Podcasts about Asco

Featuring perspectives from Dr Haley Ellis, Prof Eric Van Cutsem and Dr Zev Wainberg, moderated by Dr Lionel A Kankeu Fonkoua, including the following topics:  Introduction (0:00) Biliary Tract Cancers — Dr Ellis (1:56) Gastroesophageal Cancers — Dr Wainberg (24:27) Colorectal Cancer — Prof Van Cutsem (59:13) CME information and select publications

Dr Haley Ellis from Harvard Medical School in Boston, Massachusetts, Prof Eric Van Cutsem from University Hospitals Leuven in Belgium, Dr Zev Wainberg from UCLA School of Medicine in Los Angeles, California, and moderator Dr Lionel KankeuFonkoua from Mayo Clinic in Rochester, Minnesota, discuss recent data surrounding the management of HER2-positive GI cancers, alongside their perspectives on its clinical application and management.CME information and select publications here.

Listen to JCO's Art of Oncology article, "A Chance to Heal with Cold Hard Steel" by Dr. Taylor Goodstein, who is a fellow at Emory University. The article is followed by an interview with Goodstein and host Dr. Mikkael Sekeres. Dr. Goodstein shares a story about surgery, grief, and being courageous in the face of one's own fallibility. TRANSCRIPT Narrator: A Chance to Heal with Cold Hard Steel, Taylor Goodstein, MD Mikkael Sekeres: Welcome back to JCO's Cancer Stories: The Art of Oncology. This ASCO podcast features intimate narratives and perspectives from authors exploring their experiences in oncology. I am your host, Mikkael Sekeres. I am Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. Joining us today is Dr. Taylor Goodstein, urologic oncology fellow at Emory University and our first Narrative Medicine Contest winner, to discuss her Journal of Clinical Oncology article, "A Chance to Heal with Cold Hard Steel." Dr. Goodstein and I have agreed to address each other by first names. Taylor, thank you for contributing to the Journal of Clinical Oncology, to our contest, and for joining us to discuss your winning article. Taylor Goodstein: Thank you so much for having me. This is a great honor. Mikkael Sekeres: The honor was ours, actually. We had, if you haven't heard, a very competitive contest. We had a total of 159 entries. We went through a couple of iterations of evaluating every entry to make it to our top five, and then you were the winner. So thank you so much for contributing this outstanding essay both to our Art of Oncology Narrative Medicine Contest and also ultimately to JCO. Taylor Goodstein: Oh, thank you so much. Mikkael Sekeres: So, I was wondering if we could start by asking you to tell us something about yourself. Where are you from, and walk us through your career and how you made it to this point? Taylor Goodstein: Well, I grew up in a small town in Colorado - Glenwood Springs, Colorado. It is on the Western Slope, about 45 minutes north of Aspen. I went all the way to the east coast for college, where I ended up minoring in creative writing. So writing has been a part of my medical journey kind of throughout. I went to medical school back in Colorado at University of Colorado in Aurora, and then I did my residency training at he Ohio State University in Columbus, Ohio. And now I am at Emory University for fellowship. And I have been kind of writing all throughout, trying to make sense of the various journeys we go on throughout the experiences we have with going through our medical training. Mikkael Sekeres: That is amazing, and I noticed how you emphasized the "The" in Ohio State University. Taylor Goodstein: Yes, we fought hard for that "The." Mikkael Sekeres: Right, as do we at The University of Miami. Yes. What drew you to surgery, and specifically surgical oncology? Taylor Goodstein: My dad is a surgeon. My dad is an ear, nose, and throat doctor. And I am essentially him. We are the same person, and it made him very, very happy. So when I was looking at different medical specialties, I knew I was going to do a surgical subspecialty, and that is what I was drawn to. And then I was looking for the one that felt right, ended up finding urology, and then throughout my residency journey, I really gravitated towards cancer care. I really loved the patient population taking care of cancer patients, and surgically it felt like a way that I was going to be engaged and challenged throughout my career as there is so much that is always changing in oncology, almost too fast to keep up with all of it. But that is what really, ultimately, drew me to that career path. Mikkael Sekeres: It is great that you had a role model in your dad as well to bring you into this field. Taylor Goodstein: Well, he is very disappointed that I did urology rather than ENT, and he's in private and I am going into academics, so there is plenty of room for disappointment. Mikkael Sekeres: I am sure the last thing in the world he is is disappointed in you. And I will say, so I am able to see your background here, our listeners of course are listening to a podcast and they are not. You have a very impressive bookshelf with a lot of different types of books on it. Taylor Goodstein: This is your guys' background! This was the option of one of the backgrounds I could choose for coming onto this. I didn't want to do my real background because I have a cat who is wandering around and was going to be very distracting. Mikkael Sekeres: That's funny! Taylor Goodstein: But I did like the books. The books felt like a good option for me. I do have a big bookshelf; books are very important to me. I don't do anything on Kindle. I like the paper and stuff like that, so I do have a big bookshelf. Mikkael Sekeres: There is something rewarding in the tactile feel of actually turning a page of a book. You did writing from a very early stage as well. I was an English minor undergrad and then focused on creative writing as well and continued taking creative writing courses in medical school. Were you able to continue that during medical school and then in your training? Taylor Goodstein: Yeah, I thought that is what I was going to do when I first went to college. Like, I thought I was going to be a journalist or writer of some kind, and then I think maybe the crisis of job security hit me a little bit, and then also my desire to work with my hands and work with people. I wanted something to write about, something about my life that would be very interesting to write about, and that sort of led me initially to medicine. But then yes, to answer your question, I have been participating in a lot of writing competitions, like through the AUA, the American Urological Association, they do one every year that I have been doing in residency. And then in medical school we had some electives that involved writing and medical literature that we did. There was a collection of student writings, a book that got published during my last year of medical school that I had a couple of essays in. And the journey changes over time. When you are a medical student, you are on this grand journey and you are so excited to be there, but at the same time you feel so incredibly unprepared and useless in a lot of ways. You are just this medical student. The whole medical machinery is this well-oiled cog rotating together, and you are just this wild little- by yourself just trying to fit in. And that experience really resonated with me. And then residency has its own things that you are trying to make sense of. I think it all pales in comparison to what it is like to be a new surgeon for the first time, taking not necessarily your first big case but early in your career and having complications and making difficult decisions. I think is one of the hardest things that we probably have to deal with. Mikkael Sekeres: Well, you write about this in an absolutely riveting way. When you and your attending, you are a fellow on this case with your attending, realize that in the mess of this aggressive tumor that you are trying to resect, you have removed the patient's external iliac artery and vein, you write, and I am going to quote you now to you, which is always a little awkward, but I am going to do it anyway: "It is hard to explain what it feels like. Belly drops, hands shake, lungs slow down, and heart speeds up. It takes several seconds, marked out by the beeping metronome of the patient's own heartbeat, but eventually we return to our bodies, ready to face the error we cannot undo." As a reader, you are transported with you into that moment when, oh my God, you realize what did we do in this tremendous tumor resection you were undertaking? What was going through your mind at that moment? Taylor Goodstein: This is going to sound maybe a little bit funny, but I always think about this line from Frozen 2. I don't know if you have any kids or you have seen Frozen 2. Mikkael Sekeres: I have kids, and I have seen Frozen, but I have to admit I have not seen Frozen 2, and that is obviously lacking in my library of experiences. Taylor Goodstein: Frozen 2 is incredible, way better than Frozen 1. The adult themes in Frozen 2 go above and beyond anything in Frozen 1. But they are faced with some really big challenges and one of the themes that happens in that movie is all you can do is the next right thing. And it gets said several times. I remember connecting to that when I saw the movie, and I have said it to myself so many times in