syndrome pathogenic variant carrier should start colorectal cancer screening. Usually, we were recommending between the age of 20 and 25, and this was usually annual colonoscopy. And for years that was the standard. In more recent years, we've stuck to that tight interval, particularly in the higher risk genes, MLH1 and MSH2, although the guideline now reads every one to two years, because we recognize people need some degree of flexibility to live their lives. And there are people in the population who are more risk averse, and there are those who want a colonoscopy every year because they want to stick to that schedule. For MSH6, we recommend a somewhat later start at age 30, and that can be every one to three years for colon screening and for PMS2, similar recommendations, although I think there is a chance in the coming years, we may actually expand the screening interval even more, again, because the risks are somewhat lower. We still have ways to go in terms of screening for the other cancers in Lynch syndrome. I'll say that, for instance, endometrial cancer, which is the second most common cancer in this disease, we still struggle with what is the best way to screen women for a risk of endometrial cancer. Our guidelines in the past were always somewhat draconian, that once women sort of finish childbearing, they should immediately have a total abdominal hysterectomy and oophorectomy. And I'll say that with greater input from the gynecologic and GYN ONC community, we have somewhat softened those recommendations, especially for the endometrial cancer and also the age at oophorectomy, because we recognize that there were compensatory risks of taking the ovaries out too early in some women, risks of bone loss and cardiovascular disease. So those are the most common. For other tumors in Lynch syndrome, for instance, gastric cancer and pancreas cancer, the guidelines are still really evolving, and different groups have put out guidance for clinicians. And I'll say NCCN, which I participate in and help write those guidelines, has very good recommendations for docs. But I'll say that it is again, back to the idea that it's a moving target. And as we learn more, hopefully, we'll have better recommendations. Dr. Rafeh Naqash: I completely agree as far as a moving target is concerned, and we often look at the disconnect between the recommendations and then what's implemented or followed in the real-world setting. So I have a question in that context, and my question is, when you identify these individuals with Lynch syndrome, perhaps let's talk about academic settings, and then we can try to delve into how this might work in the real world community oncology settings, where the real world population actually exists, 60, 70% of individuals get treated in the community. So, when you talk about an academic center, what is the flow of the individual? Does the individual stay within the geneticist when they're diagnosed? Does the individual go to the primary care and the geneticist makes the recommendation and the primary care follows the recommendation? How does it work for you and what are some of the models that you've seen work best perhaps at different academic centers? Dr. Michael J. Hall: I think you get at a really great question. And I'll say there is really no one model. And I think models have to be fluid these days because people with Lynch syndrome are really being identified in more and more diverse settings, and by diverse means. I'll say at my own center, we are more of a traditional practice. So, we do the pre-test and the post-test counseling. Once we have counseled individuals identified Lynch syndrome, we will usually make referrals. If folks don't have a gastroenterologist that they have interacted with before, we keep them in our own group and follow them. But their Lynch syndrome home really sits both in a continuity clinic that I run for patients to come back and circle around every one to two years just to review guidelines and review their screening results. However, I do really make an effort to, first of all, keep primary care docs involved, because I think some of the things we recommend, it is critical that the primary care doc is aware so that patients are keeping up with some of the recommendations. For instance, we often recommend skin screening to make sure that folks have had at least one good skin exam somewhere in the 40s. And I think the primary care doc can be very helpful in making sure that happens. It is somewhat different, I think, in the community where many more patients with Lynch syndrome are being identified these days. I suspect that much more of the burden of making sure Lynch syndrome patients are well hooked in with a gastroenterologist and with a dermatologist and maybe a urologist probably does fall on that primary care doctor. In my experience, some primary care physicians have really kind of jumped up in and taken hold of this and really know their Lynch syndrome well, and I think that's amazing. I do, however, as kind of an expert in this area, I do get a lot of referrals in from the community as well, from docs who just feel that they may not have quite that expertise that they can get at a comprehensive center. So, someone may come in to me just for a consult to review what my recommendations would be, hear about research, hear about what's going on in the field, and those folks will often touch base with me again every couple year or so. Often, another thing I've started to experience is that I may meet people once or twice early on in their diagnosis, and then they go back to their primary docs and I may not hear from them again until something more profound happens in the family or into the patient and they get their screening colonoscopy and a stage 1 cancer is found. Often then, that's the patient who, after four or five years, will contact me again and say, “We haven't talked in a while, but something has happened, and can we re-consult about what would be the best way to do things?” Dr. Rafeh Naqash: Again, like you said, lots of moving targets, moving aspects to this whole care of these individuals. Do you think, in your experience, nurse navigation, maybe some centers have already implemented that perhaps you might have that, do you think nurse navigation could play a certain level of role? You know how in the multidiscipline care we have nurse navigators that coordinate care between radiation oncologists, medical oncologists, thoracic surgeons. So that's something that is being implemented. My second part of that question is telehealth in this case, maybe it's a little more difficult for somebody to drive three hours to come to you for a visit just to check in versus maybe virtually talking to you or your team getting a sense of where things are at in terms of their screening and their follow ups. Dr. Michael J. Hall: I think both are great, great questions and absolutely, we use both of those pieces in our model. And I know from colleagues that they do as well. So, in terms of navigation, we do have an embedded nurse navigator within our department. She joins and kind of helps facilitate all of our high risk follow up clinics. Mine, for GI, we have a high-risk prostate clinic, we have several high-risk breast clinics and those are populated by providers. We have a couple of nurse practitioners in my genetics group and a PA they are sort of the main provider in those clinics, but they are very much supported by that nurse navigator who, as you well point out, really helps with the coordination of the care. Telehealth as well, I do 100% support because you're absolutely right, if you look at a map of the United States and you first of all look at where there are good counseling services available, of course, there's ample counseling in the major metropolitan areas all over the U.S., but the minute you get outside of those counseling and then other management expertise, then– So we do have a model where particularly for folks who are from central Pennsylvania and sometimes more towards western Pennsylvania, I do have some individuals who've been identified with Lynch syndrome who telehealth in, again, for that follow up. A sort of side notes on telehealth, I think we learned a lot from the pandemic about how to use telehealth more effectively. And thank goodness, we've all gotten up to speed in medicine of how to be better telehealth providers. Unfortunately, I feel like with the pandemic kind of waning, there's been a little bit of a regression of the telehealth laws. So now if I want to do telehealth with someone who is from New Jersey, even though New Jersey sits very close to where I practice, it's more complicated now. Again, I have to get a license and same thing with New York and same thing with Delaware. I sort of wish we had a little bit of a better and welcoming system in the states where you could have easier ability to practice, especially when states were quite close using telehealth. But nonetheless, that's for another podcast, I think. Dr. Rafeh Naqash: Well, thank you again for some of those interesting aspects to this whole topic. But let's dive into the thing that we are here to talk about, which is aspirin in these individuals. So can you give us some context of why aspirin, what's the biology there and what's the data there, and then talk about why you did what you did. Dr. Michael J. Hall: So, we've known for many years that aspirin has preventive properties in terms of preventing colorectal cancer. Many observational studies and some interventional studies have shown us that aspirin has benefits for reducing the risk of colon cancer in an average risk population. There was even an interventional trial a number of years ago that looked at individuals who made polyps, and this looked at particularly adenomas, which we know are the precancerous polyps and adenoma prevention using aspirin. And that study clearly showed that aspirin had benefits for lowering risk of recurrent polyps and adenomas. Particularly even a lower dose of aspirin, 81 milligrams, was effective in that setting. Aspirin's also been studied in other hereditary risk syndromes, the most visible one being FAP, where data have shown that aspirin does help reduce polyp count in FAP, although is certainly not a perfect chemo prevention for that disease. So, in that background of knowing that aspirin has many benefits for colorectal cancer prevention, a study was initiated in the UK a number of years ago called the CAPP2 study, with its lead investigator being John Burn. And in this study, it was a two-arm factorial study that was not just aspirin, but they were also looking at resistant starch, which there was a lot of excitement about resistant starch back then. But in this study, they looked at using aspirin as a way of lowering risk of colorectal cancer in patients with Lynch syndrome. And that study, which was initially reported in The New England Journal, the initial outcomes did not actually show benefits in its first analyses of adenoma risk and colon cancer risk. But what they found over time was that there was a delayed effect and, in a follow, up paper looking at 10 plus years of follow up, they showed a substantial reduction in risk of colon cancer, about 40% risk reduction, which was really striking and exciting in the field to see such a large benefit from aspirin. Now, one caveat was in the analyses they performed, it was those individuals who were able to stick to the aspirin dose in that study, which was 600 milligrams a day. I always say to folks that back in the day, that was not a lot of aspirin, although I think these days we're much more skeptical about taking larger doses of any drug. So, 600 milligrams is roughly about two adult aspirin in the U.S. So those folks who were able to stick to that dose for at least two years were the ones who gained benefit from being on aspirin. And what was interesting is that benefit endured for really 10 years after those two years of being able to take aspirin. So, this was striking and it really changed our thinking about whether there may be chemo prevention options for folks with Lynch syndrome. However, and I think what formed the background of our study here was that there was a somewhat equivocal endorsement of aspirin by the major guidelines committees, mainly because, as we all know in oncology, we love one first big study, but we always really love secondary studies that solidify the finding of the first study. And so, because this was such a niche group and no one else out there was doing big aspirin studies when this result came out in 2011, we've sort of been waiting for many years for some follow up data. And the NCCN guidelines have always been a little bit equivocal that people could consider using aspirin to lower risk in their patients with Lynch syndrome, but without that kind of strong, “Everyone should do this.” And so, this has kind of formed the background of why we performed the study that we did. Dr. Rafeh Naqash: Interesting. And then you had a bunch of observations. One of the most important ones being that use of aspirin was pretty low. Could you dive into that and help us understand what were some of the factors surrounding those low implementation aspects? Dr. Michael J. Hall: Of course. So, what we were interested in then again in that background was, here's a high-risk population, docs are getting somewhat maybe ambiguous information from the guidelines, but what actually is going on out there in practice? How many patients are actually using aspirin? What doses are they using, and what are some of the factors that drive it? So, we performed a survey that actually occurred in two parts. One started at Fox Chase in our population here, and then we expanded it online to a convenience sample. Overall, we had 296 respondents. And yeah, what we found actually was the uptake of aspirin was only about roughly 30%, 35% or so among patients who were eligible to take aspirin. When you actually drill down to those people actually taking aspirin because they wanted to prevent Lynch syndrome, it was even lower. It was in the range of 25% to 30%. This somewhat surprised us. And then when we looked at the doses that people were using, of course, thinking back to that 600-milligram dose that was tested in the study, we found actually that more than half of folks were taking low dose aspirin, like an 81 milligram, and only about 8% of our study participants were using that 600-milligram range. So, again, I would say this somewhat surprised us because we thought it might be higher than this. I'll say as a somewhat caveat to this though, is that back to my comment about we always like another study that confirms our findings, and at a meeting earlier this year, there was a study performed in a New Zealand population by a medical oncologist named Rebecca Tuckey. And she actually found almost the same identical results that we did in the New Zealand population - very, very similar uptake rates of aspirin in the New Zealand population with Lynch syndrome, so kind of confirming that something we've stumbled upon appears to be true. But how do we understand why some folks use aspirin and why others don't in this condition? Dr. Rafeh Naqash: You had a very robust question there from what I saw in the paper. And some of the questions that I had around that was, did you or were you able to account for demographics, education level of the individuals? Were you also able to assess whether these individuals felt that they had been counseled appropriately when they met with either a primary care physician or of any provider on the genetic side, physician or non-physician? So how did you get an assessment of whether it was an apples-to-apples comparison or were there a lot of confounders. Dr. Michael J. Hall: Very good question. And of course, in the setting, unfortunately, we weren't interviewing people, which we could have gotten much richer data in some ways. And there were other things we were looking at in this survey as well, so our aspirin questions, we had a number of them, but perhaps in retrospect, it would have been nice to even have more. We did have some common covariates, age, sex, ancestry, marital status, which gene was affected, whether they had a history of cancer. We did not have education, unfortunately. And I think your question is a great one, but we did not actually ask folks about whether they had been counseled by their provider or their genetic counselor or someone else about whether they should use aspirin or not. We simply wanted to see whether folks were using it. We did ask them again whether they were using it because they wanted to lower their risk of a Lynch syndrome cancer or whether they were using it for another reason or a combination of both. So, yes, in retrospect, we actually do have another study plan to kind of drill deeper into these questions of is it more of a hesitancy question? Is it more of a question of just not as much awareness? Are there other reasons? I think there's a lot to answer, and I think answering these questions is really important because we both want to make sure we're talking about interventions that we think can help people, but we need to understand also some of the barriers they may face. And if people do have barriers to some forms of chemo prevention or I think about some of the vaccine research that's going on right now, if the kinds of things that we're working on to develop are actually not going to be palatable to the patient, the population, then I think we kind of need to step back and say we need to maybe understand what people want so that we can have a good meeting of what's going to work and what's going to fit the needs and lifestyles of our patients. Because these are things they might have to do for many, many years and starting maybe even in their 20s or 30s. So, it makes a difference. Dr. Rafeh Naqash: From what you learned in the study, are you thinking of any subsequent interventional approaches, whether they involve a simple phone call to the patient regularly or perhaps, even though I'm not a big fan of EMR prompts, like an EMR prompt of some sort, where they talk, where they're instructing the provider, whoever is seeing the patient physician or the APP or the geneticist that, “Hey. Did you counsel the patient?” And its sort of a metric how in the oncology side they say, “Well, your metric is you should stage all patients and you should talk about toxicities from a reimbursement standpoint and also from a quality improvement metric standpoint. “Is that something you're thinking of? Dr. Michael J. Hall: 100%. So, when we looked at the barriers, many of the kind of the things that were the strongest predictors of who used aspirin versus who didn't were really patients' perceptions of whether aspirin would cause side effects or whether aspirin would be burdensome to take on a daily basis, also, just how much benefit they thought would come from taking aspirin. So, I think there's, number one, I think an intervention and our next delve into this as an interventional study would be both education about the delta prevention benefit that you get from aspirin, the safety profile of aspirin, which is really quite excellent. And also, I think the data that are so important that in this study by Burn et al, it was actually only two years of intervention that then paid off for 10 years down the line, right? So, I think that's important. The other thing that we actually learned as an aside in this study was actually the kind of intervention that patients wanted the most was actually not a drug and was not a vaccine and was not another kind of special scope to stick somewhere. What they actually were most interested in were interventions related to diet. People really see diet as being an important part of health, or I should say diet and nutrition. And so, I think a subsequent study would perhaps wed both a nutritional intervention of some kind with a chemo prevention in some sort of time limited fashion, so that folks felt like they were both focusing on something that was more important to them, but also, something that was related to the study that we wanted to look at. So that's kind of my idea of where we're going to go in the future with this. Dr. Rafeh Naqash: Excellent. Sounds like the next big RO1 for your group. Dr. Michael J. Hall: Let's hope so. Dr. Rafeh Naqash: Well, I hope the listeners enjoyed talking about the science and learning about aspirin Lynch syndrome. The last couple of minutes are about you as an individual, as an investigator. Can you tell us what your career journey has been like, how you ended up doing what you're doing, and perhaps some advice for early career junior investigators on what this whole space looks like and how you pace yourself and how they can learn from you? Dr. Michael J. Hall: I really got interested in oncology during my residency training. I really found that I really liked oncologists. I found them to be a bit more of a science focused group. They liked research, but you're in oncology because you understand the fears and the challenges of cancer. And so, it's both a combination of that love of science, but also that real human touch of taking care of people. The thing I always tell my fellows as well is the other thing I love about oncology is if you tell people they don't have cancer, they don't want to come back to you. Now, of course, that's modified in the prevention setting. But I really like that when people come to me in my GI oncology clinic, it's because they have a diagnosis and if I say you actually don't have cancer, they go off to their life, and so you're really spending your time on real subjects. The person who really got me most interested in Lynch syndrome and this kind of prevention research was a mentor from University of Chicago, Funmi Olopade, who really has been an enormous mentor for many, many people in the field. Actually, three people in my fellowship class all went on to careers related to genetics and genomics. So, she's been highly influential and continues to mentor me even in my mid-career. I think in terms of pearls or what keeps this interesting for me, I think as much as oncology treatment and new drugs and trials is super exciting, I love being able to step away from that into my genetics and prevention population and kind of focus on treating people in a different format. Patients who are healthy but are worried about cancer because of a family history or carrying a gene or otherwise, and I feel that that's where I can have also an important impact, but on a different level in educating people and helping them understand how genetics works in an understandable and simple way, but also giving them some tools. And one reason for this study, and the reason I study preferences related to prevention is, again, I don't want to just develop something and spend 10, 15 years of my life developing some intervention that everyone looks at and is like, “I don't really want to do that.” I want to really understand what it is that is important to the patients so that we can hopefully work together to develop things that can not only have impact but have impact on a wide scale. Dr. Rafeh Naqash: Awesome. You mentioned Dr. Olopade. I crossed paths with her actually at an international medical graduate community of practice session earlier this year at ASCO where she talked about her journey as an immigrant, talked about how she started, the kind of impact that she's had. It was obvious evident in the picture that she showed with all her mentees who have kind of gone all over the world. So that was very phenomenal. And it's surprising how small of a world we live in. Everybody knows everybody else. Dr. Michael J. Hall: It's crazy. More so than anyone I think I've met in my career; she is really a huge believer in mentorship and spending that extra time with your mentees. And she has been someone who has continued to promote me as an investigator and build me up and get me involved in things. And like I said, I've been in oncology now for quite a few years. But having that person who I think is always thinking about their trainees and people who have learned and grown under them, because what it does is it gives you that fire as well as an investigator to do the same thing for the people that you are a mentor for and train. So, I try to be just as good of a mentor to my genetic counselors and the fellows who come through me and my APPs to give them opportunities to get them excited about research and when they have these big moments to do that. So, yeah, I know Funmi just has had a huge impact on the field of genetics. I still remember some of our early conversations on the wards when she said to me, “Oh, this is such an interesting case. We don't really have anyone who's studying Lynch syndrome so much right now and you should really get into this area.” And I remember thinking, “Okay, I want to develop a niche and here's a niche that's waiting.” Dr. Rafeh Naqash: Clearly it paid off big time and you're paying it forward with your mentees. So, thank you again for joining us. This was an absolute pleasure. Hopefully, the listeners learned a lot about the science and also your journey and how you're trying to impact the field. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinion, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.      

Dr. Ryan Augustin and Dr. Jason Luke discuss neoadjuvant immunotherapy and the importance of multidisciplinary team coordination, promising new TIL therapy for advanced melanoma, and the emerging role of CD3 engagers in treatment strategies. TRANSCRIPT Dr. Ryan Augustin: Hello, I'm Dr. Ryan Augustin, your guest host of the ASCO Daily News Podcast today. I'm a medical oncology fellow at Mayo Clinic in Rochester, Minnesota. Joining me today is Dr. Jason Luke, an associate professor of medicine and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh Hillman Cancer Center. I had the privilege of working as a postdoc in Jason's translational bioinformatics lab, where we investigated mechanisms of resistance to immunotherapy in melanoma and other cancers.  Today, we'll be discussing 3 important topics, including neoadjuvant immunotherapy and the importance of multidisciplinary team coordination, the impact and practical considerations for incorporating TIL therapy into melanoma, and the current and future use of CD3 engagers in both uveal and cutaneous melanoma.  You'll find our full disclosures in the transcript of this episode.  Jason, it's great to have this opportunity to speak with you today. Dr. Jason Luke: Absolutely. Thanks, Ryan. It's great to see you. Dr. Ryan Augustin: So, to kick things off, Jason, we, of course, have seen tremendous advances in cancer immunotherapy, not only in metastatic disease but also the perioperative setting. Recent data have shown that the use of neoadjuvant therapy can provide not only critical prognostic information but can also help individualize post-resection treatment strategies and potentially even eliminate adjuvant therapy altogether in patients who achieve a pathologic, complete response. This signifies a conceptual shift in oncology with the goal of curing patients with immunotherapy. In triple-negative breast cancer, the KEYNOTE-522 regimen with pembrolizumab is standard of care. In non-small cell lung cancer, there are now four FDA approved chemo-IO regimens in both the neoadjuvant and perioperative settings. And, of course, in melanoma, starting with SWOG S1801 utilizing pembro mono therapy, and now with combined CTLA-4 PD-1 blockade based on results from the NADINA trial, neoadjuvant IO is the new standard of care in high-risk, resectable melanoma. It's important to highlight this because whereas other tumor types have more mature multidisciplinary care, for example, patients with breast cancer are reviewed by the whole team in every center, and every patient with lung cancer certainly benefits from multidisciplinary care conferences, that's not always the case with melanoma, given the relative frequency of cases compared to other tumor types.  Jason, would you say that we have now moved into an era where the integration of a multidisciplinary team and melanoma needs to be prioritized. And why is it important to have multidisciplinary team coordination from the onset of a patient's diagnosis? Dr. Jason Luke: Well, I think those are great questions, Ryan, and I think they really speak to the movement in our field and the great success that we've had integrating systemic therapy, particularly immunotherapy, into our treatment paradigms. And so, before answering your question directly, I would add even a little bit more color, which is to note that over the last few years, we've additionally seen the development of adjuvant therapy into stages of melanoma that, historically speaking, were considered low-risk, and medical oncologists might not even see the patient. To that, I'm speaking specifically about the stage 2B and 2C approvals for adjuvant anti-PD-1 with pembrolizumab or nivolumab. So this has been an emerging complication.  Classically, patients are diagnosed with melanoma by either their primary care doctor or a dermatologist. Again, classically, the next step was referral to a surgeon who had removed the primary lesion, with discussion around nodal evaluation as well. And that paradigm has really changed now, where I think integration of medical oncology input early on in the evaluation of the appropriate treatment plan for patients with melanoma is quite a pressing issue now, both because we have FDA approvals for therapeutics that can reduce risk of recurrence, and whether or not to pursue those makes a big difference to the patient for discussion early on.  And, moreover, the use of systemic therapies now, prior to surgery, of course, then, of course, requires the involvement of medical oncology. And just for an emphasis point on this, it's classically the case, for good reason, that surgeons complete their surgery and then feel confident to tell the patient, “Well, we got it all, and you're just in really good shape.” And while I understand where that's coming from, that often leaves aside the risk of recurrence. So you can have the most perfect surgery in the world and yet still be at very high risk of recurrence. And so it's commonly the case that we get patients referred to us after surgery who think they're just in totally good shape, quite surprised to find out that, in fact, they might have a 20% to 50% risk of recurrence. And so that's where this multidisciplinary integration for patient management really does make a big difference.  And so I would really emphasize the point you were making before, which is that we need multidisciplinary teams of med onc with derm, with surgery early on, to discuss “What are the treatment plans going to be for patients?” And that's true for neoadjuvant therapy, so, for palpable stage 3, where we might give checkpoint inhibitors or combinations before surgery. But it's true even in any reasonably high-risk melanoma, and I would argue in that state, anything more than stage 1 should be discussed as a group, because that communication strategy with the patient is so important from first principles, so that they have an expectation of what it's going to look like as they are followed out over time. And so we're emphasizing this point because I think it's mostly the case at most hospitals that there isn't a cutaneous oncology disease management meeting, and I think there needs to be.  It's important to point out that usually the surgeons that do this kind of surgery are actually either the GI surgeons who do colon cancer or the breast surgeons. And so, given that melanoma, it's not the most common kind of cancer, it could easily be integrated into the existing disease review groups to review these cases. And I think that's the point we really want to emphasize now. I think we're not going to belabor the data so much, but there are enormous advantages to either perioperative or adjuvant systemic therapy in melanoma. We're talking about risk reduction of more than 50%, 50-75% risk reduction. It's essential that we make sure we optimally offer that to patients. And, of course, patients will choose what they think is best for their care. But we need to message to them in a way that they can understand what the risks and benefits of those treatments are and then are well set up to understand what that treatment might look like and what their expectations would be out over time.  So I think this is a great art of medicine place to start. Instead of belaboring just the details of the trial to say, let's think about how we take care of our patients and how we communicate with them on first principles so that we can make the most out of the treatments that we do have available. Dr. Ryan Augustin: That's great, Jason. Very insightful points. Thank you.  So, shifting gears now, I'd also like to ask you a little bit about TIL therapy in melanoma. So our listeners will be aware that TIL is a promising new approach for treating advanced melanoma and leverages the power of a patient's cytotoxic T cells to attack cancer cells. While we've known about the potential of this therapy for some time, based on pioneering work at the NCI, this therapy is now FDA approved under the brand AMTAGVI (Lifileucel) from Iovance Biotherapeutics, making it the first cellular therapy to be approved for a solid tumor. Now, I know TIL therapy has been administered at your institution, Jason, for several years now, under trial status primarily for uveal melanoma using an in-house processing. But for many cancer centers, the only experience with cellular therapy has come under the domain of malignant hematology with CAR T administration. At our institution, for example, we have only recently started administering TIL therapy for melanoma, which has required a tremendous multidisciplinary effort among outpatient oncology, critical care, and an inpatient hematology service that has expertise in cytokine release syndrome.  Jason, where do you see TIL therapy fitting into the metastatic space? Which patients do you think are truly candidates for this intensive therapy? And what other practical or logistical considerations do you think we should keep in mind moving forward? Dr. Jason Luke: Well, thanks for raising this. I think the approval of lifileucel, which is the scientific name for the TIL product that's on the market now. It really is a shift, a landscape shift in oncology, and we're starting in melanoma again, as seems to be commonly the case in drug development. But it's really important to understand that this is a conceptually different kind of treatment, and therefore, it does require different considerations. Starting first with data and then actualization, maybe secondarily, when we see across the accelerated approval package that led to this being available, we quote patients that the response rate is likely in the range of 30%, maybe slightly lower than that, but a meaningful 25% to 30% response rate, and that most of those patients that do have response, it seems to be quite durable, meaning patients have been followed up to four years, and almost all the responders are still in response. And that's a really powerful thing to be able to tell a patient, particularly if the patient has already proceeded through multiple lines of prior standard therapy. So this is a very, very promising therapy.  Now, it is a complicated therapy as well. And so you highlighted that to do this, you have to have a tumor that's amenable for resection, a multidisciplinary team that has done a surgery to remove the tumor, sent it off to the company. They then need to process the TIL out of the tumor and then build them up into a personalized cell product, bring it back, you have to lympho-deplete the patient, re-introduce this TIL. So this is a process that, in the standard of care setting under best circumstances, takes roughly six weeks. So how to get that done in a timely fashion, I think, is evolving within our paradigms. But I think it is very important for people who practice in settings where this isn't already available to realize that referring patients for this should be a strong consideration. And thinking about how you could build your multidisciplinary team in a way to be able to facilitate this process, I think is going to be important, because this concept of TIL is relevant to other solid tumors as well. It's not approved yet in others, but we kind of assume eventually it probably will be. And so I think, thinking through this, how could it work, how do you refer patients is very important.  Now, coming back to the science, who should we treat with this? Well, of course, it's now an air quotes “standard of care option”, so really it ought to be available to anybody. I will note that currently, the capacity across the country to make these products is not really adequate to treat all the patients that we'd want. But who would we optimally want to treat, of course, would be people who have retained a good performance status after first line therapy, people who have tumors that are easily removable and who have not manifested a really rapid disease progression course, because then, of course, that six-week timeline probably doesn't make sense. The other really interesting data point out of the clinical trials so far is it has looked like the patients who got the least amount of benefit from anti-PD-1 immunotherapy, in other words, who progressed immediately without any kind of sustained response, those patients seem to have the best response to TILs, and that's actually sort of a great biomarker. So, this drug works the best for the population of patients where checkpoint inhibitors were not effective. And so as you think about who those patients might be in your practice, as you're listening, I think prioritizing it for primary progression on anti PD-1, again and giving it ahead thought about how would you get the patient through this process or referred to this process very quickly is really important because that lag time is a problem. Patients who have melanoma tend to progress reasonably quickly, and six weeks can be a long time in melanoma land. So, thinking ahead and building those processes is going to be important moving into the future Dr. Ryan Augustin: Definitely appreciate those practical considerations. Jason, thank you.  Moving on to our final topic, I was hoping to discuss the use of immune cell engagers in melanoma. So, similar to CAR T therapy, bispecific T-cell engagers, or BiTEs, as they're commonly known, are standard of care in refractory myeloma and lymphoma. But these antibodies engaging CD-3 on T cells and a tumor specific antigen on cancer cells are relatively new in the solid tumor space. Tarlatamab, which is a DLL-3 and CD-3 bispecific antibody, was recently approved in refractory small cell lung cancer, and, of course, tebentafusp, an HLA-directed CD-3 T cell engager was approved in uveal melanoma in 2022. Both T and NK cell engaging therapies are now offering hope in cancers where there has historically been little to offer. However, similar to our discussion with TIL therapy, bispecifics can lead to CRS and neurotoxicity, which require considerable logistical support and care coordination.  Jason, I was wondering if you could briefly discuss the current landscape of immune cell engagers in melanoma and how soon we may see these therapies enter the treatment paradigm for cutaneous disease. Dr. Jason Luke: I think it is an exciting, novel treatment strategy that I think we will only see emerge more and more. You alluded to the approval of tebentafusp in uveal melanoma, and those trials were, over the course of a decade, where those of us in solid tumor land learned how to manage cytokine release syndrome or the impact of these C3 bispecifics, in a way that we weren't used to. And what I'll caution people is that CRS, as this term, it sounds very scary because people have heard of patients that, of course, had difficult outcomes and hematological malignancies, but it's a spectrum of side effects. And so, when we think about tebentafusp, which is the approved molecule, really what we see is a lot of rash because GP100, the other tumor antigen target, is in the skin. So, patients get a rash, and then people do get fevers, but it's pretty rare to get more than that. So really what you have to have is the capacity to monitor patients for 12 hours, but it's really not more scary than that. So it really just requires treating a few people to kind of get used to these kinds of symptoms, because they're not the full-on ICU level CRS that we see with, say, CAR T-cells.  But where is the field going? Well, there's a second CD3 bispecific called brenetafusp that targets the molecule PRAME, that's in a phase 3 clinical trial now for frontline cutaneous melanoma. And tebentafusp is also being evaluated in cutaneous melanoma for refractory disease. So, it's very possible that these could be very commonly used for cutaneous melanoma, moving into, say, a two-to-four-year time horizon. And so therefore, getting used to what are these side effects, how do you manage them in an ambulatory practice for solid tumor, etc., is going to be something everyone's going to have to learn how to deal with, but I don't think it should be something that people should be afraid of.  One thing that we've seen with these molecules so far is that their kinetics of treatment effect do look slightly different than what we see with more classic oncology therapies. These drugs have a long-term benefit but doesn't always manifest as disease regression. So, we commonly see patients will have stable disease, meaning their tumor stops growing, but we don't see that it shrank a lot, but that can turn into a very meaningful long-term benefit. So that's something that we're also, as a community, going to have to get used to. It may not be the case we see tumors shrink dramatically upfront, but rather we can actually follow people with good quality- of-life over a longer period of time.  Where is the field going? You mentioned tarlatamab in small cell lung cancer, and I think we're only going to see more of these as appropriate tumor antigens are identified in different tumors. And then the other piece is these CD3 engagers generally rely upon some kind of engagement with a T cell, whether CD3 engagers, and so they can be TCR or T-cell receptor-based therapies, although they can be also SCFV-based. But that then requires new biomarkers, because TCR therapy requires HLA restriction. So, understanding that now we're going to need to profile patients based on their germline in addition to the genomics of the tumor. And those two things are separate. But I would argue at this point, basically everybody with cutaneous melanoma should be being profiled for HLA-A(*)0201, which is the major T-cell receptor HLA haplotype that we would be looking for, because whether or not you can get access immediately to tebentafusp, but therefore clinical trials will become more and more important.  Finally, in that T-cell receptor vein, there are also T cell receptor-transduced T cells, which are also becoming of relevance in the oncology community and people listening will be aware in synovial sarcoma of the first approval for a TCR-transduced T cell with afamitresgene autoleucel. And in melanoma, we similarly have TCR-transduced T cells that are coming forward in clinical trials into phase 3, the IMA203 PRAME-directed molecule particularly. And leveraging our prior conversation about TILs, we're going to have more and more cellular based therapies coming forward, which is going to make it important to understand what are the biomarkers that go with those, what are the side effect profiles of these, and how do you build your practice in a way that you can optimally get your patients access to all of these different treatments, because it will become more logistically complicated, kind of as more of these therapies come online over the next, like we said, two to four years kind of time horizon. So, it's very exciting, but there is more to do, both logistically and scientifically. Dr. Ryan Augustin: That's excellent. Thanks, Jason, and thank you so much for sharing your great insight with us today on the ASCO Daily News Podcast. Dr. Jason Luke: Thanks so much for the opportunity. Dr. Ryan Augustin: And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode, and you can follow Dr. Luke on X, formerly known as Twitter, @jasonlukemd. And you can find me, @RyanAugustinMD. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers: @ryanaugustinmd Dr. Jason Luke @jasonlukemd   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures: Dr. Ryan Augustin: No relationships to disclose Dr. Jason Luke: Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