the OR since. You can't go backwards, you can't change what just happened. So all you can do is the next right thing. And so I think once the shock of what had happened kind of fades, all I am thinking in my head is like, "Okay, what is the next right thing to do here?" And obviously that was calling the vascular surgeon, and thankfully he was there and able to come in and do what needed to be done to restore flow to the patient's leg. Mikkael Sekeres: It is so interesting how we are able to compartmentalize in the moment our emotions. The way you write about this and the way you express yourself in this essay, you are horrified by what has happened. This is a terrible thing, yet you are able to separate yourself from that and move forward and just do the right thing for the patient at that time and get your patient out of this and yourself out of this situation. Taylor Goodstein: I think that is honestly, and maybe not for everybody, but for me that has been one of the challenges of becoming a surgeon is learning that level of emotional control, because all you want to do is cry and scream and pull your hair out and hit your fists against the table, but you can't do that. You have to remain in charge of that ship and keep things moving forward. And it is one of those hidden skills that you have to learn when you are going to be a surgeon that you don't get taught in medical school, and you kind of learn on the job in residency, but there is not as much explicit training that goes into that level of emotional control that you have to have. And I have kind of gone on my own self-journey to get there that has been very deliberate for me. Mikkael Sekeres: That is amazing. Do you think as we progress through our careers, and I don't want to use a term that is so dismissive, but maybe I will try it anyway, that we become more nonchalant about surgeries or writing for chemotherapy or radiation therapy to deal with cancer, or is that fear, that notion of "with great power comes great responsibility," to loosely quote Spider-Man, is that always there? Do we always pause before we start the surgery, write for the chemotherapy, or write for the radiation therapy and say, "Wait a second, what am I doing here?" Taylor Goodstein: I think it is always there, and I would argue that it even grows as you get farther along in your practice and you gain this collection of experiences that you have as a surgeon where you develop complications and from that you change your practice, you change the way you operate, the way you consider certain operative characteristics. I would argue that, as time goes on, you probably get more cautious approaching surgery for patients, more cautious considering the side effects of different treatment options that people have. Mikkael Sekeres: I think that is right. There is danger in reflecting on the anecdotes of your career experience to guide future treatments, but there is also some value to remembering those times when something went wrong or when it almost went wrong and why we have to check ourselves before doing what may become routine at one point in our careers, and that routineness may be doing a surgery or writing for chemotherapy, but always remembering that there is great danger in what we are about to embark on. Taylor Goodstein: Always, yeah. Mikkael Sekeres: Taylor, what makes this story really special and one of the reasons it won our Art of Oncology Narrative Medicine Contest is just how deep you plunged into reflecting on this surgery. And you write, I am going to quote you to you again, you reflect on how people may criticize you and your attending for embarking on this surgery, but you say: "They never met him, not like you did. They did not see him buckled over in pain, desperation in his eyes. They did not hand his wife tissues or look at photos of his pregnant daughter or hear about his dream of making it to Italy one day. They did not hug his family at the end of it all and cry together as he rattled out sharp breaths. And they certainly did not know how much it meant to get two months free of pain and just enough time to meet his granddaughter." There is a hard truth you write it just perfectly, there is a hard truth to why we don't always follow CMS guidelines for not offering treatment at the end of life, isn't there? Taylor Goodstein: Yeah, it is tough. And you know, I think a lot about this because I have heard a few times to be cautious of the armchair quarterbacks, specifically when you are talking about M&Ms. It is so easy to come in at the other side of a bad outcome and talk about how you shouldn't have done this, you shouldn't have done that. And to be fair, during the M&M in question, as I think back to it, the feedback for the most part was very constructive and ways to maybe be more prepared coming into a surgery like this. Like, there were questions about whether - here at Emory, we operate over various different hospitals - of whether the hospital, it should have been done at an even different hospital was like one of the questions, that maybe had more resources. So things like that, but it is hard I think when you get that question like, maybe you shouldn't have operated. And there is- I think one of the lessons I learned here is being unresectable doesn't mean you can't resect the tumor. We say the word 'unresectable', like we obviously we resected it, but what was the cost of that, obviously? Like we can resect a lot of things, but how much collateral gets damaged in the process of doing that? However, it is a very challenging question. I mean, this guy had one option really. I mean, chemo wasn't going to work, radiation wasn't going to work, and his goals were different than our goals are necessarily when we talk about cancer care. He wanted to be free of pain, he wanted to be able to go home. He was admitted to the hospital, he was on an IV, like Dilaudid, like he could not get off of a PCA because of how much pain he was in. And he just wanted to go home and be there for the birth of his granddaughter, and that is what we tried to do for him. In which case we were successful, but in everything else, we were not. Mikkael Sekeres: And you were successful. I could imagine that when people are in pain, their immediate goal of course is to get rid of the pain. Being in pain is an awful place to be. But with the impending birth of his granddaughter, I have to imagine you realign what your goals are, and that must have been primary for him, and you got him there. Taylor Goodstein: We did. I also talked a little bit about this later on, this idea of providing peace for families. I think that there is this sense of maybe peace and acceptance that comes from having tried to do the long shot surgery, that if you had never tried, if you come to them right away and you say, "Oh, this is- I can guarantee that this isn't ultimately going to end up well," there is still like that what's going to linger in the back of their mind if it never gets attempted versus, okay, we tried, it failed, and now we can come with this almost like satisfaction or comfort knowing that we did everything we could. So I guess I think a little bit about that as well. Mikkael Sekeres: Well, I think that is a beautiful place to end this as well. There are so many factors we have to consider when we embark on this cancer journey with our patients and when we make recommendations for treatment, and it sounds like, and it is so beautifully reflected in your essay that you thought extremely holistically about this patient and what his goals were and appreciated that those goals had to be severely modified once he had his cancer diagnosis. Taylor Goodstein: I think the most important sentence is, "I still don't know what the right answer is." And I think that is important for me to end on. Mikkael Sekeres: Well, and you are still in training. I think it is so important to acknowledge that. When you are training, it is important to acknowledge it when you are at my stage of my career as well. There are still encounters where I come out and I think to myself, I am just still not 100 percent sure what the right thing to do is. But often we let our patients guide us, and we let their goals guide us, and then we know that at least it is right for that person. Taylor Goodstein: Yeah, exactly. Mikkael Sekeres: Well, it has been such a pleasure to have Dr. Taylor Goodstein, who is a fellow at Emory University, to discuss her outstanding essay, "A Chance to Heal with Cold Hard Steel." Taylor, thank you so much for submitting your entry to our first Art of Oncology Narrative Medicine Contest, for winning it, and for joining us today. Taylor Goodstein: Thank you so much for having me. Mikkael Sekeres: If you have enjoyed this episode, consider sharing it with a friend or colleague, or leave us a review. Your feedback and support help us continue to have these important conversations. If you are looking for more episodes and context, follow our show on Apple, Spotify, or wherever you listen, and explore more from ASCO at asco.org/podcasts. Until next time, this has been Mikkael Sekeres for JCO Cancer Stories: The Art of Oncology. 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. Show Notes:   Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio: Dr Taylor Goodstein is a Fellow at Emory University.