Dr. Dionisia Quiroga discusses emerging approaches to personalizing locoregional treatment for breast cancer with Drs. Walter Paul Weber and Charlote Coles, who share insights on tailoring axillary surgery, escalating lymphatic surgery, and implementing hypofractionated radiotherapy. TRANSCRIPT Dr. Dionisia Quiroga: Hello, I'm Dr. Dionisia Quiroga, your guest host of the ASCO Daily News Podcast today. I'm a breast medical oncologist and assistant professor in the Division of Medical Oncology at the Ohio State University Comprehensive Cancer Center. On today's episode, we'll be discussing emerging approaches to personalize locoregional treatment for patients with breast cancer, including many of the latest updates on axillary surgical staging, lymphatic surgery, and evidence-based radiotherapy in the treatment of breast cancer. We're very fortunate to have joining me today for this discussion Dr. Walter Paul Weber, a professor and head at the Division of Breast Surgery at the University Hospital Basel in Switzerland, and Dr. Charlotte Coles, a professor of cancer clinical oncology and the deputy head of the Department of Oncology at the University of Cambridge in the United Kingdom. Our full disclosures are available in the transcript of this episode. Dr. Weber and Dr. Coles, it's very wonderful to have you on the podcast and thank you so much for being here. Dr. Walter Paul Weber: Thank you very much for having us. Dr. Charlotte Coles: Thank you. Dr. Dionisia Quiroga: Now, for many decades prior, axillary lymph node dissection has very much been our standard of care. But recently, axillary surgeries have been able to be gradually deescalated to spare some of our patients from relative and relevant long-term morbidity. There are still some indications in which axillary lymph node dissection still remain. And therefore, we still see breast cancer-related lymphedema, a well-known sequela of the axillary surgery to continue to be prevalent. And I think it's important also to acknowledge that today there's about an estimated 1.5 million cancer survivors who deal with breast cancer-related lymphedema. Now, Dr. Weber, at the recent ASCO Annual Meeting, you and your co-presenters discussed tailoring axillary surgery, escalating lymphatic surgery and implementing evidence-based hypofractionated radiotherapy to really personalize locoregional treatment for people who've been diagnosed with breast cancer. And in addition to that, you and Dr. Coles have also published this work in the 2024 ASCO Educational Book. Can you tell us about some of the recent advances in axillary surgery and what are really the current indications for axillary dissection? Dr. Walter Paul Weber: Yes, I'm happy to do so. So as you've said, we've known for a while that we can omit axillary dissection in patients with clinically known negative breast cancer and negative sentinel nodes. We've known for about 10-15 years that we can omit axillary dissection in patients with one or two positive sentinel nodes in many patients. But what we've learned recently is that we can omit axillary dissection also in patients with one or two positive sentinel nodes who have larger primary tumors who undergo mastectomy or who have extranodal extension. This is a landmark trial that was published just a few months ago, the SENOMAC trial that established this. The remaining indications for axillary dissection are situations where you expect a heavy tumor load in the axilla. For example, when you have more than two positive sentinel nodes or you have a patient with clinically node-positive breast cancer who undergoes upfront surgery and has palpable disease or significant disease on imaging. Patients with locally advanced breast cancer, who are considered by some to be not eligible for nodal downstaging, such as patients with CN2, CN3 disease or CT4 breast cancer. And then the big group of patients who have residual disease after neoadjuvant chemotherapy in the nodes, standard of care is still axillary dissection. But we now have some real-world evidence that it's safe for selected patients with low volume nodal disease left in the nodes, mostly isolated tumor cells, to not undergo axillary dissection. So these are the remaining indications today. Dr. Dionisia Quiroga: Can you speak to situations where maybe even sentinel lymph node biopsies might be omitted? I know you spoke a little bit about the use of imaging in your work. Dr. Walter Paul Weber: Yes, this is correct. So, we started about maybe 7 or 8 years ago to omit sentinel lymph node biopsy in older patients above 70 years of age who have luminal disease, according to recommendations from the Choosing Wisely initiative. And now indeed there are several ongoing randomized trials that investigate if axillary imaging can replace surgical staging of the axilla. And the first of these trials was published recently, the SOUND trial with almost 1,500 patients, who underwent breast conserving surgery and had small tumors and all had a negative ultrasound of the axilla. And then they were randomized into a sentinel lymph node biopsy versus no axillary surgery. And that trial showed non-inferiority of the omission of sentinel lymph node biopsy in these patients. Now, it's a bit early to roll out the Choosing Wisely recommendation to all patients who have a negative ultrasound. The SOUND trial showed that about 14% had a false-negative ultrasound. So, in the control arm, they actually did have a positive sentinel node. And in patients where that one missed sentinel node makes a big difference in terms of systemic therapy, most experts would still recommend sentinel biopsy, and these are patients mainly with HER2-positive or triple-negative breast cancer or premenopausal patients or those who have G3 biology. Dr. Dionisia Quiroga: I think you bring up a very important point. Coming from the side of a breast medical oncologist, we're also very interested to see what these studies show because many of our practices are based on what we find out from our lymph node biopsies. So, I think a lot of interesting prospective studies to look at in the future. Dr. Walter Paul Weber: Absolutely. Dr. Dionisia Quiroga: One other topic we wanted to discuss was local regional management of stage four disease and particularly oligometastatic disease. And this is not a new topic of interest. We've been speaking about this for a long time in breast cancer management, but can you address some of the axillary management strategies that you currently use for stage 4 disease? Dr. Walter Paul Weber: Yes, it depends on your intention. If your intention is to cure the patient, then you would apply all the locoregional standards that apply in the curative setting, which means lymph node biopsy with or without axillary dissection. Now in a palliative situation, it's individualized. Very often you don't touch the axilla and sometimes you open it and just remove palpable disease, trying to minimize morbidity. The question of which intent you should follow is controversial; three out of the four randomized trials did not show a benefit for locoregional surgery in patients with de novo stage 4 disease. However, experts seem to disagree. The last St. Gallen consensus recommendation was in favor of the curative intent in such a patient with oligometastatic disease; 85% favored the curative intent. So there's a bit of discrepancy there, but everybody would agree, and this is what has been done in all of these trials, that if you try to cure the patient, then you should apply the curative standards of sentinel and axillary dissection that you use also in early-stage breast cancer. Dr. Dionisia Quiroga: Thank you. Now, moving on from surgical axillary management and more into lymphedema prevention and treatment. Can you speak to some of the promising advances that have happened in this field? Dr. Walter Paul Weber: Yes, so the best way to prevent lymphedema still is not to perform axillary dissection, which is the number 1 risk factor, which is all the axillary surgery de-escalation research that we've just discussed is all about. Prevention of lymphedema is one major aim of this. Now, once you indicate axillary dissection and you expect the patient to be at high risk – for example, if there are other risk factors such as obesity or neoadjuvant chemotherapy or extended regional nodal radiotherapy, then indeed there are emerging techniques that really seem to work. There is some evidence supporting it, which is categorizable as immediate lymphatic repair basically or bypass. And that is usually in a patient who undergoes axillary dissection, and also undergoes axillary reverse mapping. That allows the identification of the lymph nodes that are probably most relevant to the drainage of the lymphatic fluid from the arm. And then you can try to spare these. But if you decide, and this is effective, there is a consistent body of evidence, not phase 3 trials, but pretty consistent evidence that axillary reverse mapping works just by sparing the identified nodes. But if you decide that you have to remove these nodes as part of the radical concept of axillary dissection, then immediate lymphatic repair is also increasingly being done and is also supported by consistent evidence, even some single center randomized trials, low volume, but all consistently showing quite a striking benefit of this immediate lymphatic repair technique. There are different ways you can do it. You can either use it the microscope, and it's being done by the plastic surgeons, but it's also a simplified technique described that can be used by specialized general and breast surgeons. Both techniques seem to really work based on what we know from the studies, but also based on our common sense. Dr. Dionisia Quiroga: You talked about the procedures that can be offered to patients at time of breast surgery. And unfortunately, many of our patients maybe did not have the availability of those techniques when they undergo their initial breast cancer treatment. Once lymphedema is developed in a limb following breast cancer diagnosis, can you speak to other interventions that can be done to potentially help mitigate lymphedema? Dr. Walter Paul Weber: Right, so for patients who no longer benefit from or wish to further undergo conservative treatment of lymphedema, there are emerging procedures that are now out of my personal comfort zone because they're being performed by plastic surgeons; they use the microscope. There are two groups, the lymphovenous anastomosis and then the real vascular lymph node transfer as a free flap. And both of these procedures (there are no randomized trials yet published), but some really good ones are on the way and currently recruiting based on the evidence we have, which is over 20 observational studies all consistently again showing a benefit in terms of what you can measure in terms of centimeters or with a bioimpedance spectroscopy, or also when you ask the patients, you see quite some dramatic improvements by both of these techniques. And it's increasingly being done. Personally, I strongly believe that it works based on everything we know and understand from lymphedema development, but also prevention and treatment. So I am quite sure that in 5-10 years, we will see much more surgical treatment of patients with lymphedema by highly specialized plastic surgeons. Dr. Dionisia Quiroga: That's my hope as well. Now, another important component of local regional treatment we know is of course radiotherapy. And there have been many incredible advances in breast radiotherapy over the past decades, which has really improved cancer control and decreased side effects in our patients. Dr. Coles, you've led practice changing radiotherapy trials in the past and your research has really influenced international hypofractionation policy. Can you expand upon the emergence of hypofractionated radiation for breast cancer and the effects that it can have on our patient care? Dr. Charlotte Coles: Yes, so thank you very much, Dr. Quiroga. So I think the first thing to say is that radiotherapy hypofractionation isn't a new concept. And in fact, the breast radiotherapy hypofractionation trial started around three decades ago. And the rationale for this was the hypothesis that breast cancer is as sensitive to fraction, which is the treatments that we give, we split it into fractions, is sensitive as late responding tissue. So what does this mean? It means that the small traditional 2 Gy fraction spare tumor and normal tissues equally, so there's no advantage. So therefore, fewer fractions with a larger dose per fraction are worth testing. The problem is there's a concern that hypofractionation might increase the risk of side effects, and that includes the really important one we've been talking about, lymphedema. But we can reduce this risk by reducing the total radiotherapy dose over the whole course. But the question was by how much. So that's why randomized trials were needed. And there's been really high-quality trials with robust radiotherapy quality assurance, and they've been designed in partnership with patients. So just a very quick run through: A landmark trial was the UK START B trial. And this was a pragmatic design that compared 50 Gy in 25 fractions, which was commonly used in the south of the country with 40 Gy in 15 fractions, which was used at that time in the north [of the UK]. And this recruitment was around in the late 1990s and early 2000s. What we knew was that the three-week regimen was actually radiobiologically lower dose. And therefore the results that we got, it wasn't surprising that the 40 Gy was actually gentler on the normal tissue. So that's an advantage for patients. But what was surprising was it wasn't gentler on the tumor and non-inferiority was proven. So this suggests that overall treatment time is important for local control. So this fits with hypofractionation. Way back in 2009, 40 Gy in 15 fractions to both the breast and regional nodes became standard of care in the UK. But five-week nodal and actually breast as well remained standard of care in many countries for many years after that, a little bit to do with the fact that there were few patients treated in the START trial in terms of treating the node. So more recently we've had more randomized trials, particularly for nodal radiotherapy. And this includes the recently reported Danish SKAGEN 1 trial and also the French HypoG-01 trial, which was actually presented at ESMO in Barcelona a couple of weeks ago. So we've now got data for over 5,800 participants in really high-quality randomized trials testing three weeks and five weeks of nodal radiotherapy. And there's no statistically significant difference in late normal tissues for any of these, including lymphedema. So certainly, in my opinion and reflecting in many of the European guidelines, five-week radiotherapy is no longer indicated and three-week nodal radiotherapy is the international standard of care. So, in conclusion, the question is can we hypofractionate even further? So the UK FAST-Forward trial tested three weeks with two different dose levels of one week for the whole breast. Primary endpoint was ipsilateral breast tumor response. More than 4,000 patients participated and this was reported in 2020 with a median follow -up of six years and this was very timely because this is a time of COVID and the results showed non-inferiority for local control with similar late normal tissue side effects and we've also had other results from the UK IMPORT HIGH trial which shows that we can safely deliver a small, highly targeted team of boost simultaneously with the whole breast in all in three weeks. Finally, these two landmark trials have come together for the design of the UK FAST-Forward Boost Study led by my colleague Dr. Anna Kirby. And this is going to test three-week simultaneous integrated boost with two levels of one-week simultaneous integrated boost. And it's also going to test the safety of 5 fraction nodal radiotherapy, including the internal mammary node. Primary endpoint is ipsilateral breast tumor response, multiple normal tissue endpoints, including patient-reported outcomes of course, and the target recall is large with 4,800 participants. So, in summary, I would say that hypofractionation is efficacious, has similarly reduced toxicity. Importantly, it reduces patient burden and that's incredibly important because it means that people can get back on with their life quicker. It reduces health system costs, and also increases equity of access. So we really do need to continue to recruit and design high quality trials in this area. Dr. Dionisia Quiroga: Thank you, Dr. Coles. I think you highlight that there really aren't any downsides to looking into hypofractionated radiotherapy at this point. So excited to see what those future trials yield. And I want to thank you so much, Dr. Weber and Dr. Coles for sharing your valuable insights with us today on the ASCO Daily News Podcast. Dr. Walter Paul Weber: Thank you very much. Dr. Charlotte Coles: Thank you. Dr. Dionisia Quiroga: And thank you to our listeners for joining us today. Our listeners will find a link to our guests' article from the ASCO Educational Book in the transcript of this episode, as well as a link to their presentation from the most recent ASCO Annual Meeting. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today's speakers:   Dr. Dionisia Quiroga @quirogad Dr. Walter Paul Weber Dr. Charlotte Coles Follow ASCO on social media:     @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn    Disclosures: Dr. Dionisia Quiroga: No relationships to disclose Dr. Walter Weber: Honoraria: MSD Dr. Charlotte Coles: No relationships to disclose

JCO PO author Dr. Amar U. Kishan, Professor, Executive Vice Chair, and Chief of Genitourinary Oncology Service in the Department of Radiation Oncology at the University of California, Los Angeles, shares insights into his JCO PO article, “Transcriptomic Profiling of Primary Prostate Cancers and Nonlocalized Disease on Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography: A Multicenter Retrospective Study.”  Host Dr. Rafeh Naqash and Dr. Kishan discuss the relationship between Decipher genomic classifier scores and prostate-specific membrane antigen (PSMA) PET/CT-based metastatic spread. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO articles. I'm your host, Dr. Rafeh Naqash, Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today we are joined by Dr. Amar Kishan, Executive Vice Chair of the Department of Radiation Oncology at the David Geffen School of Medicine at UCLA and UCLA Jonsson Comprehensive Cancer Center, and also the corresponding and senior author of the JCO Precision Oncology article entitled, “Transcriptomic Profiling of Primary Prostate Cancers and Non Localized Disease on Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography/Computed Tomography: A Multicenter Retrospective Study.” Dr. Kishan, welcome to our podcast and thank you for joining us today. Dr. Amar Kishan: Thank you so much for that kind introduction and the invitation to be here today. Dr. Rafeh Naqash: Well, it seems to me that there's a theme that people in the GU space, investigators in the GU space, are very interested in trying to understand risk predictors for prostate cancer. We had somebody, I believe from Huntsman Cancer Center a few months back on a previous podcast, where they were trying to do risk prediction modeling as well. Could you tell us why that's something that the GU community is very interested in? What's the background? Is it because there's no risk prediction approaches currently? And would this somehow influence management in the near future? Dr. Amar Kishan: Yeah, that's a great question. So, I think this goes back to the point that we're in the era of precision medicine now, and many cancers have these molecular stratification scores and all that. Prostate cancer has lagged a little bit behind in that regard, despite the fact that it's such a common cancer that affects so many people across the country and across the world. So, we do have risk stratification schemes for prostate cancer. These are based off clinical and pathologic variables, like the level of PSA, the size of the tumor on digital rectal examination, now, we're incorporating MRI imaging as well, and then what the cancer looks like under the microscope, the Gleason score. And now there have been revisions to the Gleason score, but it's really kind of the architecture, what the biopsy looks like. And this was kind of developed many, many years ago by Donald Gleason, a pathologist at the VA. What we're not necessarily taking into account routinely is kind of the biology of the cancer per se. You know, what are the molecular drivers? How could that influence ultimate outcome? And that's very important because we have these risk groups, low risk, very low risk, favorable intermediate risk, unfavorable intermediate risk, high risk, very high risk. But within each of those groups, based on the clinical kind of pathological characteristics, there's a huge heterogeneity in outpatients too, and our treatments are effective, but they can be morbid. Putting someone on hormone therapy for an extended period of time has a lot of side effects. Dose escalating radiotherapy or doing surgery and then radiation afterwards, these are big things that have a big impact on the patient, and I think we really need better risk stratification tools to understand who needs intensification and who we can de-escalate treatment for. Dr. Rafeh Naqash: I think those are absolutely valid points, perhaps not just for prostate cancer, more so for all cancers that we currently treat, especially in the current day and age, where we have a tendency to add more and more therapies, combination therapies for patients, and as you mentioned, risk stratification to help identify high risk versus low risk, where you can de intensify treatment, is of high value from a patient standpoint as well as from a financial toxicity standpoint. So then, going to this next part of the approach that you used, and from what I understand in this paper, you had the radiological aspect, which is the PSMA PET, which we'll talk about. Then you had the genomic aspect, where you did some genomic risk-based stratification. Then you had the transcriptomic score based on the Decipher score. So, could you go into some of the details, first, for the PSMA PET, when is it used? What is the utilization? What is it based on, the science behind the PSMA PET? And then we can talk about some of the other genomic transcriptomic predictors that you use in this study. Dr. Amar Kishan: Sure. Absolutely. So, a PSMA PET is an advanced molecular imaging tool. PSMA stands for prostate specific membrane antigen. It's a membrane protein that is expressed on the surface of prostate cancer cells. It is expressed elsewhere in the body as well. The utilization of this for imaging has been a revolution in the staging of prostate cancer, both upfront and in the recurrent setting. We basically had fairly recent approval for PSMA PET being used more routinely in upfront staging and recurrent staging in 2022. Essentially, what this is it gives us an ability to detect whether prostate cancer has spread at a time of diagnosis or try to localize the recurrence. Now, no imaging test is perfect, of course, and a PET has a resolution of about 3 mm. There are questions about the sensitivity of the PET. You get it on a patient with high-risk disease, the PET is negative; you do surgery, there are positive lymph nodes. That can happen, but it's far superior to the tools that we have had before. For instance, beforehand, all we would have is a contrast enhanced CT, bone scan, and MRI. And the sensitivity of those is far below that of a PSMA PET. And that has actually been shown in a randomized trial called the ProPSMA trial out of Australia, where they compared conventional upfront imaging versus PSMA upfront imaging with a crossover design, and there was better detection of disease with the PSMA PET. So that's been a revolution in how we stage prostate cancer. But I'm sure many of your listeners and others are aware of the concerns. When you get a new test and you're detecting disease that's extra prostatic, for instance, are you seeing truly significant new disease that we do need to change our management for, or are we just seeing stuff that wasn't there before that actually wouldn't impact anything? And what I mean by that is, let's say you're seeing things that would never have made a difference to the patient, but now you're saying they have metastatic disease. You're changing their entire treatment paradigm, all kinds of things like that. There's implications to this that hasn't been fully fleshed out. But very recently, like we're talking in July of 2024, essentially, there was a Lancet Oncology paper that looked at the long-term prognosis of patients who had extra prostatic disease on PSMA PET, judged by something called a PROMISE score, kind of gives a quantification on the volume of disease, the brightness of disease, and they correlated that with long term outcomes. And that was really the first time that we have long term follow up data that this extra prostatic disease on PSMA PET actually is prognostically important. So, we're getting there. I mean, now that it's approved and, in some sense, the