Dr. Mary-Ellen Taplin joins the podcast to discuss the latest changes to the living guideline on metastatic castration-resistant prostate cancer (mCRPC). She reviews new treatment options for patients treated with ADT alone, ADT and an ARPI, ADT and docetaxel, and ADT, an ARPI, and docetaxel whose disease has progressed to mCRPC and the evidence that underpins these changes. Dr. Taplin highlights the updated algorithms within the guideline and the living format which will provide rapid, up-to-date, evidence-based information for clinicians and patients. Read the full living guideline update, "Systemic Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer: ASCO Living Guideline, Version 2026.1." at www.asco.org/genitourinary-cancer-guidelines TRANSCRIPT This guideline, clinical tools and resources are available at www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology,  https://ascopubs.org/doi/10.1200/JCO-25-02693 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Mary-Ellen Taplin from Dana-Farber Cancer Institute, lead author on "Systemic Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer: ASCO Living Guideline, Version 2026.1." Thank you for being here today, Dr. Taplin. Dr. Mary-Ellen Taplin: Thank you, Brittany. It is a pleasure. Brittany Harvey: Before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Taplin who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. To dive into the content here and what we are here today to talk about, this living clinical practice guideline for systemic therapy for patients with metastatic castration-resistant prostate cancer is updated on an ongoing basis. Dr. Taplin, what prompted this latest update to the recommendations? Dr. Mary-Ellen Taplin: Thank you, Brittany. Several things prompted the latest update. There have been several phase III trials that have been practice-changing that have resulted in the last several years that needed to be added to the guidelines to inform clinicians of comprehensive treatment options. Brittany Harvey: Great, and it is great to have this updated guideline for readers. I would like to review the changes to the recommendations in this latest iteration across the patient populations that are outlined in the guideline. So, starting with: What are the updated recommendations for patients previously treated with androgen deprivation therapy alone whose disease has progressed to metastatic castration-resistant prostate cancer? Dr. Mary-Ellen Taplin: A nice feature of this guideline is that in addition to the tables, which provide detailed options, is at the end of the guidelines, our readers will find very clear algorithms that describe past treatment scenarios that patients could have had and then outline their treatment options. So it is very clear. Our clinicians will love these algorithms. And one of the changes for the disease state that you mentioned, which is the least treated castration-resistant state of prostate cancer which is previously treated with ADT alone, is that we recommend testing for mutations in the HRR, homologous recombination repair, genes. And the ones that are specifically known and applicable to prostate cancer are the BRCA genes. So there is clear recommendation of testing to remind us, as treating physicians, that now is the time, if it hasn't been done before, to institute both germline and somatic testing. And somatic testing, if it can be done on tissue, is preferable, but if not, the liquid biopsy approaches, the ctDNA approaches, have now advanced to the point that most patients with metastatic prostate cancer will be able to successfully have testing on the liquid biopsies. So that is number one, testing. And then the new treatment options include, if a patient does have an HRR gene alteration, and maybe about 20-25 percent of patients will be in that category, the combinations of an androgen pathway inhibitor and a PARP inhibitor are now treatment options. So for instance, talazoparib and enzalutamide; olaparib and abiraterone; or niraparib and abiraterone are some of the newer treatment options if the patient is HRR-positive. So, Brittany, in regard to patients treated with ADT alone, another new treatment option is the combination of radium-223 with enzalutamide. This is data based on the PEACE-3 trial which did show both an rPFS and OS benefit. For the patient who is HRR-negative and has previously not had an ARPI, just ADT alone, the combination of radium and enzalutamide is a new recommendation added to the algorithm. Brittany Harvey: Great. Thank you for reviewing those options for that patient population. And as you mentioned, I think those algorithms are very helpful as figures in the document. They are clear and can be used as at-a-glance tools for clinicians in their busy clinics. So then the next patient population that the guideline addresses: What is new for patients previously treated with androgen deprivation therapy and an androgen receptor pathway inhibitor whose disease has now progressed to metastatic castration-resistant prostate cancer? Dr. Mary-Ellen Taplin: Right, so there are several new treatment options. So one is lutetium-PSMA-617, the trade name of which is Pluvicto. So that has now been FDA approved to use after progression on an AR pathway inhibitor and prior to the use of docetaxel chemotherapy. Brittany Harvey: Thank you for reviewing that new option for patients treated with androgen deprivation therapy and an ARPI whose disease has progressed. So then moving into the next set of recommendations, what does the panel now recommend for patients previously treated with androgen deprivation therapy and docetaxel whose disease has progressed to metastatic castration-resistant prostate cancer? Dr. Mary-Ellen Taplin: The next group of patients is those treated with ADT and docetaxel but haven't had an AR pathway inhibitor. Treatment options, again the HRR testing is important. So all patients with metastatic castration-resistant prostate cancer should be considered for both germline and somatic testing. I will repeat that. And if they are BRCA mutation positive, then the option of talazoparib and enzalutamide; olaparib and abiraterone; and niraparib and abiraterone.  So the AR pathway inhibitors plus the PARPs. There are three choices, so that can be somewhat complicated to think through, but most practitioners will get familiar with one of those combinations and be their go-to. So those are for BRCA-positive or HRR-positive. The talazoparib/enzalutamide trial also included non-BRCA HRR-positive gene mutations. And if they are HRR-negative, the option that we discussed above of radium and enzalutamide is new to the guideline. Brittany Harvey: Great. And then the last category of patients that is addressed in this update: What has changed for patients previously treated with androgen deprivation therapy, an androgen receptor pathway inhibitor, and docetaxel whose disease has now progressed to metastatic castration-resistant prostate cancer? Dr. Mary-Ellen Taplin: Well, in this space, patients who are heavily pretreated with ADT and ARPI, one or even two, and chemotherapy, generally with docetaxel, the recommendations are not new within the last year or two. And they include Pluvicto; a PARP inhibitor if HRR-positive and they have not had one; second-line chemotherapy such as cabazitaxel. And if they are a very rare group and they have been sequenced and they are MSI-high, then considering a PD-1 inhibitor such as pembrolizumab can be considered. I will note that this is a very small percentage of mCRPC patients, probably in the order of 5 percent or less. Brittany Harvey: Understood. And I appreciate you reviewing the recommendations across all of these patient populations. It sounds like some of the key points is that HRR testing is very important for this patient population, and that the algorithms and the tables in the manuscript provide the full list of options that clinicians and patients can refer to. Dr. Mary-Ellen Taplin: Those are the highlights. And I will note in the tables, all the sections have "Special Considerations" sections because patients never fall into the black and white of one category. And those practical information or special situations sections of each of the recommendations can also help clinicians think about the individual patient in front of them and how they might choose one therapy over another since there are generally choices in all of these treatment situations. Brittany Harvey: Absolutely. That information for the individualized patient-clinician decision-making is really key when, as you said, there is a list of options to choose from. So in your view, what should clinicians know as they implement this living guideline update, and how do these changes impact patients? Dr. Mary-Ellen Taplin: I am so excited about this living document. ASCO has invested to developing the software to, in real time and iteratively, assess the new data that is published in prostate cancer and other diseases. So now we don't have to wait many years for the next guideline to come out. The guidelines will be updated every six months in prostate cancer based on this automatic search of the literature and a standing panel of both academic and community experts in prostate cancer treatment. So we no longer have to wait. That is what makes this guideline stand out to other guidelines. And in the digestible format that we have made, a clinician can seek out the table and read some details, seek out practical information for the recommendations, or they can just go right to the clear figure algorithm and take a quick snapshot. "Yep, I need to do HR testing. Done. Oh, okay. HR-positive or negative, these are my options," and then think about the individual patient in front of them when there is more than one option. For instance, a patient with cardiovascular history, abiraterone might not be a good choice for them. Or a patient with neuropathy, docetaxel might not be a good choice for them. But, within this guideline, it really will be up to date and focused on the busy clinician and knowing what the options are for their patient. Brittany Harvey: Definitely. This new era of living guidelines is very exciting and can provide even more up-to-date, evidence-based recommendations to really support clinicians and patients with metastatic castration-resistant prostate cancer. So in that vein, finally, what is the panel examining, and what are you excited for for new data coming out for future updates to this living guideline? Dr. Mary-Ellen Taplin: The future updates will depend on the results of phase III clinical trials. You know, there are many phase III trials ongoing in advanced prostate cancer, some of which include targeted therapy, which has been long awaited in prostate cancer. So such compounds as antibody-drug conjugates that are targeting certain proteins in prostate cancer cells, such as STEAP1, KLK2, B7-H3. So I think we are entering a new era in prostate cancer where we will be targeting cells and delivering drugs and applying them to prostate cancer if the trials are positive. So I think with AI and a large investment in prostate cancer clinical drug development, I think the treatment options for our patients will be rapidly evolving in a manner not previously seen. So the guidelines need to follow along with these developments. Brittany Harvey: Definitely. It sounds like an exciting time for research in metastatic castration-resistant prostate cancer. And we will await the result of those phase III trials to inform this guideline and lead to future updates. So I want to thank you so much for your work to rapidly and continuously update these guidelines and for your time today, Dr. Taplin. Dr. Mary-Ellen Taplin: Oh, it was my pleasure. ASCO has been a leader in this area, and as a practicing clinician, we are thankful for the investment and guidance that ASCO gives us. Brittany Harvey: Absolutely. And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App, available in the  Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. 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.