cat is out of the bag, patients are coming in asking for a PSMA PET, etc. I'm sure everyone has experienced that, but I think we now do have good evidence that it actually is prognostically important as well. Dr. Rafeh Naqash: Thank you for that explanation. And again, to put this into context for things that I've seen and that might also help the listeners in other tumors, so, for example, melanoma surveillance tends to be or while on treatment, patients tend to have more PET scans than what you see, maybe in individuals with lung cancer, where you get a baseline PET and then you have follow up CT scan based imaging is that something that you guys have shifted from in the prostate cancer space with the approval for PSMA PET, where follow up imaging, whether patient is on treatment or surveillance imaging, is PSMA PET based? Dr. Amar Kishan: Yeah, that's a good question. I think there's actually less robust data to support it as a means of treatment response. But in terms of evaluating a recurrence, then, yes, that has become kind of a standard tool. It's very complicated because all of the metrics that we have for, say, a treatment failing are based on conventionally detected metastases or something that shows up on a CT or bone scan. So, again, that question arises if someone is on systemic therapy and then you see something on a PSMA PET, are you going to abandon the therapy that you're on? It technically would be earlier than you would otherwise have done that, or what are you going to do? So, that hasn't been fully fleshed out, but it is used in that circumstance. So, I'd say less for treatment monitoring and more for evaluation of suspected recurrence. Dr. Rafeh Naqash: Understood. And I'm guessing, as a futuristic approach, somebody out there may perhaps do a trial using PSMA PET based imaging to decide whether treatment change needs to be made or does not need to be made. Dr. Amar Kishan: Yeah. It is being incorporated into trials as we speak, I think. Dr. Rafeh Naqash: Now, going to the second part of this paper is the Decipher score. Could you explain what the score is, what its components are, how it's calculated? Is it DNA, is it RNA, is it both combined? Is it tissue based; is it blood based? Dr. Amar Kishan: Yeah. So, the Decipher is also an approved test now, was approved in 2018. What it is, essentially, and how it's derived is based on the idea originally that patients might have a recurrence after surgery for prostate cancer. And it's just a PSA recurrence. It's this way. It's literally what we call a biochemical recurrence. That patient might not have any problems, whereas other patients with a recurrence might go on to develop metastatic disease. And we didn't have a good way of determining which patient is which. Get back to that prognostic problem that we have. So, some investigators, they looked at men that had radical prostatectomy from 1987 to 2001 at the Mayo Clinic that had archived tissue. They looked at FFPE, or basically paraffin embedded tissue. They extracted the RNA and then did a microarray analysis and looked at transcriptomic signatures and wanted to see, could this discern the patients who had mets, who had clinically significant recurrences from those that didn't? And out of that exercise came the Decipher Genomic Classifier, which basically is based on 22 genes. These are involved with cell proliferation, etc., but it's an RNA-based, tissue-based assay. So, if you wanted to order a Decipher on somebody, you would need to use a biopsy or prostatectomy specimen to do so. Essentially, that the samples, they would take the highest grade, highest Gleason grade specimen, send it to their lab. Their main lab is in California. The company is called Veracyte. And then they will do this RNA express analysis with a microarray and then return a score. The score is 0 to 1. Basically, 0 is the lowest, one is the highest, and it is a way of prognosticating the risk of metastasis. Originally, when you get a Decipher report, it actually will tell you the 5 and 10-year risks of distant metastasis, and we'll quantify that. Dr. Rafeh Naqash: And you said this is approved or has been approved in 2018. So, is this insurance reimbursable at this point? Dr. Amar Kishan: Most insurances do, not all, and the criteria for getting it can vary, so we can talk about it, but it was initially developed in this post-op setting. On the basis of a significant amount of validation studies, it has been moved to being used in the upfront setting as well. So, if you look at some of the ongoing NRG trials, for instance, they are stratifying patients based off the upfront Decipher score. And this is based off of validation studies that have been conducted looking at past RTOG trials and other trials. That said, sometimes it is not approved by commercial insurances in the upfront setting, because that wasn't where it was initially validated and derived. But honestly, here in 2024, that's very uncommon. It's much more common that it's approved. Dr. Rafeh Naqash: Understood. And in your practice, or the medical oncologist practice at your institution or other institutions, is this something that is commonly used for some sort of treatment decision making that you've seen? Dr. Amar Kishan: Yeah. So, as a radiation oncologist, I do think it's a useful test, because my approach is, if we're talking about adding hormone therapy, for instance, which is oftentimes dominating the conversation, we know that it offers a relative benefit to a lot of patients. We've published on this; others have published on it. Let's say it reduces the chance of metastasis by about 40%. 10-year risk of metastasis has a ratio of 0.6. So, 40% reduction. But if your risk of metastasis is 2%, that benefit is not that much in absolute terms. And we don't historically have a great way of saying, what is your absolute risk of metastasis? And I think Decipher is one tool that does tell us that - it literally gives it on the report. Now, is that a holy grail? Is it 100% accurate? Nothing is 100% accurate. But it does give us some quantification. Then I can go back to the patient and say, yes, you will get a benefit from adding hormone therapy, but you're talking about going from 2% to 1%, and so they can decide if that's worth it to them. Conversely, it could be a situation where they really don't want hormone therapy, but it comes back that their risk of metastasis is 20%, and then there's actually a big absolute benefit. So that's how I use it as a radiation oncologist, and we would use it upfront. Now surgeons, and if I was consulting on a post operative patient, maybe it plays more of a role. And do we need to do post operative radiotherapy on this patient, or do we need to add hormone therapy in the postoperative situation? From the medical oncology perspective, there are emerging data that may be useful in the choice of systemic therapy for metastatic disease, but that is a little bit earlier in the investigational stage, I would say. So, when I'm working with medical oncologists, it's often still in this localized setting, and typically, do we add hormone therapy or not, and that type of thing. Dr. Rafeh Naqash: Understood. And from a reporting standpoint, so the Decipher score, I'm guessing it's some sort of a report that comes back to the ordering physician and you basically see the score, it gives you a potential recurrence free survival percentage or a metastasis percentage of what is your risk for having metastasis in the next five years - is that how they generally do it? Because I've personally never seen one, so I'm just curious. Dr. Amar Kishan: Yeah, essentially, it comes back with a score, a numerical score, again, from 0 to 1, and it will basically give you the five-year risk of distant metastasis. The ten-year risk of distant metastasis. You can request an extended report that provides additional, not as well supported signatures that are out there, like ADT response signature, etc. But those maybe may have been published, but are not clinically validated as much, but the actual Decipher report, which goes to patients too, just has this kind of 5,10-year risk of distant metastasis. They have some estimations on prostate cancer specific mortality as well. Dr. Rafeh Naqash: Sure. Now, the third part of this project, and correct me if I'm wrong, the grid database of the 265 genomic signature score. From what I understood, this is a different component than the Decipher score. Is that a fair statement? Dr. Amar Kishan: Yeah. No, that's exactly correct. And that was an exploratory part of this analysis, to be honest. Basically, I think our main focus in the paper was those advances that we've talked about PSMA and Decipher, those happened concurrently. People started developing PSMA PET, people started developing Decipher. And so, what we wanted to understand was, if you have a patient that has extra prosthetic disease on PSMA PET, are those biologically more aggressive cancers, is their Decipher score going to be higher? What can we learn about the biology of this? And we were the first, to my knowledge, where we actually had a large data set of patients that actually received PSMA PETs and Decipher. And that's kind of the gist of the paper. We have patients in the upfront setting, patients in the post radical prostatectomy setting, and we're essentially showing that there is this correlation. In the upfront setting, the odds of extra prosthetic disease are higher for higher Decipher scores, which is kind of maybe validating that this biology is capturing something that's akin to this ability to spread. And in the post-op setting, because we have time to failure, technically, we can calculate a hazard ratio rather than odds ratio. So, we have a hazard ratio that's significantly associated with an increased risk of spread for patients with higher Decipher. The grid portion, which is the genomic resource information database, was more of an exploratory part where I mentioned the Decipher score is based off this microarray, they're looking at 1.4 million transcripts. Only 22 are part of the Decipher, but you can request the rest of the signature data as well. And so, we wanted to look at other pathways, other signatures that have been published, like looking at DNA repair, neuroendocrine pathway, just to see if we could see any correlations there that's not necessarily as clinically actionable. These are more exploratory. But again, we were trying to just look at whether patients who had non localized disease on their PSMA PET, whether their primary had more aggressive biology. We did see that. So that's kind of loosely speaking things like PTEN loss, androgen receptor, DNA repair, metabolism, neuroendocrine signaling, which are thought to be portenders of aggressive disease. Those pathways were upregulated at the RNA level in patients who had non-localized disease. And that's kind of the take home from that. But I wouldn't say any of that is clinically actionable at this point. It's more kind of defining biology. Dr. Rafeh Naqash: Some of the interesting correlations that you make here, at least in the figures that we see, you're looking at different local occurrences, nodal metastases, M1A and M1B disease. And one thing that I'm a little curious about is the Decipher score seems to be lower in pelvic nodal metastasis, that is, PSMA PET positive versus local recurrence, which has a slightly higher Decipher score. Is that just because of a sample size difference, or is there a biologically different explanation for that? Dr. Amar Kishan: Yeah, that's a good point. I would assume that's probably because of a sample size in this case, and it's a little bit complicated. It wasn't statistically different. And it was 0.76 on average for patients with local recurrence and 0.7 for patients with a pelvic nodal metastasis. Well, what I think is interesting is we can maybe think that in this post-op setting the time to failure could have been long in some of these cases. So, it is conceivable that an isolated nodal recurrence 10 years after the surgery, for instance, is not as aggressive a cancer as a local recurrence in a short time after the surgery. And that's not taken into account when you're just looking at median scores like we are in this fox and whiskers plot. But overall, I think what it's suggesting is that there are patients who have more indolent disease. That's actually pretty widespread there. There are pretty indolent cases that have these nodal metastases. So just because you have a nodal metastasis doesn't mean it's an incredibly aggressive cancer, biologically. Dr. Rafeh Naqash: Now, the exploratory component, as you mentioned, is the grid part where you do look at TP53, which is a cell cycle gene, and higher TP53 associated with worse recurrences, from what I understand. Do you see that just from a cell cycle standpoint? Because from what I, again, see in the paper, there's a couple of other cell cycle related signatures that you're using. Is that just a surrogate for potential Gleason score? Have you guys done any correlations where higher Gleason score is associated with maybe higher cell cycle checkpoint, pathway related alterations and replication stress and DNA damage and perhaps more aggressive cancers? Dr. Amar Kishan: Yeah, that's a great question. We haven't done that in this paper, but it has been published before that there is this correlation loosely between grade and some of these parameters - so repair, metabolism, androgen receptor signaling. However, it's a very great point that you bring up, which is that it's pretty heterogeneous and that's why we need something like this as opposed to Gleason score. So, you can have Gleason 10 cancer. I mean, that would be pretty uncommon. But within the Gleason 9, at least, which we have published on and looked at, there's a heterogeneity. There are some that are biologically not that aggressive. And the converse Gleason 7, you can have some that are actually biologically aggressive. That's why it may be useful to move away from just the pathological architecture and get a little bit more into some of these pathways. Dr. Rafeh Naqash: What's the next step here? I know this perhaps isn't ready for primetime. How would you try to emphasize the message in a way that makes it interesting and clinically applicable for your colleagues in the GU community? Dr. Amar Kishan: Yeah. I think for me, what I would try to emphasize here and what I think is the main takeaway is this is kind of a validation that having extra prostatic disease on PSMA PET is likely suggestive of a more aggressive disease biology. And I think what this stresses to me is the importance of getting a PSMA PET, particularly in patients with high-risk prostate cancer. This isn't always happening. And I think if we see things on a PSMA PET, we really need to consider systemic therapy intensification. And what do I mean by that as a practical point? You have a high-risk prostate cancer patient. You get a PSMA PET, you see an isolated pelvic lymph node. If we believe the results of the study, that's a more aggressive biology likely. Whether we have the Decipher or whether we have genomic signatures, which we may or may not have, maybe that patient should get treated with something like an androgen receptor signaling inhibitor in addition to ADT, more akin to a clinically node positive case. So, intensify the systemic therapy, more aggressive disease. That's how I would incorporate it practically into my practice, that really what we're seeing on the PSMA PET is real. It's a reflection of biology that's aggressive. It's not just some Will Rogers effect where you're upstaging stuff needlessly. I think this is telling us some true biology. So that's kind of what my takeaway would be. I think future areas of investigation would be, honestly, to try to have a better idea of what's going on in these metastases. So, if you could design a study potentially, where your biopsy some of these and actually do sequencing and understand a little bit more of that. And so, we're looking into stuff like that. But my takeaway for like the everyday clinician would be to try to get a PSMA PET, if you can, and to intensify therapy on the basis of that, or at least consider it, discuss it in a multidisciplinary setting. Dr. Rafeh Naqash: And I'm guessing somebody out there, perhaps even you, are thinking or planning on doing a ctDNA MRD based correlation here, since that's up and coming in this space. Dr. Amar Kishan: That is up and coming, I think one of the challenges in prostate cancer is the amount of ctDNA can be low. But yes, you're right, that's certainly things that a lot of us are looking at, too. Dr. Rafeh Naqash: Excellent. Well, thank you for the science discussion, Dr. Kishan, could you tell us a little bit about yourself, your career trajectory, where you started, what you're doing, and perhaps some advice for early career junior investigators, trainees, things that might have worked for you, that could also work for them as they are progressing in their careers. Dr. Amar Kishan: Sure. So, yeah, I'm a radiation oncologist at UCLA. I run the prostate cancer radiation program. Clinically. I'm also heavily involved in our research enterprise, so I kind of oversee the clinical and translational research aspect. That's what I do currently. So, I did my residency in radiation oncology at UCLA. Just on a personal note, my wife is from LA, her parents live in LA. We really wanted to stay in LA, so I was fortunate to be able to join the faculty here. I always liked GU oncology, so that was kind of a natural thing for me to kind of go into this position here and try to build the GU program. I've been very fortunate to have great collaborators. My message to students and trainees is to try to reach outside your department for mentorship as well. It's important to have people inside your department who can mentor you. But as a radiation oncologist, I work so closely with urology, so closely with medical oncology that I'm very fortunate to have individuals in those departments who have a vested interest in me and my success as well. I like working with them. It's important to be a team player. If they need help, you help them. If you need help, you ask for help from them. So, I think that's the single biggest thing that I would say to any trainee is don't be intimidated. Please reach outside of your department. Lots of people are willing to help and provide mentorship, and it's helpful to have that perspective. We are in a very multidisciplinary environment and era of practicing medicine. Dr. Rafeh Naqash: Well, thank you again for those personal insights and especially for submitting your work to JCO PO. And we hope to see more of this work perhaps in the subsequent sessions for JCO PO, and maybe we'll bring you back again. And at that point, the Decipher and the PSMA PET scan will have more data, more implementation in the clinically relevant real-world setting. Dr. Amar Kishan: Thank you very much. And if I could just give one quick shout out. The first author of this work, which I presented, was Dr. John Nikitas, who is a trainee that works with me here at UCLA a PGY5 resident. So, I do want to give credit to him as well. Dr. Rafeh Naqash: And John, if you're listening to this hopefully, it's always great to get a shout out from your mentor. Thank you both again for putting in the work and effort to submit this manuscript. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Disclosures  Dr. Kishan Honoraria Company: Varian Medical Systems, Boston Scientific,  Janssen Oncology  Consulting or Advisory Role Company: Janssen, Boston Scientific, Lantheus  Research Funding Company: Janssen , Point Biopharma

Dr. Merry Jennifer Markham and ASCO CMO Dr. Julie Gralow discuss the shortage of IV fluids and other challenges that have emerged from Hurricane Helene as high-risk areas brace for impact from another storm, Hurricane Milton. In a conversation with Dr. John Sweetenham, they highlight resources for oncologists and patients and stress the importance of crisis preparedness at cancer centers. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. Hurricane Helene made landfall on September 26th in Florida and raged over parts of Georgia, North Carolina, Tennessee, and Virginia. The disaster has claimed over 230 lives. Many people are still missing, and many thousands are homeless. The hurricane has exacerbated the nation's IV fluid shortage, and some health care facilities have begun implementing conservation strategies. Meanwhile, Hurricane Milton, another powerful hurricane, is expected to wreak havoc as Florida braces for back-to-back hurricanes in parts of the state. On today's episode, we'll be discussing the impact of these events on cancer care, including the shortage of IV fluids. Joining me for this discussion is Dr. Merry Jennifer Markham, a professor and research lead for the University of Florida Health Cancer Center's Gynecologic Cancer Disease Site Group. I'm also delighted to welcome Dr. Julie Gralow, the chief medical officer at ASCO. Our full disclosures are available in the transcript of this episode. Merry Jennifer and Julie, many thanks for joining us for the podcast today. Dr. Julie Gralow: Thanks for having us, John. Dr. Merry Jennifer Markham: Yes, thank you. Dr. John Sweetenham: Merry Jennifer, can you tell us your exact location today and how your patients and institution have been impacted by Hurricane Helene so far? Dr. Merry Jennifer Markham: I am in the north-central part of Florida. I'm in Gainesville, Florida, which is the home of the University of Florida, where I practice medicine. And we are physically about two hours north of Tampa, two hours north of Orlando, and about an hour and a half southwest of Jacksonville. So right in the middle. And we are currently in the track for the next storm. Helene was a really a devastating storm and what our area felt was primarily what we tend to get in most storms here in the center part of the state, which is a lot of rain, a high risk for tornadoes and a lot of power outages. And one of the challenges that my center in particular faces, and some of the local cancer centers and cancer care providers around in our region, is our patients live in a very rural population. So for those patients who are not in downtown Tampa, downtown Orlando, for example, the rest of the state, especially in the northern part, tends to be quite rural. And so many of our patients had loss of power and a lot also in those regions are on well water. And so when the power goes out, it's not just a matter of losing air conditioning and losing access to Wi-Fi, but it's also losing access to fresh, clean water. Dr. John Sweetenham: Wow, it sounds very challenging. And of course, there are growing concerns at the moment about the IV fluid shortage that's being caused by Hurricane Helene and some hospitals have already begun conserving IV fluid supplies. Can you tell us a little bit about your experience with IV fluid shortages so far and whether you are anticipating other medical supplies to be affected by these shortages in the days or weeks ahead? Dr. Merry Jennifer Markham: Well, the IV fluid shortage has definitely impacted us. I happened to be on service last week and this week, and, working in the inpatient setting right now on our oncology inpatient service, we are having to conserve all IV fluid, and the entire hospital has been directed to find workarounds. And it's not always easy to find workarounds. It has definitely impacted our ability to safely discharge patients and to sometimes adequately give people the hydration, for example, that they need. A lot of the cancer therapies, we also use intravenous fluids to pre-hydrate or post-hydrate, and it's a challenge when we also need to conserve those IV fluids for other critical needs in the hospital setting. And for me, the shortage is really being felt in that inpatient setting right now. I think that other centers are still going through. And what we learned from the pandemic is that when there is a shortage, and it's not just actually the pandemic that we learned this from, but from any of the supply chain issues that we've had is then centers start buying it up, right? And so there's a bit of a panic in the healthcare field where if we're short on IV fluids, then well, now everybody is buying up the remaining IV fluids. And I think that does impact, unfortunately, everyone in a negative way. Dr. John Sweetenham: Yeah, I was reading some news reports earlier today actually about stockpiling and the efforts that some of the companies are going to control their outward going supplies to hopefully prevent some of that stockpiling. As if life for you and your patients wasn't difficult enough, you now have the prospect of another major storm, Hurricane Milton, which is headed your way and predicted to be among the most destructive hurricanes ever on record in central Florida. What are your major concerns in the days ahead and for what this might mean for the longer-term impact on cancer care? Dr. Merry Jennifer Markham: It's concerning. We are definitely in the path and the hospital is currently in sort of crisis preparedness mode. My concerns are always for the patients and for the teams caring for them, especially in my current work in the inpatient setting, these last two weeks. Our patients, because they come from such rural areas, are going to lose power. We will probably lose power, but we have generators at the hospital system, so we're a bit protected. But in many of these areas around us, there will be high winds, there will be flooding for those along the coast, and just the access to a clean, safe living environment is going be in jeopardy during and after the storm. What concerns me about our patients in particular with cancer are the ones who are undergoing treatments and who may have complications and may not be able to reach the help that they need during the storm or in the days following. I have patients that I have been caring for in the last week who still haven't recuperated, still haven't recovered their power from Helene. And so this is just adding insult to injury. I think that the impact on medical supplies is still to be seen. The challenge is always when a storm wipes out the major manufacturer of a particular product, I think we'll probably continue to have the IV fluid shortages. And I think it's just going to be a matter of preparing for a worst-case scenario but being prepared. Dr. John Sweetenham: Absolutely, yes. I think you've already alluded to the fact that as each of these successive disasters affect the country, we sort of learn a little bit more each time. And ASCO has provided resources on its website for disaster assistance. We'll share a link in the transcript of this episode to connect providers and patients to the Hurricane Helene-specific resources, government agencies, and also to patient and caregiver groups. Julie, as ASCO's chief medical officer, you've been speaking to stakeholders across the oncology community, as well as many groups that are responding to the crisis. What's your message to ASCO members and patients and caregivers today? Dr. Julie Gralow: Our main message at ASCO to our members, our immediate outreach was, ‘We're thinking of you, we're here for you, let us know how we can help you.' As you've already said, we've learned from past natural disasters. We had Katrina way back when, specifically for the IV drug shortages. We had a shortage back in 2014 due to a problem in Norway, but in 2017 we had another hurricane, Maria, which impacted Puerto Rico and majorly impacted IV fluids. So we have knowledge that we've gained, we as the whole medical community have gained on how to adapt and where we can hydrate orally or, you know, give electrolytes and where we can reserve things. I think one of our main messages at ASCO is that while our members are those who treat patients with cancer, we use IV fluid everywhere in the hospital, the operating room, the emergency room, the ICUs. We are all in this together, and so, while we have some specific things related to oncology where we can probably save fluid and conserve, etc., we need to work as a whole team, a whole body to protect each other. So, if you're developing an incident management team at your institution or whatever, it needs to be multidisciplinary. We all need to be protecting each other's patients as well. Dr. John Sweetenham: Yeah, absolutely. Just briefly on the subject of IV fluids, do you think it will be necessary to mitigate the IV fluid issue by bringing IV fluids in from other countries? Dr. Julie Gralow: I think the full impact, how long this is going to be, how much we can ramp up domestically, is really yet to be seen. all looking at this. So Baxter, which supplies about 60% of hospital IV fluids and peritoneal dialysis solutions, it was flooded essentially at their big plant in North Carolina. They have several other plants in the US and some internationally too. So the question will be, did those other plants also make IV fluids? Can they be ramped up? There are another at least two companies in the U.S. that make IV fluid. What will be their ability to ramp up? we already do. Baxter says they've already; I think Merry Jennifer alluded to this, they've already instituted a mitigation strategy where they're placing products on a protective allocation. So they are really trying to protect against stockpiling, et cetera. The FDA has come out and said it will consider reviewing potential temporary imports. It also is looking at expediting reviews once the manufacturing lines are up and going again, it will expedite those as well. And they're looking at alternative providers. IV drugs are officially on the FDA's drug shortages list, and that allows certain flexibilities, I am told, in terms of, for example, being able to make sterile IV fluids at a local site if it's on the FDA drug shortage list. And there are some other things that go along with it. It's really hard to find on the FDA drug shortage site. You have to use the right keyword. You have to look it up under sodium chloride for injection. You can't look up saline on it. But it is now there. I think it just got placed in the last 24 hours or so. And so that does allow some additional flexibilities. Dr. John Sweetenham: Okay, great. Thank you. So a question for both of you. A couple of years ago, we covered the consequences of Hurricane Ian on this podcast. And Helene and Milton will presumably not be the last storms which are going to disrupt cancer care and undoubtedly cause a great deal of hardship to many people, both our patients and our caregivers, those who are giving care. Climate change probably predicts that this is going to be an ongoing event. You know, these events have undoubtedly tested the disaster preparedness plans of cancer centers in the region. I wonder how you would assess the readiness of cancer centers to respond to these big disasters, which are undoubtedly in our future, and what areas of care do you think would need more attention? Merry Jennifer, maybe I'll start with you for that question. Dr. Merry Jennifer Markham: I think cancer centers, working within their health system, really should have a disaster preparedness plan in place. Here in Florida, I am very used to the preparedness plans that my system has developed really for every hurricane season. And because hurricane season is from June to the end of November, we are fully aware of this plan and can start taking action. And a lot of that deals with when do we close particular clinics? What areas do we need to prioritize? How do we make sure we've got proper staffing? I think that is the type of thing that cancer centers should have really in a written protocol – here's what we do when this news is coming out of the weather center or something along those lines. One of the challenges that we face, and I think probably this is, I guess I'm going to speak for all of the Southeast who is in the, you know, a hurricane, you know, risk area is disaster fatigue. And I think that is a problem. I don't know if it's unrecognized. I fully recognize it because I feel it. think earlier when we were talking, you mentioned Hurricane Ian and I don't even remember, Ian, because we have so many of these hurricanes. Every year there's a new one or multiple, and they all seem to bring the same kind of disasters. Usually on a local scale; I think what we've seen with Helene has just been so massive across multiple states. But the fatigue, that disaster fatigue, I think can lead people to become a little lax. And there is a risk. If we think of all of us as caregivers for all of our patients and for the physicians and teams practicing, it's easy to become numb and tired and worn out of preparing for these disasters. So, I think it's very important that this stays top of mind and that centers are preparing and also cognizant of the fact that fatigue is also a real potential issue. Dr. John Sweetenham: Right, thanks. Julie. Dr. Julie Gralow: We learn from each event and the events have come closer and closer, at least the hurricanes have. I totally agree with Merry Jennifer that we can't have disaster fatigue. Each one does have its unique component. For example, Helene, while we could see the path and it didn't stray that far from its path, did we really expect that this region, this Appalachian region would be the one most impacted? They're nowhere near a coast, you know, it was a bunch of flooding and dams breaking, so each one is different. From ASCO's perspective, we've learned and we've developed both a domestic crisis response team and plan, as well as an international one. And it's, besides hurricanes and major storms, you know, we've had fires and earthquakes and for our international crisis response team, we've been dealing with conflict and getting cancer care delivery in regions of conflict. So by having a team formed, by learning from each event, and then quickly communicating with members when we can get ahold of them on the ground as to what the real situation is and how we can help, I think we've gotten stronger over the years. It's still, with each one, it's horrible for the people on the ground and our job really is to best support our members and their patients as they're trying to get their lives back together. Dr. John Sweetenham: Thank you. So, I think that winds up most of the issues we wanted to cover today. And I wanted to thank you both Dr. Markham and Dr. Gralow for being on the podcast today and sharing your insights on what is, of course, an extremely challenging situation. I should remind listeners that they will find links to disaster resources for providers and patients on the ASCO website at asco.org. You can also follow Dr. Markham on X. Her tag is at @DrMarkham, where she has been sharing key information and resources. And Dr. Julie Gralow will continue to share resources on X. You can find her @jrgralow. We want to wish you, Merry Jennifer, and our many colleagues in the affected regions, all the best during what we know are very challenging times. Dr. Merry Jennifer Markham: Thank you. And thanks to you, Dr. Gralow, for sharing your insights and thoughts with us today as well. Dr. Julie Gralow: Thanks for having us, John. Dr. John Sweetenham: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. The guests on this podcast express their own opinions, experience, and conclusions. Guest statements do not necessarily reflect the opinions of ASCO. Mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today's guests: Dr. Merry Jennifer Markham @DrMarkham Dr. Julie Gralow @jrgralow Follow ASCO on social media:  @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. John Sweetenham No relationships to disclose Dr. Merry Jennifer Markham: Stock and Other Ownership Interests (Immediate Family Member): Pfizer Research Funding (Inst.): AstraZeneca, Merck Dr. Julie Gralow: No relationships to disclose

Dr. Fumiko Chino and Dr. Raymond Osarogiagbon share highlights from the 2024 ASCO Quality Care Symposium, including patient perspectives and compelling research on topics like equity, supportive care, survivorship, and technology and innovation. TRANSCRIPT Dr. Fumiko Chino: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Fumiko Chino, an assistant professor in radiation oncology at the MD Anderson Cancer Center. On today's episode, we'll be highlighting key research and compelling perspectives that were featured at the 2024 ASCO Quality Care Symposium. I was delighted to serve as the chair-elect of this meeting's program committee, and I'm overjoyed to welcome its chair, Dr. Raymond Osarogiagbon, to the podcast today. He is the chief scientist at the Baptist Memorial Health Care Corporation and the director of the Multidisciplinary Thoracic Oncology Program at the Baptist Cancer Center in Memphis, Tennessee. Our full disclosures are available in the transcript of this episode, and we've already agreed to go by our first names for this podcast today. Ray, it's so great to speak with you today. Dr. Raymond Osarogiagbon: Thank you, Dr. Chino, and thank you for letting me call you by your first name. Dr. Fumiko Chino: I think both of our names are complicated enough and so I appreciate the level of familiarity that we've had with each other during the planning process for this fantastic meeting. Now, the Quality Care Symposium featured some really compelling research on very timely topics that address a wide range of issues in cancer care, including quality, safety, equity, supportive care, survivorship, and technology and innovation. Wow, what a lot to cover. Ray, do you mind sharing with me some of the key sessions that really stood out for you? Dr. Raymond Osarogiagbon: Yes, Fumiko, this was such a great conference. Our tagline this year was ‘Driving Solutions, Implementing Change.' We had more than 700 attendees in person and virtually. The Symposium featured many fantastic speakers, oral abstracts, posters, and we had networking opportunities for junior colleagues to interact with leaders in the space. We had conversations that will surely inspire future collaborations to improve quality cancer care. We had patients, advocates. I was inspired by the patient perspectives that were presented, learned a lot. And I really felt like this enhanced our understanding of some of the key issues that we see in our clinics. I was honored to be able to introduce my dear friend, Dr. Ethan Basch from the University of North Carolina, Chapel Hill, who received the Joseph Simone Quality Care Award this year. Dr. Basch gave a talk titled, “On the Verge of a Golden Age in Quality Cancer Care.” In his talk, which received a standing ovation, Dr. Basch tracked his personal development from fellowship training at Memorial Sloan Kettering through a junior faculty position at the same institution under the mentorship of Dr. Deborah Schrag, and ultimately to his current position as chair of oncology at the University of North Carolina and as physician-in-chief at the North Carolina Cancer Hospital. In parallel, with the evolution of the patient-reported outcomes movement that he has been right at the heart of, and also the evolution of cancer care delivery research into its current position of prominence in oncology. That was a spectacular talk, and it rightly received a standing ovation. We also had presentations and panel discussions that addressed patient navigation and cancer care moving from theory to practice, which provided wonderful, diverse perspectives on the evidence-based approaches to patient navigation and cancer care. And a wonderful session on the complexities of the pharmaceutical supply chain and what everyone in oncology should know that looks at the current challenges in the pharmaceutical supply chain. Leveraging technology to support patient-centered multidisciplinary care [was also covered], and we talked about health-related social needs and the impact of diversity, equity and inclusion on the oncology workforce. Patient care perspectives were just incredible. So, Fumiko, as an equity researcher, I really want to hear your key takeaways from some of these discussions. Dr. Fumiko Chino: I have to say, I was so impressed with not just the science that was presented, but also the passion from some of our educational speakers who are really speaking from their expertise and their commitment to try to continue to advance equity in the field of cancer care. And as someone who is still a relatively junior researcher, I feel that the work that I've done over the last decade has really been built on the shoulders of these giants. Just harkening back to you had mentioned that Dr. Basch essentially gave an overview of his career and as a young health services researcher, I've been really impressed about how generous the leaders in the field have been with their time not only to discuss their research at this conference, but also to talk to trainees and fellows and junior researchers and really share the wealth of their knowledge. In terms of equity research presented at the conference though, I was really struck by the overview we were able to provide about the best care to provide to LGBTQ patients. Dr. Mandy Pratt-Chapman actually gave a really lovely overview that was always centered in the patient. It really taught me a lot about what the best practice is to not just collect SOGI data to improve research, but also that there's billing codes that can actually help decrease the chance that a patient may be misbilled based on anatomical misunderstanding of their gender identity. I was very impressed about the capacity for some of our researchers to really think outside of the classic box for DEI research. So not just race as a social construct, ethnicity, but also health literacy barriers. There was a fantastic analysis looking at a randomized control trial (Abstract 385) that actually showed that patients with low health literacy actually got the most benefit from a digital intervention that involved text reminders to increase adherence. And the flip side of health literacy is that we know that the specific interventions that we do really need to be explicitly designed for the populations that they will be implemented on. Dr. LoConte actually had the results from her intervention looking at a radon mitigation indigenous communities (Abstract 44). And I was so impressed about her commitment to the process of listening to the communities and what their needs were, what their concerns were, and then implementing this community led intervention that helped mitigate the radon risk from many households where the actual radon levels were surprisingly high, beyond what they were that what they were anticipating. And so, it's all of these manifestations of how do we actually improve research, how do we advance the field and further the conversation in an era when it seems like DEI is really under attack. Well, I know you've long been an advocate for equity for lung cancer. And I know that you were actually involved in one of the amazing abstracts being presented that was essentially a decade- long QI (quality improvement) project to try to improve standards of care for lung cancer in a high-risk community in the Mississippi Delta (Abstract 278). And it actually showed over time that this surgical pathology intervention actually was able to improve overall survival for lung cancer. I know that this is part of the work that you've been doing for years. Can you talk a little bit about what was presented within the Symposium specifically for lung cancer, including your study? Dr. Raymond Osarogiagbon: Yes, Fumiko. The member of my team, Olawale Akinbobola, who has an MPH that he actually acquired within my research team I'm proud to say, had the wonderful opportunity to present this work on implementing surgical quality improvement, and in parallel, pathology quality improvement in a well-defined population involving 14 hospitals in seven health care systems across five contiguous hospital referral regions in Mississippi, Arkansas, and Tennessee, at the heart of the Mississippi Delta region. So Olawale showed that over the course of four consecutive 5-year time spans, the quality of surgery has improved from a time when using current objective benchmarks of surgical quality, anywhere from 0-5% of resections met these current standards. So basically, applying today's standards, but retrospectively, to where, as the interventions took hold, we now got to a point where about 67% of the sections in this population now attain surgical quality. And we saw in sequential lockstep with that, that the hazard of death among these patients has significantly decreased. All the way, I think using the first 5 years as the reference, the hazard reduced about 64%. Really amazing to see. But you know, there were other fascinating abstracts. There was a randomized controlled trial, Abstract 185, that demonstrated that olanzapine therapy was actually way more effective than prochlorperazine for patients with intractable chemotherapy-induced nausea and vomiting. I found that very compelling abstract. And then there was Elyse Richelle Parks who reported on the effectiveness of a virtual sustained tobacco treatment, Abstract 376 [a clinical trial conducted by ECOG-ACRIN within the NCI Community Oncology Research Program]. This tobacco control intervention is remotely administered using technology that was presented in today's session on leveraging technology to enhance multidisciplinary care delivery.  