We're kicking off 2026 with practice-changing data fresh from GI ASCO 2026. In this episode, we were joined once again by Dr. Rachna Shroff from the University of Arizona Cancer Center to break down the four most pivotal studies in upper GI and colorectal cancers presented at the GI ASCO 2026. We dived into the latest updates that will directly impact your clinical decisions, from new standards in perioperative therapy to revolutionary front-line regimens for metastatic disease. Key topics covered in this episode: ● MATTERHORN update: Surgical outcomes & FLOT modifications with Durvalumab in resectable gastric/GEJ cancer ● HERIZON-GEA-01: Zanidatamab + chemo + Tislelizumab the new frontline standard for HER2+ gastric cancer ● BREAKWATER: Confirming Encorafenib + Cetuximab + chemo (FOLFOX or FOLFIRI) for BRAF V600E mCRC ● COMMIT: Chemo + Atezolizumab vs. Atezolizumab alone in MSI-H/dMMR metastatic colorectal cancer Tune in for this dense, insightful recap and stay ahead of the curve. Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Don't forget to subscribe for more expert analysis on treatment algorithms and major conference highlights! #OncologyBrothers #GI26 #GastricCancer #ColorectalCancer #HER2 #BRAF #MSI #OncologyPodcast

In this episode of SurgOnc Today, we discuss the recently updated ASCO guidelines for axillary staging with sentinel lymph node biopsy in breast cancer, as well as considerations for their application in a multidisciplinary setting. This episode is moderated by Dr. Ashley Woodfin from the University of Wisconsin, who is joined by Dr. Clara Park from Brigham and Women's Hospital and Dr. Andrea Abbott from Medical University of South Carolina for a in-depth discussion regarding the guidelines implementation and important considerations.

Listen to JCO's Art of Oncology article, "The Quiet Work of Clarity" by Dr. Henry Bair, who is an ophthalmology resident physician at Wills Eye Hospital. The article is followed by an interview with Bair and host Dr. Mikkael Sekeres. Dr. Bair explores how vision care can honor end-of-life goals and helps a patient with failing sight write to his children. TRANSCRIPT Narrator: The Quiet Work of Clarity, Henry, Bair, MD  Mikkael Sekeres: Welcome back to JCO's Cancer Stories: The Art of Oncology. This ASCO podcast features intimate narratives and perspectives from authors exploring their experiences in oncology. I'm your host, Mikkael Sekeres. I'm professor of medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. What a pleasure it is to have joining us today Dr. Henry Bair, an ophthalmology resident physician at Wills Eye Hospital, to discuss his Journal of Clinical Oncology Art of Oncology article, "Quiet Work of Clarity". At the time of this recording, our guest has no disclosures. Dr. Bair and I have agreed to call each other by first names. Henry, thank you for contributing to the Journal of Clinical Oncology and for joining us to discuss your article. Henry Bair: Thank you very much for having me. Mikkael Sekeres: I love starting off by getting a little bit of background about our guests. I know a little bit about you, but I'm not sure all of our listeners do. Can you tell us about yourself and how you reached this stage of your training? Henry Bair: Sure thing. Happy to start there. I was born and raised in Taiwan. I came to the United States when I was 18 for college. I was at Rice University. I was drawn to it because the Texas Medical Center was right over there, but the university had a small liberal arts feel and the university did not box me into any specific discipline. I went there and we didn't have to declare anything and we could take any class from any school over there. And I actually fell in love with medieval studies of all things. I just came upon it in one of the survey courses and I went deeper and deeper and deeper and eventually wrote my thesis on medieval Irish manuscripts. That was really interesting. At the same time I was doing some clinical work and I realized that medicine might be a way to combine my interest in storytelling and the humanities with making a tangible difference in people's lives. Then I was in medical school at Stanford University, which was, in a similar way, I found a place that really let me explore what it meant to be a physician because the medical school let me take classes from all across the university: so the law school, the school of humanities, school of engineering, the business school. I got a chance to do a little bit of a lot of different things to try to figure out what I actually wanted to do with life. And I spent a lot of time actually doing a little bit of palliative care, a little bit of oncology, some medical education, some medical humanities. I had a lot of time thinking about, "Okay, what kind of specialty do I want to do?" I found myself really enjoying procedural specialties, but also really liking the kinds of patient interactions and conversations I had in palliative care and oncology, and eventually found ophthalmology, interestingly. I often have to remind myself or explain myself how those two connect. And to me, the way they connect is that ophthalmology lets me do very fascinating, intellectually challenging things in terms of working with my hands, very rewarding surgical procedural work. But at the same time, the conversations that I get to have with patients about seeing well, I saw so many parallels between that and living well. To me it was so much about quality of life. And that's how I knew that ophthalmology was the right move for me. And so now I'm an ophthalmology resident. Mikkael Sekeres: Fascinating. When I was an undergrad, the person who had the most influence on me was an English professor who was also a medievalist. There must be something about the personality and pouring over these old texts and trying to read things in Middle English that appeals to some character trait in those of us who eventually become physicians. I also remember when I was in medical school, we could also take classes throughout the university. So I wound up taking some writing classes with undergrads and with graduate students. It adds to this holistic education that we bring to medicine because it's not all about the science, is it? Henry Bair: Yeah, it's also different ways of thinking and seeing the world and just hearing people's different stories. It's the people I've met in a lot of those different settings outside of medical school that I think really enhanced my formative years in medical education. Mikkael Sekeres: You certainly bring it all together in this essay, which was just lovely. And I wonder if we could dive into some of the aspects of this essay. I'm dying to know, when you went to see this man, the main character of your essay, did you have any idea what the consult would be about? Henry Bair: No. So when we're in the hospital and as the ophthalmology resident on consult, we get notifications. These pop up whenever a primary team puts in a consult and it's usually fairly vague. It's usually no more than "blurry vision, please evaluate," "eye pain, please evaluate." As an ophthalmologist, getting a consult for blurry vision is kind of like a cardiologist getting consulted for chest pain. You're like, "Okay, but it could be something, it could be nothing, it could be something terrifying, it could be dry eyes, or it could be end-stage glaucoma, or it could be, who knows?" You really genuinely never know what you're getting yourself into until you actually go in there and talk to the patient, which can be frustrating, but also kind of an interesting experience. Mikkael Sekeres: I worry I'm guilty of submitting some of those consults to ophthalmology. Henry Bair: I didn't realize this fully until I started working on the ophthalmology side. I think non-ophthalmologists get so little exposure and training in ophthalmology. Of course, when I think about it, I didn't get any ophthalmology in medical school. So it's understandable. Mikkael Sekeres: In your essay, you write, and I'm going to quote you to you, "I am still learning what we can treat and what we can only tend. My training has taught me well how to assess visual acuity, intraocular pressures, and retinal nerve fiber layer thickness, but standing at his bedside, the index that mattered was none of these, but whether we could help him read for one more day." "What we can treat and what we can only tend." That's such a beautiful line. Is that something that only comes with years of experience, determining what we can treat and what we can only tend, or is it a dawning sense as we get to know our patients when we are trying to stop the inevitable from happening? Henry Bair: That is an interesting question because I think of it more almost as a fundamental shift in mindset. And I'm coming from someone who I think had the benefit of having had mentors, having had clinical experiences in palliative care in medical school. As I mentioned earlier, I was drawn to a lot of those patient conversations. So I think in some ways, starting in residency, I had long been primed to think about tending to a patient's concerns. And yet, even having been primed, even having the benefit of all those experiences and those conversations with amazing clinicians and with patients, maybe it's subject matter specific. I mean, ophthalmology tends to be a specialty, in my experience, my limited experience, ophthalmology tends to be one of those specialties that focuses so much on fixing things and treating things and reversing things. And in fact, that's one of the beautiful things of ophthalmology: how often you can reverse things or completely stop the progression of disease. And so I think in some ways, I am having to relearn what it means to see something not always as, "Okay, what's a problem here? What is the fix? How do I reverse this?" and go back and reach back to those experiences, those conversations I had with patients about trying to figure out, "Okay, the things that we can't fix, what can we still do?" To most people who have come across palliative care, this sentiment is by no means novel, the sentiment that there is always something we can do. You often hear about people talking about, "Oh, there's nothing more we can do." And I sort of try to bring that approach into the clinical encounters that I have. It's very reflexive to think that, "Okay, a person has lost vision from end-stage glaucoma or they have a blind painful eye. Well, there's nothing more we can do. You know, we've done all the conventional surgeries, we've done all the therapies, the medications," but I always have to pull myself back and say, "But there's always something we can do here." Mikkael Sekeres: It's so interesting how you frame that. We're problem solvers. We're trained to solve problems. A