That too was amazing to behold. Dr. Fumiko Chino: I've been so impressed within my, at least my interactions with the Quality Care Symposium for the last several years about how this meeting really creates the perfect space for this type of science, which can be frankly underappreciated at other meetings. You know, something like a QI project, a quality improvement project leading to an overall survival benefit or a trial like you mentioned, the randomized control trial for olanzapine, which specifically had a quality-of-life endpoint, meaning that patient quality-of-life was a compelling justification for optimal nausea control. These things are really underappreciated sometimes at the larger scientific meetings, and the ASCO Quality Care Symposium is really where these types of studies and this type of research really shines; it's very patient-centered. You mentioned the patient voice being a really integral part, and I certainly agree with that. The entire meeting started with a session featuring a phenomenal patient advocate, Jamil Rivers, who was diagnosed with de novo stage 4 metastatic breast cancer. And her experience with her primary treatment really highlighted some of the care gaps that Black women experience in their journey with breast cancer. And it really charged her to actually create a patient navigation organization to help Black women with breast cancer get more evidence-based care to make sure that they were actually asking the questions that needed to be asked, getting the resources that they qualified for, and making sure they were getting evidence-based care. Now shifting gears a little bit, in oncology and across medicine, there's actually been some major challenges with drug shortages. I'd like to ask you about the session that was featured to inform oncologists about what we need to know about navigating the complexities of the pharmaceutical supply chain. Do you mind sharing highlights from that discussion, Ray? Dr. Raymond Osarogiagbon: I will, Fumiko, but before I do that, I have to follow up on what you said about Jamil Rivers, the breast cancer survivor and advocate who leads the Chrysalis Initiative. She made the statement of the meeting [in my opinion] when she said, “A hospital encounter for a Black woman is like a Black man being pulled over by the police.” Wow. I mean, that's a direct quote. It suddenly helped me understand my wife's many years-long anxiety whenever she has to deal with encounters with clinicians and health care systems. But about that wonderful session on the challenges with the pharmaceutical supply chain. For me, there were two key highlights. One was Dr. Deborah Patt's discussion on the growing influence of pharmacy benefit managers, PBMs, on the cost and delivery of cancer care. And then there is Jason Weston's discussion of how U.S. generic oncology drug manufacturing has moved almost entirely out of the U.S. with this incredible unrealistic price focus, almost so focused on price competition, almost totally ignoring quality and safety. And paradoxically, that fierce competition has inhibited competition, right? So as the margins have shrunk and all these generic drug manufacturers have moved overseas with little oversight, the supply chain gets disrupted because these companies are not able to invest in processes, in their manufacturing facilities and so on. So, when something goes wrong, all of us become vulnerable. And the other striking thing I learned from Jason was this problem is not new. It is not new. It's been with us for decades. And without comprehensive solutions, unfortunately, it's not going to go away. So, these are some of the examples of things that I would really love the podcast audience to go and check out for themselves. Dr. Fumiko Chino: I will just highlight one additional aspect of that session, which was actually the oral abstract (Abstract 1) that was embedded into the session that was specifically about how when during the cisplatin shortage of last year, when that drug was out of stock, which is honestly a very widely available, typically cheap medication, Dr. Jody Garey actually presented on the fact that the things that were substituted were actually far more expensive, and that actually led to not just people not getting the standard of care due to the drug shortages, but also increased costs. So, the bizarre side effect of the race to the bottom in terms of price competition is the fact that during these shortage periods, there's actually a sharp increase in the overall cost, not just to the administration, but also in terms of payer costs and patient cost sharing. So, it is sort of a lose-lose situation. And that was really highlighted to me by that abstract. And I'm so grateful for the research that really puts these experiences that we see in our clinic, things like drug shortages, in a larger perspective of how things like health policy and reimbursement and some of the nitty-gritty that goes on beyond the scenes in terms of oncology practice really is ending up impacting patient care. Now Ray, is there anything else you'd like to highlight before we wrap up the podcast? Dr. Raymond Osarogiagbon: One I maybe should highlight was the discussion about DEI, which is obviously a contentious topic. And we had Dr. Tawana Thomas Johnson with the American Cancer Society tell us how DEI has evolved from something that everybody seemed like they were eager to support and champion in 2020 to a kind of backlash...how we moved from $5 billion in pledges by corporations to support DEI initiatives in 2020 after the George Floyd murder to now where everybody is wanting to roll things back. And yet in the face of this, wanting to roll things back, wanting to respond to the inevitable backlash, there is this commitment still that some companies have had to DEI and workforce development ideas, so nevertheless, ongoing support. For me, that was a bright spot. Dr. Fumiko Chino: I have to say, as someone who started going to the ASCO Quality Care Symposium as a trainee, I've been really encouraged myself in terms of bright spots for this meeting about the engagement from trainees, from medical students to residents and fellows to early faculty. We even had someone who had just graduated high school ask us one of the questions in a session. And that really highlighted for me that this meeting is a very young meeting. It really is the next generation of health services researchers. And that has always been one of the joys about some of the discussions because I feel like the science presented, the education presented is sparking new collaborations, new research paradigms, new mission driven research for another generation. And it's been just simply phenomenal. Dr. Raymond Osarogiagbon: Yeah, the networking opportunities. Wow. It was such a joy to behold people getting together, breaking off in small clusters, interacting with each other, strangers meeting and hitting it off. I mean, just what a wonderful meeting this is. Dr. Fumiko Chino: Yeah, I have to highlight that. Certainly, at my first ASCO Quality meeting at this point, I think eight years ago, I went to one of those Meet the Expert luncheons, had a great conversation with a phenomenal researcher who I still obviously very much admire. And I was sitting at a table at a Meet the Expert luncheon today. And I just felt so invigorated by some of the conversations that I had with the next generation of researchers about how to define their lane, their passion, and how to continue to advance the field. Thank you, Ray, for sharing your key takeaways from the 2024 ASCO Quality Care Symposium and for leading a truly robust program this year. Dr. Raymond Osarogiagbon: Thank you, Fumiko. This has been a labor of love as you will find when you take on this responsibility for next year's meeting. This has been my pleasure. Dr. Fumiko Chino: Thank you so much. I'm really excited about the program that we're going to start planning in Chicago next year. Everyone listening can mark their calendars for October in Chicago. I really want to thank our listeners for your time today. You will find the links to the sessions and the abstracts that we discussed in the transcript of this episode. And if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer:    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers: Dr. Fumiko Chino @fumikochino Dr. Raymond Osarogiagbon  @ROsarogiagbon    Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures:  Dr. Fumiko Chino: No relationships to disclose Dr. Raymond Osarogiagbon:   Stock and Other Ownership Interests: Lilly, Pfizer, Gillead  Honoraria: Medscape, Biodesix  Consulting or Advisory Role: AstraZeneca, American Cancer Society, Triptych Health Partners, Genetech/Roche, National Cancer Institute, LUNGevity  Patents, Royalties, Other Intellectual Property: 2 US and 1 China patents for lymph node specimen collection kit and metho of pathologic evaluation   Other Relationship: Oncobox Device, Inc.

Navigating the Journey of Fatherhood Fatherhood is a complex and rewarding journey that demands a unique balance of strength, empathy, and patience. For fathers of daughters, the stakes can feel particularly high. In a recent episode of the Dads with Daughters podcast, hosts Dr. Christopher Lewis, Michael Ramos, and Steven Manchester delve into the nuances of raising daughters, from the initial trepidation to the ongoing quest to raise strong, independent women. Embracing the Journey Together Dr. Christopher Lewis opens the episode by emphasizing the importance of community and learning from one another's experiences. "All of our journeys is a little bit different," he notes, "we can learn from each other... as long as you're willing to open yourself up to learning." This sentiment sets the stage for an enlightening conversation with guests who have both navigated this journey and sought to share their wisdom with others. The Initial Fear and Responsibility When asked about their first reactions to learning they were going to be fathers to daughters, both Steven Manchester and Michael Ramos admit to feelings of terror. Such an emotional response is not uncommon; many fathers experience fear when anticipating the responsibilities of raising a daughter. Manchester explains, "I needed to do it the right way... kids don't necessarily listen, but they do watch." Ramos, reflecting on his own experience, highlights the ongoing nature of parenthood: "I just had a little baby girl and I brought her home from the hospital... I was going to learn every single day and never stop learning." Addressing the Biggest Fears Lewis probes deeper, asking about their biggest fears. Here, Manchester articulates the weight of setting a high standard, "I want me to be the example of what she should expect." For Ramos, the sentiment is similar. He emphasizes the importance of modeling respectful behavior to set high expectations for how his daughters should be treated by others, and also how his sons should treat others. Overcoming Challenges Every parent faces challenges, but raising daughters comes with its own unique set of difficulties. Manchester likens raising boys to "playing checkers" and raising daughters to "playing chess." The complexity, he notes, requires a deeper level of empathy and understanding. Ramos concurs, describing the intricate personalities of his daughters and the importance of adapting his approach to meet each of their unique needs. Building Strong, Unique Relationships Fostering strong relationships with daughters involves more than just being present; it requires emotional vulnerability and genuine connection. Ramos shares that learning to be nurturing, sensitive, and empathetic was crucial for forging these bonds. Manchester underscores the importance of having individual relationships with each child, independent of the rest of the family. The Genesis of "The Dad Bag" The conversation then shifts to the inspiration behind The Dad Bag, a book co-authored by Manchester and Ramos. From the anxious moments of early fatherhood to the realization that parenting lacks an instruction manual, Ramos recounts his journey towards writing a guide that offered practical, heartfelt advice for new fathers. Manchester, an accomplished author, saw an opportunity to create something impactful, noting, "This book has the potential to have more of a positive impact than most of the stuff that I've written." Lessons from The Dad Bag The Dad Bag uses the metaphor of a "dad bag" filled with symbolic items to represent life lessons. These items serve as visual aids to reinforce critical messages, making the lessons accessible and memorable for both the father and child. The book aims to break through stereotypes and offer a new model of fatherhood defined by empathy, vulnerability, and engagement. Be There and Don't Give Up As the podcast concludes, Dr. Lewis asks for their final piece of advice to fathers. Manchester succinctly states, "Be there," while Ramos elaborates, “Don't give up. You got this." Their words resonate as a reminder that fatherhood is a journey filled with highs and lows, but with presence and perseverance, every dad can make a profound impact on their daughters' lives. For more insights and to get your copy of *The Dad Bag*, visit [Amazon](https://www.amazon.com). Fatherhood is a journey best taken together, learning and growing every step of the way. Here's to raising strong, independent women, one day at a time.   TRANSCRIPT Dr. Christopher Lewis [00:00:01]: Welcome back to the dads with daughters podcast, where we bring you guys to be active participants in your daughter's lives, raising them to be strong, independent women, Really excited to have you back again this week. As always every week, I love being on this journey with you, an opportunity to be able to welcome alongside you as you're working to raise those strong independent women that you want to grow up in society today. And all of our journeys is a little bit different. We're all on a unique journey, but we can learn from each other. We have an opportunity to learn from each other. And every day that we walk on this journey, there's something new that we can learn from the person next door, from the person on the other side of the earphones. It doesn't matter as long as you're willing to open yourself up to learning. And that's what's important. Dr. Christopher Lewis [00:00:50]: And every week I work to be able to help you to meet new people, fathers or others with resources, people that can help you to be able to see fatherhood in a little bit different way. Every father fathers in a little bit different way. And there's a lot of resources that are out there as well. Today, we've got 2 great dads with us. Steven Manchester and Michael Ramos is with us today. They both are fathers of 4. We're gonna be talking about their journey as fathers, but also authors. We're gonna be talking about a book that they put out just recently called The Dad Bag, and we're gonna be talking about that as well. Dr. Christopher Lewis [00:01:27]: So I'm really excited to have them here today and have you learn from their journeys. Steven, Michael, thanks so much for being here today. Steven Manchester [00:01:33]: Thanks for having us, Chris. Michael Ramos [00:01:34]: Thank you very much, Chris. Dr. Christopher Lewis [00:01:35]: It is my pleasure having you here today. And first and foremost, I wanna turn the clock back in time because I have that power and I love to be able to have our dads do some self reflection here. And I wanna go back to that first moment that you found out that you were gonna be a father to a daughter. What was going through your heads? Steven Manchester [00:01:52]: Tara. Absolutely, Tara. I think for me, Chris, it was a lot of weight. Right? Because I needed to do it the right way. And we've, you know, as you know, and Mike knows clearly, kids don't necessarily listen, but they do watch. So from the moment we had our daughter, Isabella, I can honestly say she's made me a better person, a better man. And I've been really conscious of what I've done and the things I've said because of wanting to be that dad to her. Michael Ramos [00:02:13]: I think Steve probably echoed my exact sentiments with Tara, uncertainty. I know I figured it out. I I knew I'd figure it out eventually, and some things would be innate, but there were so many questions that I didn't have. And I think the answer is that I didn't have to questions. And I won't tell you where the dad bag came from yet, but it does directly connect to the moment that I realized, like, I just had a little baby girl and I brought her home from the the hospital. But I think I learned within the first few months that this was a journey and not a destination being a dad, specifically to girls, that I was going to learn every single day and never stop learning because things would always change. And that's exactly what has happened and continues to happen, even with the oldest one being 19. Dr. Christopher Lewis [00:02:58]: Now, both of you said that your first reactions were terror. And that being said, I hear that from a lot of dads, especially dads with daughters, that there is fear, the fear going along with raising daughters. Talk to me about your biggest fear in raising a daughter. Steven Manchester [00:03:12]: It's my true belief that our job is to to raise them, right? Not keep them. So even from the time that they're young, again, it's all about setting that example, but whoever she ends up with or whoever she has contact with as far as boys or men, I want me to be the example of what she should expect, right? Like the bar should be raised very high. So for me, the tarot really comes from the weight of responsibility, right? Of getting it right. You know what I mean? And it's never gonna be perfect, we all know that. God knows I've made my fair share of mistakes, but the intentions of being conscious of the fact that listen, I need to do the best I can do so that she understands what, you know, what she deserves. Right? Michael Ramos [00:03:56]: And I think for me, it was very much the same. It's funny because I tell the story and it it applies to both my boys my boy and my girls. But, as far as Steve said, setting the bar. I always wanted my girls to know what the expectation was from the boys that would they would come in contact with. And then I wanted to be the same example for my son so he would know how to treat all of the people, and lead by example in that way. And and somebody had once shared a story, and that's where I learned this from. They shared a story once with me and they said, I want if my daughter goes out on her 1st date at whatever age it is and somebody treats her disrespectfully, I want it to be a red flag. I don't want it to be something that feels normal or feels like she's seen or experienced at home. Michael Ramos [00:04:48]: So although I think that's who I am anyways, is to be very respectful at all times. It especially made me conscious of the fact that I need to be respectful at all times in my treatment of all women, whether it was a partner, a mother, a grandmother, a sister, because that's the example that I was setting for them. Dr. Christopher Lewis [00:05:04]: And raising kids is never easy. There is definitely high points, but there is challenges, there's hard parts. Talk to me about the hardest part in raising a daughter. Steven Manchester [00:05:14]: Well, I can tell you from experience, you know, I've raised a couple sons and that was like playing checkers. And then along comes my girl and now I'm playing chess at an advanced level. So it's amazing. I mean, you almost have to become an empath in a sense where it's not just the way that you think, it's the way that you feel and trying to understand how they feel and and providing what they need. So for me, the hard part was, I guess, getting out of my way and not trying to fix everything for her. Just being able to listen and just be there for her. Michael Ramos [00:05:40]: Again, similar. It was being able to determine when I needed to listen and when I needed to solve the problem because they're very different and there will never be any instruction given. There's almost an expectation that and I said because I've had hundreds of conversations with my 2 teenage daughters where sometimes I got it right and sometimes I was listening when I should have been solving and sometimes I was solving when I should have been listening. And I think to answer the question more specifically, what's been the most difficult part for me, I think has has been learning their personalities because I feel like they're a little more deeper and complex than my boy, and I can only draw from that example. But my 3 daughters are all very different from each other. And there's an expression in psychology that they use where you peel the layers of the onion back to get what's inside, to get to what, you know, the deep root of what's inside is. And one daughter wants me to peel the onion very, very slowly over the course of 45 minutes to get to that. The other daughter wants me to smash the onion, which is more my style. Michael Ramos [00:06:45]: Get what's inside. And then the other one wants me to peel it, like, ever so slowly, then start smashing the load, then go back to peeling. You know, so I think that's been the most difficult part is trying to understand how complex and beautiful their personalities are, how unique they are, and then how I need to then respond differently, learn and grow and do things that don't feel natural to me because my personality tells me to handle everything one way, but they are very different human beings and need me to handle things differently. Dr. Christopher Lewis [00:07:11]: Now you talk about the fact that every child