patient presents with X, a problem, we have to be clever enough to figure out how to solve it. I wonder if what you're saying indirectly is sometimes we're identifying the wrong problem. Henry Bair: I think so, yeah. Mikkael Sekeres: There may be a problem that we can't solve. Someone is actively dying from cancer. We can't solve the problem of curing them of their cancer. But there are other problems that we can potentially solve, and maybe that's where we have to be clever in identifying the problem. Henry Bair: I think so. And it's also what's in our textbooks and what's not. So we spend hundreds of hours in lecture and we pour over so many textbooks, and I do question banks now for board exams preparation. It's all on the textbook presentations, the textbook solutions. The problems are, you know, the retinal artery occlusions, it's about the really bad diabetic retinopathy. And then the answers to those things would be a stroke workup, would be some kind of injection into the eye. But like the problem that I encountered in this story that I talked about was this patient trying to write letters to his kids. That's not going to show up on any exam. We don't have lectures about talking about those things. Mikkael Sekeres: So, as I think you know, I wrote an essay in 2010 for Art of Oncology and for a book that I wrote about a woman who inspired me to go into oncology. She was a woman in her 40s who was a pediatric attending who had advanced ovarian cancer. The story I wrote about her was how she spent her final night on this earth in the intensive care unit writing cards for her children, too. It's fascinating how history repeats itself in how we care for people who have cancer. You have a really a beautiful way of saying this. You talk about, "an ordinary father sharing ordinary advice for an ordinary day. Illness had made that ordinariness remarkable. Our work that day was to protect the ordinary." Can you talk a little bit, I mean given the woman I wrote about and the man you wrote about, about this need to communicate with your family after you're gone? Henry Bair: To me, one of the biggest lessons I've learned working in healthcare is that what defines most of our lives, what defines the most meaningful, the most purposeful, the most rewarding aspects of our lives is our relationships. You can explore this from myriad perspectives. You can explore this from like a psychosocial perspective and look at all those studies showing that people who have better social connections and better ties with their families live longer lives and actually healthier lives, have decreased rates of mental health problems. Or we can just approach this from like a more humanistic perspective and explore it and think and listen in on the conversations people have with people around them, that patients have, the conversations patients have during the most difficult times of their lives. They don't talk about their work, they don't talk about their accomplishments, they talk about their relationships with their kids, with their spouses, with their parents. In my experience when people are at critical junctures of big life changes, whether it's people about to go into major surgery, people grappling with the idea of losing their vision or losing their lives, any sort of big pivotal change, they want to talk to their families and explore gratitude and regret and all these things. These are the themes that come up over and over and over again. In some ways it does not surprise me at all, this need to communicate with the family at the end of life. In some ways that's how you live on, that's how we feel, that's how patients feel their lives are defined by is that lasting relationship, that lasting impact at the end, or even transcending the end. Mikkael Sekeres: This is going beyond the end, isn't it? Henry Bair: Yeah. Mikkael Sekeres: These are letters and notes being written to children to be handed to them after death. And I think one of the reasons, in my case, the woman I encountered when I was in training who inspired me to go into oncology, I've been thinking about her for 25 years off and on. Both the incredible spirit to be able to do that on your last night on this earth, but also the flip side to it: there are potential downsides to doing this, aren't there? That, you know, I think about it from the perspective of her kids who at the time were 8 and 10 years old in my case. And I wonder what it was like for them to open up that birthday card when they were 17 or 18. And I wonder if you've kind of wondered the same about your patient and his children. Henry Bair: Yeah, I think when we think about these letter-writing projects, legacy-type projects, I hear about in hospitals around the country, there are teams that try to implement legacy-type things: whether it's doing video messages, whether it's stitching together short documentary film for patients who are in hospice. I feel like I see these things popping up a lot. You raise a very important point, and I actually didn't think about this until I was writing the essay. It's not an unambiguous good because it's the impact is variable, and it's really hard to predict that. How did you grapple with that in your essay? How did you make sense of it all at the end? Mikkael Sekeres: I don't think I did. I don't think I still have, which is why I think I still reflect back 25 years later on this episode and thinking about her children and how they're now, maybe they're still continuing to receive these cards from her and whether that's something they really appreciate and are like, "Boy, this is great, I get a little piece of mom still even now," or do they look at her unsteady hand as she's writing these cards and say, "That's not the mom I want to remember." Henry Bair: Yeah, that's a really good point. In the essay, I talk about that moment when the patient recognizes these are very imperfect letters, imperfectly written. We talked a little bit about that. And the patient makes a point, very wisely. I had suggested, "Oh, what if you want me to correct things?" And he's like, "No, no, no, the mistakes are part of it. It's part of the message. The message is that this was me at a difficult time in my life. I cannot control my hands the way that I used to, but that's still part of me. That makes it more genuine and authentic, mistakes and all built in." He wanted his children to see him for who he fully was in that moment. Mikkael Sekeres: And that was such a poignant part of your essay and probably the one that jumped out at me the most. Like as a dad, you want your kids to see you for who you are, right? You're not a superhero. In this case, this is somebody who was going to succumb to his illness, who did, but he was their dad and wanted them to remember him for all of who he was at that moment. Before I let you go, Henry, because I feel like we could probably talk for hours about this, before we started this podcast, I noticed you had better podcast equipment than I do, and sure enough, you copped to the fact that you do host your own podcast. You want to tell us a little bit about that? Because it touches on so many themes we touched on here in Cancer Stories. Henry Bair: Yeah, well thanks for asking me about that. Yeah, don't mind if I plug a little bit. Yes, so in medical school, this was 2021, around 2022, we were emerging from the COVID pandemic, and one of the things I was seeing around me as a medical student were physicians and nurses leaving the profession in droves. Like, there were so many reports and surveys coming out of the AMA discussing how more than half of all physicians are burned out, a third of physicians can't find meaning in their work anymore. And that was really scary. As a clinical trainee, what was I getting myself into? These weren't just some clinicians somewhere. These were often times- I was hearing these kinds of conversations about losing sight of why they even come in in the first place to work. I was hearing these conversations from professors that I thought were well-accomplished. These were people who had gone to the right residencies, the right fellowships. They had the right publications. These are people who I aspired to be, I suppose, and they were talking about leaving clinical practice. A wonderful mentor of mine who is an oncologist, still an oncologist at Stanford, we started talking about these things. And I asked him, "You seem to love your job." He was a GI oncologist dealing with very, very sick patients day in and day out. I've seen him in clinic. And I asked him, "What's your secret? What keeps you coming back over and over and over again?" And so that led to a conversation. And then we realized, "Wait a second, there are people, a third of physicians losing meaning in their work meant that two thirds of physicians have meaning in their work. Okay, let's talk about that." So we started exploring, we started just asking clinicians who have found true purpose in their work. And then we asked them to share their stories. And that's how the podcast was born. It's called The Doctor's Art, and at this point, we've expanded and we interview nurses and patients and caregivers. We interview philosophers and filmmakers, journalists. We interview ethicists and religious leaders, really anyone who might have some insight about what living well means either from the clinician perspective or from the patient perspective. And guess what? Everyone is going to be either a caregiver or a care recipient at some point in their lives. It's still ongoing and it's ended up being something where we explore very universal themes. Mikkael Sekeres: Well, it sounds great, Henry, and it sounds like a perfect complement to what we're doing here in Cancer Stories. It has been such a pleasure to have Dr. Henry Bair, who is an ophthalmology resident at Wills Eye Hospital, to discuss his essay, "The Quiet Work of Clarity". Henry, thank you so much for submitting your article to the Journal of Clinical Oncology and for joining us today. Henry Bair: Thank you very much, Mikail, for letting me share my insights and my story. It was a wonderful opportunity. Mikkael Sekeres: If you've enjoyed this episode, consider sharing it with a friend or colleague, or leave us a review. Your feedback and support helps us continue to have these important conversations. If you're looking for more episodes and content, follow our show on Apple, Spotify, or wherever you listen, and explore more from ASCO at asco.org/podcasts. Until next time, this has been Mikkael Sekeres for Cancer Stories. 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. Show notes:Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio: Dr Henry Bair is a ophthalmology resident physician at Wills Eye Hospital and podcast host of The Doctor's Art.

Dr. Hope Rugo and Dr. Vivek Subbiah discuss innovative trial designs to enable robust studies for smaller patient populations, as well as the promise of precision medicine, novel therapeutic approaches, and global partnerships to advance rare cancer research and improve patient outcomes. TRANSCRIPT  Dr. Hope Rugo: Hello and welcome to By the Book, a podcast series from ASCO that features engaging conversations between editors and authors of the ASCO Educational Book. I am your host, Dr. Hope Rugo. I am the director of the Women's Cancers Program and division chief of breast medical oncology at the City of Hope Cancer Center [in Los Angeles]. The field of rare cancer research is rapidly transforming thanks to progress in clinical trials and treatment strategies, as well as improvements in precision medicine and next-generation sequencing that enable biomarker identification. According to the National Cancer Institute, rare cancers occur in fewer than 150 cases per million each year, but collectively, they represent a significant portion of all cancer diagnoses. And we struggle with the appropriate treatment for these rare cancers in clinical practice. Today, I am delighted to be joined by Dr. Vivek Subbiah, a medical oncologist and the chief of early-phase drug development at the Sarah Cannon Research Institute in Nashville, Tennessee. Dr. Subbiah is the lead author of a paper in the ASCO Educational Book titled "Designing Clinical Trials for Patients with Rare Cancers: Connecting the Zebras," a great title for this topic. He will be telling us about innovative trial designs to enable robust studies for small patient populations, the promise of precision medicine, and novel therapeutic approaches to improve outcomes, and how we can leverage AI now to enroll more patients with rare cancers in clinical trials. Our full disclosures are available in the transcript of this episode.  Dr. Subbiah, it is great to have you on the podcast today. Thanks so much for being here. Dr. Vivek Subbiah: Thank you so much, Dr. Rugo, and it is an honor and pleasure being here. And thank you for doing this podcast for rare cancers. Dr. Hope Rugo: Absolutely. We are excited to talk to you. And congratulations on this fantastic paper. It is such a great resource for our community to better understand what is new in the field of rare cancer research. Of course, rare cancers are complex and multifaceted diseases. And this is a huge challenge for clinical oncologists. You know, our clinics, of course, cannot be designed as we are being very uni-cancer focused to just be for one cancer that is very rare. So, oncologists have to be a jack of all trades in this area. Your paper notes that there are approximately 200 distinct types of rare and ultra-rare cancers. And, by definition, all pediatric cancers are rare cancers. Of course, clinical trials are essential for developing new treatment strategies and improving patient outcomes, and in your paper, you highlight some unique challenges in conducting trials in this rare cancer space. Can you tell us about the challenges and how really innovative trial designs, I think a key issue, are being tailored to the specific needs of patients with rare cancer and, importantly, for these trials? Dr. Vivek Subbiah: Rare cancers present a perfect storm of challenges. First, the patient populations are very small, which makes it really hard to recruit enough participants for traditional type trials. Second, these patients are often geographically dispersed across multiple cities, across multiple states, across multiple countries, across multiple zip codes. So, logistics become complicated. Third, there is often limited awareness among clinicians, which delays referrals and diagnosis. Add to that regulatory hurdles, funding constraints, and you can see why rare cancer trials are so tough to execute. To overcome these barriers, we are seeing some really creative novel trial designs. And there are four different types of trial designs that are helping with enrolling patients with rare cancers. The first one is the basket trial. So let us talk about what basket studies are. Basket studies group patients based on shared genetic biomarkers or shared genetic mutations rather than tumor type. So instead of running separate 20 to 30 to 40 trials, you can study one therapy across multiple cancers. The second type of trial is the umbrella trial. The umbrella trials flip that concept of basket studies. They focus on one cancer type but test multiple targeted therapies within it. The third category of innovative trials are the platform studies. Platform trials are another exciting innovation. They allow new treatment arms to be added or removed as the data matures and as the data evolves, making trials more adaptive and efficient. The final category are decentralized tools in traditional trials, which are helping patients participate closer to where they are so that they can sleep in their own bed, which is, I think, a game changer for accessibility.  These designs maximize efficiency and feasibility for rare cancer research and rare cancer clinical trials. Dr. Hope Rugo: I love the idea of the platform trials that are decentralized. And I know that there is a trial being worked on with ARPA-H (Advanced Research Projects Agency for Health) funding in triple-negative breast cancer as well as in lung cancer, I think, and others with this idea of a platform trial. But it is challenged, I think, by precision medicine and next-generation sequencing where some patients do not have targetable markers, or there isn't a drug to target the marker. I think those are almost the same thing. We have really seen that these precision medicine ideas and NGS have moved the needle in helping to identify genetic alterations. This helps us to be more personalized. It actually helps with platform studies to customize trial enrollment. And we hope that this will result in better outcomes. It also allows us, I think, to study drugs even in the early stage setting more effectively. How can these advances be best applied to the future of rare cancers, as well as the challenges of not finding a marker or not having a drug? Dr. Vivek Subbiah: Thank you so much for that question. I think precision medicine and next-gen sequencing, or NGS, are truly the backbone of modern precision oncology. They have transformed how we think about cancer treatment. Instead of treating based on where the tumor originated or where the tumor started, we now look at the genetic blueprint of cancer. The NGS or next-gen sequencing allows us to sequence millions of DNA fragments quickly. Twenty, 30 years ago, they said we cannot sequence a human genome. Then it took almost a decade to sequence the first human genome. Right now, we have academic centers and commercial sequencing companies that are really democratizing NGS across all sites, not just in academic centers, across all the community sites, so that NGS is now accessible. This means that we can identify these actionable alterations like picking needles in haystacks, like NTRK fusions, RET fusions, or BRAF V600E alterations, high tumor mutational burden. This might occur across not one tumor type, across several different tumor types. So for rare cancers, this is critical because some of these mutations often define the best treatment option. Here is why this matters. Personalized therapy, right? Instead of a one-size-fits-all approach, we can tailor treatment to the patient's unique molecular profile. For trial enrollment, this can definitely help because patients can join biomarker-driven trials even if their cancer type is rare or ultra-rare. NGS technology has also helped us in designing rational studies. Many times monotherapy does not work in these cancers. So we are thinking about rational combination strategies. So NGS technology is helping us. Looking ahead, I see NGS becoming routine in clinical practice, not just at major niche academic centers, but everywhere. We will see more tumor-agnostic approvals, more molecular tumor boards guiding treatment decisions in real time. And I think we are seeing an expanded biomarker setup. Previously, we used to have only a few drugs and a handful of mutations. Now with homologous recombination defects, BRCA1/2 mutation, and expanding the HRD and also immunohistochemistry, we are expanding the biomarker portfolio. So again, I personally believe that the future is precision. What I mean by precision is delivering the right drug to the right patient at the right time. And for rare cancers, this isn't just progress. It is survival. And it is maybe the only way that they can have access to these cutting-edge precision medicines. Dr. Hope Rugo: That is so important. You mentioned an important area we will get to in a moment, the tumor-agnostic therapies. But as part of talking about that, do you think that the trials should also include just standard therapies? You know, who do you give an ADC to and when with these rare cancers? Because some of them do not have biomarkers to target and it is so disappointing for patients and providers where you are trying to screen a patient for a trial or a platform trial where you have one arm with this mutation, one arm with that, and they do not qualify because they only have a p53 loss, you know? They just do not have the marker that helps them. But we see this in breast cancer all the time. And it is tough because we don't have good information on the sequencing. So