is unique, and that's definitely the case. You can have 2 kids that you come from the same parents, and they can be completely different individuals, and we always see that. So talk to me about with your kids, especially your daughters, how have you been able to build those strong, unique relationships with each of your daughters? And what's your favorite thing that you do and share with your daughters? Michael Ramos [00:07:42]: So important to me. I think learning that it was okay to be nurturing, learning that it was okay to be sensitive, learning that it was okay to cry. And I'm not saying breakdown crying every 15 minutes throughout the day, but learning that it was okay for me to have emotions because society has dictated to me that I can only be tough, that men don't cry and that men don't have emotions and reactions like that. So I was able to connect with my daughters because I was able to be vulnerable. I was able to connect with my daughters because I knew empathy, because if I didn't know empathy, how could I understand them and be compassionate and be empathetic if I couldn't be that myself? So through a 13 week curriculum that I became a nurturing father's facilitator and worked with a lot of dads and some incarcerated dads. I learned a lot of things that later on in life where I was I was able to, to apply. But I think those things were so critical in order for me to be able to connect with them at the level that that I do where they're so comfortable. They'll talk to me about literally anything. Steven Manchester [00:08:42]: That's not gonna be easy to follow, Chris. That was fantastic. But I will just add to that and say that for me and Bella, it was just 1st and foremost just being there, making sure that she knows that I'm a vet. I don't care what it is like I'm there. And secondly, I think it's so important to have relationships with each of your kids that are independent of everybody else in the family. So there are times the whole family is doing things, and then there's times where I just go out to to lunch with my daughter. And then we talk about and it's a a relationship that I've established just between her and I, and I think that's where the trust is born and it's kind of built on. I don't ever want her to play, you know, need to feel like she used to play favorites, but it's, it's also, it's very, very important to me if you're feeling down, you'll just need to go to your mother. Steven Manchester [00:09:23]: You can come to me as well. And to Mike's point, being aware of the fact that I need to have that empathy, I need to show that empathy, and And I may not have all the answers. And even if I do, she probably doesn't wanna hear them anyway. So again, it's just being available and and, making sure she knows that I have her back, which is an odd way to put it. Dr. Christopher Lewis [00:09:42]: But Now I mentioned at the beginning that the 2 of you came together to write a newer book called dad bag or the dad bag. And, I guess I wanna go back before I ask you some questions about the book itself. Let's go back to the genesis of this because I know, Steve, you've been an author for many years, your style of writing is a bit different than what this is. So so talk to me about how the 2 of you came together and why you decided to come up with this concept and put it onto paper. Michael Ramos [00:10:12]: So, let me just stop by saying I just need to give a little kudos to the amazing human being, father, and friend that Steve is because Steve Manchester, I've known as an author and I've known as a friend. I don't consider myself to be an author. This was something very important to me, and he's done presentations for me and in front of dad's groups and for private agency and also some state agencies. So I knew that he would be the perfect person. Where it came from was early, you asked, the terror feeling of knowing that I was having a little girl, but also just like a child, period. I remember bringing my daughter home from the hospital and putting her on the floor in the car seat. And I was sitting in the living room by myself, and I looked down at her in the car seat, sitting there between my legs. And I said, geez, what do I do now? And I went, well, I guess I should take her out. Michael Ramos [00:10:58]: That's a stop. Let me take her out of the car seat. And I mean, I kinda knew what to do, but, like, I also didn't. So I figured it out, stumbled along over the next, like, you know, week or 2, and then the remote control broke for the TV. So I went to RadioShack for anybody under 40 who's listening. That's, an electronics saw that once was in business. But I went to RadioShack and I bought a new new remote control for the TV. I brought it home and I opened it up. Michael Ramos [00:11:27]: It was like $6.99, and it had 12 pages of instructions in 5 different languages. And I said, this remote control comes with that many pages of instructions in so many different languages. And I just brought a beautiful little human being home from the hospital with, like, no directions whatsoever, with no instruction, with no anything. And I said, gee, someone should write a book, not only just for parents to come home from, like, you know, the the hospital with, but especially dads. And that's where the dad bag came from. Steve and I had already worked together doing some fatherhood work, him mostly doing some presentations. And I was already doing nurturing fathers and also some a lot of presentations nationally. And I reached out to him and just just like that, he said, love it. Michael Ramos [00:12:14]: Love the idea. Let's do it. And I know that fatherhood is so important to him. I knew it just would be a great marriage to, get the book written. Steven Manchester [00:12:22]: I gotta tell you, it was a no brainer for me because first and foremost, I really admire Mike. The things that he's done in the community, for the state, the impact that he's had on people, how can you not get your wagon to that? So some of the themes that I've had in my writing over the last 30 years really has a lot to do with fatherhood. Mike and I are really big on there's a big difference between being a father and being a dad, and it's like kinda hammering that stuff home. I also have a background in the prison system. I worked for the Department of Correction for 10 years. So I saw guys that were leaving without a clue on how to father their children. And you think, what a tragedy, right? Because generationally, that's, you know, that's potentially, you know, absolutely awful, right? So, it made perfect sense. And when we got together Mike's concepts, we were able to flesh them out. Steven Manchester [00:13:04]: It took some time. We had to find the right illustrator in Stephanie Grassi, who's just a wonderful person as well. So this hasn't been any work at all. For me, it's been a joy. And I really think, I mean, I normally write adult novels, write 90,000 words. This book, I don't know what even it came in at, but I think this book has the potential to have more of a positive impact than most of the stuff that I've written. And I I'm grateful to Mike for that opportunity to be able to be a part of Michael Ramos [00:13:29]: it. Ironic. I'm more grateful to you. So that's really nice. Steven Manchester [00:13:33]: And I I do mean that sincerely, right, for the people that are listening. I think, you know, Michael will get into this a little bit too, but it's not a bad bag, but it's really I think it's for the family. I think it's for the entire family. I think it's for the dad kind of being able to help mom out or step up and and, you know, do what he's supposed to do. But in a way that what I love about this is it's really almost an instruction guide that's disguised as a children's book. So if dad's reading that to to, you know, his child and dad's also learning as well. Right? And I'm a firm believer we're all in the same boat. Right? It's just you gotta pick up a paddle and start rowing, and I think that's what this book's about. Michael Ramos [00:14:08]: There's so much data and statistics out there that prove that mom's health is increased significantly when dads are engaged. There's factors and indicators for breastfeeding that more moms breastfeed and are likely to breastfeed if they have dads engaged. And it makes sense why. And it makes sense that there's moms that are under less stress when dads are involved because dads are helping out. And we know parenting for mom or dad, because both are critically important, is very difficult if you're doing it alone. I mean, I think that's also one the things that we like to drive home is that dads really need to be engaged and involved. And the difference between being a dad and being a father is exactly that. It's not just buying a ball for your kid and saying, oh, here, I bought this ball for you. Michael Ramos [00:14:49]: And then going in the house, it's stopping to teach the rules, to play the game, to, you know, to teach kids how to self regulate. It's all of those things. And while you're doing that, mom gets a break too and vice versa. Dr. Christopher Lewis [00:15:02]: Now in the book, one of the things that I noticed was that the father in the story talks about the importance of effective communication. How do you think his approach to communication differs from the conventional methods and why do you think it's effective? Michael Ramos [00:15:18]: I think it's because mostly what I was saying before about empathy and compassion and being able to look at the communication from a different perspective and not from the more conventional model. And although I I think there's been a lot of movement more recently with lots of men in this country and lots of dads. I still think there's a lot of dads that still believe that they are the disciplinary, that they shouldn't cry, that they shouldn't have emotion, that they are supposed to be strong and tough. And you can be those things too, but you can also have compassion, be empathetic, and be an engaged dad. It'd be nurturing. And I think that's the difference in the approach. That's the difference in the patience. That's probably a keyword there. Michael Ramos [00:16:02]: The patience that it takes to develop those relationships and understand that with 3 daughters, the dad in the book was specifically just the boy and the girl, but the dad in the book's ability to understand and that that's what it took in order to connect with the children and was that a level of patience to really understand them and be able to see that empathy and that compassion. Steven Manchester [00:16:24]: For me, like the communication, this book in many respects is, I think we're trying to break through some stereotypes. And when you look at a generation just prior to us, my father and his brothers and my grandparents, and it went from you to be seen and not heard to my father would listen, but empathy, I'm not sure, was at the top of the list. He was putting food on the table, shoes on your feet, and if you cry, then he didn't care for it. So for me, and I'm gonna just switch real quickly right to my sons. If my sons fell down and scraped their knee, I don't I don't want anybody crying. Right? We we talked about that. But if there's something that really hurt them and it hurt their soul, I'll sit and cry with them. And it was so, so important, like, when my parents passed, I watched my kids watching me and I didn't hold back. Steven Manchester [00:17:05]: And I also talked about it. So Mike brought up the word earlier, vulnerable, and I think that's the key here. I believe some men see things as weakness, right, when they show their feelings. For me, that's true strength. I mean, that's strength to be able to show your children, I also have feelings, I also mourn and grieve and, you know, I'm happy and I'm sad. By sharing that with your children, you also give them permission to do the same. And I think it just bonds you closer. Right? My kids are more apt to come to me because I'm not going to judge them based on their emotional reaction. Steven Manchester [00:17:33]: And I think that's one of the things I really love about this book. And Mike's concepts, even, you know, very early on from boys playing with a doll or girls asking questions, like, for me, it was like kinda let's let's just break through that and be honest. Just be vulnerable and honest. And and I think that's where the magic is in this book. Michael Ramos [00:17:49]: You know, to expand a little bit on what Steve said with a slightly different concept, it also makes me feel strong to be able to care for my my children. So, yeah, it's a it's a sign of strength, like like Steve said, to be able to be vulnerable and to be able to give your children permission to feel those feelings too. But it also makes me feel strong to change a diaper and to be able to cook food and to be able to care for my children and nurture my children because culturally and also generationally, historically in my family, that's not something that men do. Men don't change diapers. Men don't wash clothes, do laundry. They don't do any of those things. I've always seen that as a sign of weakness. It makes me feel strong to know that I can take care of myself and my children at all times if I need to. Michael Ramos [00:18:31]: It feels completely opposite to me if I have to rely on someone else to do those things because I I'm just not or I don't know how. So also, I think that's to answer your question too a little bit, that's probably a less conventional approach, but I think that's changing and I'm very happy that that's changing. Dr. Christopher Lewis [00:18:46]: I noticed also in the book that the book is called The Dad Bag. The father uses various items from his dad bag as symbolic representations of life lessons. Can you discuss the significance of the metaphor that you're using here and how it adds depth to the narrative? Steven Manchester [00:19:03]: I think this is very intentional, right, right from the beginning that we were gonna use a backpack called the dad bag, much like a mom would have a diaper bag. The dad has the because this book was written really for for families and and children from, you know, because this book was written really for families and children from 5, you know, 5 years old on. So to look at visuals and then hear the narrative that goes along with it, I think it helps the dad or the protagonist within the story, as well as the dad who's reading the book, you know, to to his child, right? Whether it be a boy or a girl. For me, it's just again, I think kids are very visual and I think it helps to carry those lessons. It's easy to remind a kid, if you're talking to them about a certain lesson in years and a prop, later on, all you have to do is pull up the prop, and the message has been received again. Michael Ramos [00:19:50]: I love the representation of each item, and I feel like there could be a 1,000 things in every dad bag because of all the the life lessons, but that's where the onion peeling, that's a very personal family specific story with one of my daughters. We've we've talked about this. She'll actually reference it and say, papa, I need you to peel the onion. So we use that. It's a metaphor and it's something that, you know, you way of addressing and and introducing something in the book, but it it comes from draws from a an an actual experience that's really helped with communication that's been used a number of times where one daughter will say, you could just bust the onion because, like like, I'm going out tonight. Like, my friends are picking up in 10 minutes. You know what I mean? Or they'll say, I'm a you could just bust that onion open. So with that, everybody that ends up buying, I'm gonna send onions to everyone. Michael Ramos [00:20:39]: No. Nobody's getting onions. I'm just I'm just kidding. Dr. Christopher Lewis [00:20:42]: Now I'm not gonna give up the end of the book, but I will say that the father at the end does share a heart felt letter that he wrote to his kids before they're born. How do you think this letter really encapsulated or encapsulates the father's hopes and aspirations for his children's future? Steven Manchester [00:20:59]: I think it's a representation of the responsibility that he feels. I think the important piece here, Chris, is that he wrote it before that child was born. So to Mike's earlier point, it's so important to learn each of their personalities and to be able to almost retrofit how you father, right, or how you parent. What I like about that piece of the book is that he wrote it from his heart before this child was born, right? So these are his aspirations, his dreams, and also the responsibility he feels, right, to be the right dad for this kid. And in Dr. Christopher Lewis [00:21:25]: the end, as people are reading this book, as they are reading it to their own kids, what are you hoping that the fathers that are reading this are gaining from it personally? And what are you hoping that their families gain from it? Michael Ramos [00:21:39]: I'm hoping that at the very, very least, just a sliver, if the dad learns or a light turns on that there is more than one way and that there's a possibility to think outside of the box and it helps him have less fear, not have that terrified feeling. And that's why the goal for me is to have this this book literally in every single hospital in the country. Because for me, it doesn't make sense that any dad should ever leave the maternity ward of a hospital with a human being without having this book in their hand because it exists. And because it's an instructional manual, it just makes sense to me because then dads don't have to be afraid. Dads won't buy remote control that have more instructions than their child's will have that they will have brought their child to him from the hospital and it'll help with that fear. And that's what I hope the dad gets from it. And if the dad gets that, the family gets everything. So I don't even need to say what the family will get from it because if the dad, they all win. Steven Manchester [00:22:31]: That's a great answer. For me, I get, you know, I I've read this book 7000 times. Right? So you get to the end of it. It's almost like a sub, like a subtle contract, right, between the father and his child, where it's like, I'm setting some expectations for you, but really what's happening is he's setting expectations for himself. He's kinda laying it out there for his daughter or his son. So I love that piece of it. We don't use a sledgehammer to, you know, slam people over the head with it, but dad legitimately sits down and reads this to his daughter, then there are some expectations that are there. And so to to Mike's point, right, some of the fear hopefully gets dispelled and and this dad understands stands. Steven Manchester [00:23:05]: He's not the only one in the boat. We got a lot of people in the boat, so stop rowing. Mike's tying. Dr. Christopher Lewis [00:23:09]: And now we always finish our interviews with what I like to call our fatherhood 5, where I ask you 5 more questions to delve deeper into you as dads. So I'm gonna ask you both. So first and foremost, in one word, what is fatherhood? Love. Steven Manchester [00:23:21]: I'm gonna say commitment because you use love. Dr. Christopher Lewis [00:23:24]: Now when was the time that you felt that you finally succeeded at being a father to a daughter? Steven Manchester [00:23:31]: Never. I'll say the same. I can't use one word, but it still hasn't happened. And I'm not sure it will until I draw my last breath. Dr. Christopher Lewis [00:23:37]: Now, if I was to talk to your kids, how would they describe you as a dad? Michael Ramos [00:23:41]: I would say loving. It depends on the kids. I hear cool a lot, but that's I sing in a rock band, and I have lots of tattoos. So, like, to daughters, I'm like a really cool dad. There's a lot of words, but I do hear cool a lot. Like, I'm a cool dad. Dr. Christopher Lewis [00:23:55]: Now who inspires you to be a better dad? Steven Manchester [00:23:57]: I would say the kids. I would say each one of my children because I owe that to them. Michael Ramos [00:24:01]: Everything that was missing in my life from a father. Dr. Christopher Lewis [00:24:05]: Now you've both given a lot of pieces of advice today, things that you shared in the book, but also things that you've learned in your own journeys. As we finish up today, what's one piece of advice you'd want to give to every dad? Steven Manchester [00:24:18]: For me, it's 2 words, be there. Above all things, just be there. Michael Ramos [00:24:22]: I'd add on to it. Don't give up. You got this because I think that's what I've learned from working with so many dads over the past 15 years or so is that a lot of dads just give up or they don't feel like they're good enough. And if they can't be perfect, then they don't wanna let their kids down. So that's why they check out and that's why they're not engaged. And they're not there, like Steve's saying, to be there. Don't give up on yourself. You got this. Michael Ramos [00:24:44]: And, yes, be there. It'll all come. And make the mistakes. It's okay to make the mistakes. We all do. That's called being human. It has nothing to do with being a father. It has to do with being you. Dr. Christopher Lewis [00:24:53]: Now if people wanna find out more about the book or about either of you, where should they go? Steven Manchester [00:24:57]: First and foremost, amazon.com would be the first place that they can go to. So the book's available as an ebook. So we you have the electronic version and it's also print. It's done in print as well. And we have some I don't think it's something we'll talk about today, but we have some big plans for this book to introduce to the masses. And the hope is, again, to Mike's point, whether it be hospitals, prisons, to get this book out in mass where we can make as much impact as possible. Dr. Christopher Lewis [00:25:27]: A stories, your journey today. I truly appreciate you being here, for sharing your voice, and I wish you both the best. Steven Manchester [00:25:34]: Thanks, Chris. We appreciate you. Michael Ramos [00:25:35]: Yeah. Yeah. Absolutely, Chris. And thank you for being such an amazing host and making such a comfortable interview. Steven Manchester [00:25:39]: And thank you for everything you're doing for the dads out there, Chris. We appreciate that. We really do.