I wonder, you know, just because for some of these rare cancers it is not even clear what to use when with standard treatments. And then that kind of gets into this idea of the tumor-agnostic therapies that you mentioned. There are a lot of new treatments that are being evaluated. We have seen approval of some treatments in the last few years that are tumor-agnostic and based on a biomarker. Is that the best approach as we go forward for rare cancers? And what new treatment options are most exciting to you right now? Dr. Vivek Subbiah: Tumor-agnostic therapies, really close to my heart, are real breakthrough therapies and represent a major paradigm shift in oncology. Traditionally, for the broad listeners here, we are used to thinking about designing clinical trials and therapy like where the cancer originated, breast cancer, kidney cancer, prostate cancer, lung cancer. A tumor-agnostic therapy flips that model. Instead of focusing on the organ, they target the specific genetic alteration or biomarker that drives cancer growth regardless of where the tumor started, regardless of the location of the tumor, regardless of the zip code of the tumor. So why is this so important for rare cancers? Because many rare cancers share molecular features with more common cancers. For instance, NTRK fusion might occur in pediatric sarcoma, a salivary gland tumor, or a thyroid cancer. Historically, each of these would require separate trials, which is nearly impossible, unfeasible to conduct in these ultra-rare cancers like salivary gland cancer or pediatric sarcomas. Tumor-agnostic therapies allow us to treat all those cancers with the same targeted drug if they share that biomarker. Again, we are in 2025. The first tissue-agnostic approval, the historic precedent, was in fact an immunotherapy. Pembrolizumab was approved in 2017, May 2017, as the first immunotherapy to be approved in a tumor-agnostic way for a genomic biomarker, for MSI-High and dMMR cancers. Then came the NTRK inhibitors. So today we have not one, not two, but three different NTRK inhibitors: larotrectinib, entrectinib, and repotrectinib, which show response rates of nearly more than 60 to 75% across a handful of dozens and dozens of cancer types. Then, of course, we have RET inhibitors like selpercatinib, which is approved tissue-agnostic, and pralsetinib, which also shows tissue-agnostic activity across multiple cancers. And more recently, combination therapy with a BRAF and MEK combination, dabrafenib and trametinib, received tumor-agnostic approval for all BRAF V600E tumors with the exception of colorectal cancer. And even recently, you mentioned about antibody drug conjugates. Again, I think we live in an era of antibody drug conjugates. And Enhertu, trastuzumab deruxtecan, which was used first in breast cancer, now it is approved in a histology-agnostic manner for all HER2-positive tumors defined by immunohistochemistry 3+. So again, beyond NGS, now immunohistochemistry for HER2 is also becoming a biomarker. So again, for the broad listeners here, in addition to comprehensive NGS that may allow patients to find treatment options for these rare cancers for NTRK, RET, and BRAF, immunohistochemistry for HER2 positivity is also emerging as a biomarker given that we have a new FDA approval for this. So I would say personally that these therapies are game changers because they open doors for patients who previously had no options. Instead of waiting for years for a trial in their specific cancer type, they can access a treatment based on their molecular profile. I think it is precision medicine at its finest and best. Looking ahead, the third question you asked me is what is exciting going on? I think we will see more of these approvals. My hope is that today, I think we have nine to ten approvals. My hope is that within the next 25 to 50 years, we will have at least 50 to 100 drugs approved in this space based on a biomarker, not based on a location of the tumor type. Drug targeting rare alterations like FGFR2 fusions, FGFR amplifications, ALK fusions, and even complex signatures like high tumor mutational burden. I think we will be seeing hopefully more and more drugs approved. And as sequencing becomes routine, we will identify more patients for these therapies. I think for rare cancers, this is not just innovative approach. This is essential for them to access these novel precision medicines. Dr. Hope Rugo: Yeah, that is such a good point. I do think it is critical. Interestingly in breast cancer, it hasn't been, you know, there is always like two patients in these tumor-agnostic trials, or if that. You know, I think I have seen one NTRK fusion ever. I think that highlights the importance for rare cancers. And you know, I am hoping that that will translate into some new directions for some of our rarer and impossible-to-treat subtypes of breast cancer. It is this kind of research that is really going to make a difference. But what about those people who do not have biomarkers? What if you do not fit into that? Do you think there is a possibility of trying to do treatments for rare cancers in some prospective way that would help with that? You know, it is really a huge challenge. Dr. Vivek Subbiah: Absolutely. I think, you know, you're right, usually many of these rare cancers are driven by specific biomarkers. And again, some of the pediatric salivary gland tumors or pediatric sarcomas like fibrosarcomas, they are pathognomonic with NTRK fusions. And again, given that we have a tumor-agnostic approval, now these patients have access to these therapies. And I do not think that we would have had a trial just for pediatric fibrosarcomas with NTRK fusions. So that is one way. Another way is SWOG, right? The SWOG DART [1609] had this combination dual checkpoint, it was called the DART study dual combination chemotherapy with ipi/nivo. Now here the rare cancer subtype itself becomes a biomarker and they showed activity across multiple rare cancer subtypes. They didn't require a biomarker. As long as it was a rare or ultra-rare cancer, these patients were enrolled into the SWOG DART trial and multiple arms have read out. Angiosarcoma, Kaposi sarcoma, even gestational trophoblastic disease. Again, they have shown responses in these ultra-rare, rare cancers. Sometimes they might be seeing one or two cases a whole year. And I think this SWOG effort, this cooperative group effort, really highlighted the need for such studies without biomarkers as well. Dr. Hope Rugo: That is such a fantastic example of how to try and treat patients in a collaborative way. And in the paper, you also emphasize the need for collaborative research efforts, you know, uniting resource expertise across different ways of doing research. So cooperative groups, advocacy organizations that can really help advance rare cancer research, improve access to new therapies, and I think importantly influence policy changes. I think this already happened with the agnostic approvals. Could you tell us more about that? How can we move forward with this most effectively? Dr. Vivek Subbiah: Personally, I believe that collaboration is absolutely critical and essential for rare cancer research. No single institution, no single individual, or no single state or entity can tackle these challenges alone. The patient populations are small and dispersed. So pooling resources is the only way to run these meaningful trials. Again, it is not like singing, it is like putting a huge, huge, I would say, an opera piece together. It is not a solo, vocal therapy, but rather putting a huge opera piece like Turandot. You know, you mentioned cooperative groups. Cooperative groups, as I mentioned earlier, the SWOG DART program, the ASCO [TAPUR study]. ASCO is doing a phenomenal work of the TAPUR study. Again, this ASCO TAPUR program has enrolled so many patients with rare cancers who otherwise would not have treatment options. NCI-MATCH, the global effort, right? NCI-MATCH and the ComboMATCH are great examples. They bring together hundreds of sites, thousands of clinicians to run large-scale trials that would be impossible for any individual center or institution. These trials have already changed practice. For instance, the DART demonstrated the power of immunotherapy in rare cancers and influenced NCCN guidelines. One of the arms of the NCI-MATCH study from the BRAF V600E arm contributed towards the BRAF V600E tissue-agnostic approval. So, the BRAF V600E tissue-agnostic approval was by a pooled analysis of several studies. The ROAR study, the Rare Oncology Agnostic Research study, the NCI-MATCH dataset of tumor-agnostic cohort, and another pediatric trial, and also evidence from literature and evidence of case reports. And all this pooled analysis contributed to the tissue-agnostic approval of BRAF V600E across multiple rare cancers. There are several patient advocacy organizations which are the real unsung heroes here. Groups like, for instance, we mentioned in the paper, Target Cancer Foundation, don't just raise awareness for rare cancer research, they actively connect patients to trials providing financial, emotional support, and even run their own studies like the TRACK trial. They also influence policy to make access easier. On a global scale, initiatives like DRUP in the Netherlands, the ROME study in Italy, the PCM4EU in Europe are expanding precision medicine across these borders. These collaborations accelerate research, improve trial