Dr. Lillian Siu and Dr. Melvin Chua discuss the new technologies and novel therapeutics that were featured at the 2024 ASCO Breakthrough meeting. TRANSCRIPT Dr. Lillian Siu: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Lillian Siu, a medical oncologist and director of the Phase 1 Trials Program at the Princess Margaret Cancer Center in Toronto, Canada, and a professor of medicine at the University of Toronto. On today's episode, we'll be discussing key takeaways from the 2024 ASCO Breakthrough meeting in Yokohama, Japan. Joining me for this discussion is Dr. Melvin Chua, who served as the chair of Breakthrough's Program Committee. Dr. Chua is the head of the Department for Head, Neck and Thoracic Cancers in the Division of Radiation Oncology at the National Cancer Center in Singapore. Our full disclosures are available in the transcript of this episode. Dr. Chua, it's great to be speaking with you today and congratulations on a very successful Breakthrough meeting. Dr. Melvin Chua: Thanks Dr. Siu. It was really inspiring to come together again to showcase the innovative work of world-renowned experts, clinicians, researchers, med-tech pioneers, and drug developers from around the globe. Our theme this year was inclusivity and thus it was important to bring people together again in the Asia Pacific region and to foster international collaborations that are so important in advancing cancer care. This year, we invited 65 international faculty, of which 55% were from Asia. Also, importantly, we achieved approximately a 50-50 split for male to female representation. These are remarkable statistics for the meeting, and we really hope to retain this for future Breakthrough [meetings]. Dr. Lillian Siu: The meeting featured renowned keynote speakers who shared great insights on new technologies and therapies that are shaping the future of drug development and care delivery. Let's first talk about artificial intelligence and the keynote address by Dr. Andrew Trister. He gave a very interesting talk titled, “Plaiting the Golden Braid: How Artificial Intelligence Informs the Learning Health System.” What are the key messages from his talk? Dr. Melvin Chua: Couldn't agree with you more, Dr. Siu. Dr. Trister is the chief medical and scientific officer of Verily, a precision health company. He previously worked in digital health and AI at The Bill and Melinda Gates Foundation, and worked at Apple where he led clinical research and machine learning with Apple partners. But perhaps it was really his background and training as a radiation oncologist that was most pertinent as he was able to weave both the components of new AI models and the applications and pitfalls in the clinic to the audience. Dr. Trister provided a very high-level view through the history of AI and showcased the progression of the different AI models and he basically explained between deep and shallow methods as well as deductive logic versus inductive probabilistic methods. He then provided several clinical examples where these models have shown their utility in the clinic, for example, pathology and so forth. At the same time, he illustrated several pitfalls with these models. So overall, I think Dr. Trister's talk was very well received by the audience with several key messages, including the importance of [using] high-quality data as the basis of a good AI model. AI was also addressed in an Education Session that looked at Artificial Intelligence in the Cancer Clinic. And we had a panel of experts that highlighted current progress and successes with AI in the clinic, advances with AI assisted pathology for clinical research and precision medicine, large language models (LLMs) for applications in the clinic, and how we could leverage AI in precision oncology. And from this session, I had several key takeaways. Dr. Alexander Pearson [of the University of Chicago] gave a very illustrative talk on how multimodal information across clinical omics, radiological information and multi omics could be used to improve diagnostic tasks and clinical prediction across different cancers. And Dr. Joe Yeong [of Singapore General Hospital] gave a very good talk on how AI can be applied in digital pathology to accelerate research in immunology and help in the development of immunotherapies. Dr. Danielle Bitterman [of Brigham and Women's Hospital] shared very good examples of how LLMs could be used in a clinic. And I think the example that really stood out for me was how LLMs could be deployed to create responses to patient queries. And of course, the big question in the room was: How could AI eventually encapsulate compassion in their response? I think this again showcased how LLMs could really help to accelerate our clinical work going forward. And ultimately circling back to data, Dr. Caroline Chung [of MD Anderson] gave a very poignant description on the importance of data quality and how poor-quality data could eventually lead to underperforming AI models. So all in all, I think this was a great session. And what do you think, Dr. Siu? Dr. Lillian Siu: Melvin, I totally agree with you. I like all your comments and I really enjoyed the keynote as well as the session on AI in the cancer clinic chaired by Dr. Pearson. I think all these sessions were really informative. Discussions on the latest AI and machine learning, algorithms and technologies on digital pathology, LLMs and big data, as you said, really enables the attendees, especially clinicians like me, to gain a deep understanding of how AI can be translated to practical applications. Dr. Melvin Chua: Great. So, Dr. Siu, let's talk about some of the novel therapeutics that were featured at the meeting. Again, this was an important session for Breakthrough, and it's always been there. So could you share some highlights from the sessions on novel drug development from your perspective? Dr. Lillian Siu: Yes, indeed. Drug development is such an exciting aspect of this meeting. On Day 3 of the meeting, we had a keynote by Dr. Shimon Sakaguchi of Osaka University, who discussed “Targeting Regulatory T cells (Tregs) in Cancer: The Science, Trials, and Future.” And he talked about T cells, especially Treg biology, the role of Tregs in immune regulation, new developments in Treg immuno-oncology drugs, and how we can actually target Tregs to treat early cancers, etc. This talk is particularly exciting because there are now anti CCR8 antibodies in the clinic that specifically target Tregs, and some early signals of anti-tumor activities are already being observed. Dr. Sakaguchi also emphasized the importance of combination sequence and timing of drugs for the successful use of cancer immunotherapeutic agents. I also want to emphasize the Education Session that followed, titled, “The Future of Immunotherapy, New Drugs and New Ideas.” In that particular session, we heard about engineering T-cell immunity to eradicate tumors. We heard about CAR T-cell therapy in GI cancers, novel immunotherapeutic combinations, and T-cell engagers, which are bispecifics in cancer. While success with some of these immunotherapeutic modalities, such as cell therapies and T-cell engagers have been largely seen in hematological malignancies, we are beginning to observe efficacy signals in solid tumors. For example, the CAR T targeting Claudin18.2 in gastrointestinal cancers and the recently approved FDA-approved DLL3/CD3 bispecific T-cell engager, tarlatamab, in small cell lung cancer are really exciting examples. We also heard from investigators who are exploring neoadjuvant therapies in the neoadjuvant therapy session, and the key takeaway from that session is that we have growing interest in using neoadjuvant therapy or perioperative therapy. In other words, neoadjuvant plus adjuvant therapy in different cancers. In the neoadjuvant session, there were updates provided by different experts on the roles of neoadjuvant therapy in melanoma, liver cancer, bladder cancer, and nasopharyngeal cancer. Increasingly, there is randomized trial evidence to support the use of neoadjuvant therapy or perioperative immunotherapy in several cancer types with survival-based endpoints. Very exciting indeed. Dr. Melvin Chua: Indeed, I couldn't agree with you more. I think one of the things that went into designing the case-based discussions this year was that we wanted to talk about cancers that were relevant to this part of the world and hence we again showcased lung cancers, gastric cancers and melanomas, and whereby we have again perspectives from an expert from the West coupled to an expert from the East, thereby showcasing the diversity of practice around the world. The other thing that we did this year was we decided to pair the case-based discussions with the keynotes and the Education Sessions as well. For example, on Day 3, we had Dr. Sakaguchi speak on Tregs, as you mentioned. And this was followed by an in-depth session on new immunotherapies, and then followed by a case-based discussion on different melanoma cases on the role of neoadjuvant immunotherapy in this disease, and the strikingly relevance of response to prognostication. This is an important trait that we're seeing now that seems to pan out across different cancers, where we find that neoadjuvant response to combination systemic therapies and/or radiotherapy is a strong prognosticator. Dr. Lillian Siu: So, Dr. Chua, we've discussed some breakthrough treatments and promising advances in cancer care, and we've touched upon some barriers to success in cancer treatment. I would like to ask you about the keynote address by Dr. Raffaella Casolino of the World Health Organization, who spoke passionately about efforts by the WHO and its partners to build equity in cancer care. Can you share some highlights with us? Dr. Melvin Chua: Absolutely, Dr. Siu. In spite of the tremendous advances we've seen in recent years in oncology, there are still major disparities in cancer care, such as cost and access, which affect patients worldwide. I think Dr. Casolino's talk was a very nice overview whereby she showed, first of all, the WHO's impact in terms of the WHO Cancer Resolution initiative that was implemented in 2017, where through this initiative, WHO has impacted 100 countries, invested $1 billion in funds, and that has led to millions of lives saved. But she then really drilled down to some of the key examples of the focus of the WHO in terms of equalizing care in cancer. I think one which struck me was the appreciation of the disparities in the clinical trials landscape. I think it is clear that there's still a huge barrier to clinical trials between the high- and middle-income countries and the low- and middle-income countries, and the majority of clinical trials these days are industry sponsored and we really need to look at leveling the playing field in this regard. Then she highlighted the WHO's work on trying to lower the barriers to precision oncology. And I think there are several issues in that sense, but I think what the WHO has really worked hard on is promoting education for genomic medicine, where they've done several reviews with experts around the world to educate the field across the world on how we interpret and apply genomics in the clinic. So all in all, it was very interesting to hear Dr. Casolino's insights from a policy perspective, and again, this emphasizes that there's so much work to be done at the end of the day and the dialogue needs to continue. We also heard about policy, academic and industry perspectives in the context of clinical trials, and that led to a discussion on real-world evidence generation for regulatory approvals. It was very nice that we had a session on that at the end of Breakthrough 2024 (Real-World Evidence and Clinical Trials: Beyond the Ivory Tower). And in that session, we heard from Dr. Shaalan Beg [of the NIH], and Dr. Janet Dancey [of Queen's University] who represented views from academia and Dr. Hidetoshi Hayashi [of Kindai University Hospital] shared perspectives on decentralized trials. I'd like to encourage our listeners to watch these sessions if they were unable to attend. The content is very rich, and I'm sure they'll learn from it. Dr. Lillian Siu: Thank you so much, Dr. Chua. Is there anything else you would like to cover before we wrap up the podcast today? Dr. Melvin Chua: Thank you, Dr. Siu. The thing I really want to emphasize is, apart from all these Educational Sessions and having very eminent keynote speakers, one of the key points that we really want to bring out for Breakthrough is to showcase the high-quality research. This year we had 300 abstracts submitted and they were all high quality, cutting across trials, omics research, AI and technology, and eventually we selected 235 of them and we were able to showcase some of them across three oral sessions over three days. I think this is an important component of Breakthrough that we really wish to continue building upon where people are now excited to use this forum to present their work. Dr. Lillian Siu: Thank you so much, Dr. Chua. I really enjoyed our discussions today. I look forward to seeing how the Breakthrough meeting will continue to grow in future years. Dr. Melvin Chua: Thank you again, Dr. Siu. Thank you for all your leadership and efforts in making Breakthrough a successful meeting series the past few years. Dr. Lillian Siu: Thank you to our listeners for your time today. You'll find links to the session discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:   Dr. Lilian Siu  @lillian_siu  Dr. Melvin Chua  @DrMLChua    Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Lillian Siu:  Leadership (Immediate family member): Treadwell Therapeutics  Stock and Other Ownership Interests (Immediate family member): Agios    Consulting or Advisory Role: Merck, AstraZeneca/MedImmune, Roche, Voronoi Inc., Oncorus, GSK, Seattle Genetics, Arvinas, Navire, Janpix, Relay Therapeutics, Daiichi Sankyo/UCB Japan, Janssen, Research Funding (Institution): Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Bayer, Amgen, Astellas Pharma, Shattuck Labs, Symphogen, Avid, Mirati Therapeutics, Karyopharm Therapeutics, Amgen   Dr. Melvin Chua:  Leadership, Stock and Other Ownership Interests: Digital Life Line  Honoraria: Janssen Oncology, Varian  Consulting or Advisory Role: Janssen Oncology, Merck Sharp & Dohme, ImmunoSCAPE, Telix Pharmaceuticals, IQVIA, BeiGene  Speakers' Bureau: AstraZeneca, Bayer, Pfizer, Janssen   Research Funding: PVmed, Decipher Biosciences, EVYD Technology, MVision, BeiGene, EVYD Technology, MVision, BeiGene  Patents, Royalties, Other Intellectual Property: High Sensitivity Lateral Flow Immunoassay for Detection of Analyte in Samples (10202107837T), Singapore. (Danny Jian Hang Tng, Chua Lee Kiang Melvin, Zhang Yong, Jenny Low, Ooi Eng Eong, Soo Khee Chee)