enrollment, and ensure patients everywhere can have access to these cutting-edge therapies. Again, it is truly a team effort, right? It is a multi-stakeholder approach. Researchers, clinicians, investigators, industry, regulators, academia, patients, patient advocates, and their caregivers all working together. And it takes a village. Dr. Hope Rugo: Absolutely. I mean, what a nice response to that. And I think really exciting and it is great to see your passion about this as well. But it helps all of us, I think, getting discouraged in treating these cancers to understand what is happening moving forward. And I think it is also a fabulous opportunity for our junior colleagues as they rise up in academics to be involved in these international collaborative efforts which are further expanding. One of the things that comes up for clinical trials for patients, and I think it is highlighted with rare cancers because, as you mentioned, people are all over the place, you know, they are so rare. They are all far away. Our patients are always saying to us, "Should I go here for a phase 1 trial?" Can you talk a little bit about how we can overcome these financial and geographic burdens for the patients? You talked about having trials locally, but it is a big financial and just social burden for patients. Dr. Vivek Subbiah: Great point. Financial cost is a major barrier in rare cancer clinical trials. It is a major barrier not just in rare cancer clinical trials, but in clinical trials in general. The economics of rare cancer research are one of the toughest challenges we face. Developing a new drug is already expensive, often billions of dollars. On an average, it takes 2 billion dollars or 2.8 billion dollars according to some data from drug discovery to approval. For rare cancers, the market is tiny, which means the pharmaceutical companies have really little financial incentive to invest. That is why initiatives like the Orphan Drug Act were created to provide tax credits, grants, and market exclusivity to encourage development for rare diseases. Clinical trials themselves are expensive because the small patient populations mean longer recruitment times and higher per-patient costs. Geographic dispersion, as you mentioned, for the patients adds travel, coordination. That is why we need to think out of the box about decentralized trial infrastructure so that we can mitigate some of these expenses. Complex trial designs like basket or platform trials sometimes require sophisticated data systems and regulatory oversight. That is a challenge. And I think some of the pragmatic studies like ASCO TAPUR have overcome those challenges. Advanced technologies like next-gen sequencing and molecular profiling also add significant upfront cost to this. Funding is also limited because rare cancers receive less attention compared to common cancers. Public funding and cooperative group trials help a lot, but I think they cannot cover everything. Patient advocacy organizations sometimes step in to bridge these gaps, but sustainable financing remains a huge challenge. So, the bottom line is without financial incentives and collaborating funding models, many promising therapies for rare cancers would never make it to patients. That is why we need system-wide policy changes, global partnerships, and innovative, effective, seamless trial designs which are so critical so that they can help reduce the cost and make research feasible so that we can deliver the right drug to the right patient at the right time. Dr. Hope Rugo: There is a lot of excitement about the future integration of AI in screening. Just at the San Antonio Breast Cancer meetings, we have a number of different presentations about AI to find markers, even like HER2, and using AI where you would screen and then match patients to clinical trials. Do you have any guidance for the rare cancer community on how to leverage this technology in order to optimize patient enrollment and, I think, identification of the best treatment matches? Dr. Vivek Subbiah: I think artificial intelligence, AI, is a game-changer in the making. Right now, clinical trial is clunky. Matching patients to trial is often manual, time consuming, laborious. You need a lot of personnel to do that. AI can automate this process by analyzing genomic data, medical records, and trial eligibility criteria to find the best matches quickly, accurately, and effectively. For the community, the key is to invest in data standardization and interoperability because AI needs clean, structured data to work effectively. Dr. Hope Rugo: Thank you so much, Dr. Subbiah, for sharing these fantastic insights with us on the podcast today and for your excellent article. Dr. Vivek Subbiah: Thank you so much. Dr. Hope Rugo: We thank you, our listeners, for joining us today. You will find a link to Dr. Subbiah's Educational Book article in the transcript of this episode. And please join us again next month on By the Book for more insightful views on key issues and innovations that are shaping modern oncology.  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. Hope Rugo   @hoperugo   Dr. Vivek Subbiah @VivekSubbiah Follow ASCO on social media:        ASCO on X  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. Vivek Subbiah: Consulting/Advisory Role: Loxo/Lilly, Illumina, AADI, Foundation Medicine, Relay Therapeutics, Pfizer, Roche, Bayer, Incyte, Novartis, Pheon Therapeutics, Abbvie Research Funding (Inst.): Novartis, GlaxoSmithKline, NanoCarrier, Northwest Biotherapeutics, Genentech/Roche, Berg Pharma, Bayer, Incyte, Fujifilm, PharmaMar, D3 Oncology Solutions, Pfizer, Amgen, Abbvie, Mutlivir, Blueprint Medicines, Loxo, Vegenics, Takeda, Alfasigma, Agensys, Idera, Boston Biomedical, Inhibrx, Exelixis, Amgen, Turningpoint Therapeutics, Relay Therapeutics Other Relationship: Medscape, Clinical Care Options

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Dr. Monty Pal and Dr. Hope Rugo discuss advances in antibody-drug conjugates for various breast cancer types as well as treatment strategies in the new era of oral SERDs for HR-positive breast cancer. TRANSCRIPT Dr. Monty Pal: Hello, and welcome to the ASCO Daily News Podcast. I'm your host, Dr. Monty Pal. I'm a medical oncologist and vice chair of academic affairs here at the City of Hope Comprehensive Cancer Center, Los Angeles. Today, I'm thrilled to be joined by Dr. Hope Rugo, an internationally renowned breast medical oncologist and my colleague here at City of Hope, where she leads the Women's Cancers Program and serves as division chief of breast medical oncology. Dr. Rugo is going to share with us exciting advances in antibody-drug conjugates (ADCs) that are expanding treatment options in various breast cancer types. She'll also address some of the complex questions arising in the new era of oral SERDs (selective estrogen receptor degraders) that are revolutionizing treatment in the hormone receptor-positive breast cancer space. Our full disclosures are available in the transcript of this episode.  Dr. Rugo, welcome, and thanks so much for being on the podcast today. Dr. Hope Rugo: Thank you. Pleasure to be here. Dr. Monty Pal: So, I'm going to switch to first names if you don't mind.  The first topic is actually a really exciting one, Hope, and this is antibody-drug conjugates. I don't know if I've ever shared this with you, but I actually started my training at UCLA, I was a med student and resident there, and it was in Dennis Slamon's lab. I worked very closely with Mark Pegram and a handful of others. This is right around the time I think a lot of HER2-directed therapies were really evolving initially in the clinics. Now we've got antibody-drug conjugates. Our audience is well-familiar with the mechanism there but tell us about how ADCs have really started to reshape therapy for HER2-positive breast cancer. Dr. Hope Rugo: Yeah, I mean, this is a really great place to start. I mean, we have had such major advances in breast cancer just this year, I think really changing the paradigm of treating patients. But HER2-positive disease, we've been used to having sequenced success of new agents. And I think the two biggest areas where we've made advances in HER2-positive disease, which were remarkably advanced this year in 2025, have been in antibody-drug conjugates with trastuzumab deruxtecan and with new oral tyrosine kinase inhibitors (TKIs) that have less of a target on EGFR and more on HER2, so they have an overall more tolerable toxicity profile and therefore a potentially better efficacy in the clinic. At least that's what we're seeing with these new strategies that we couldn't really pursue in the past because of toxicities of the oral TKIs. So, although our topic is ADCs, I'm going to include the TKI because it's so important in our thinking about treating HER2-positive disease. In the metastatic setting, we've seen these remarkable improvements in progression-free and overall survival in the second-line setting with T-DXd, or trastuzumab deruxtecan, compared to T-DM1. And then sequencing ADCs with giving T-DXd after T-DM1 was better than an oral tyrosine kinase or a trastuzumab combination with standard chemotherapy. That was DESTINY-Breast03 and DESTINY-Breast02. So, then we've had other trials since then, and T-DXd has moved into the early-stage setting, which I'll talk about in just a moment. But the next big trial for T-DXd in HER2-positive disease was moving it to the first-line setting to supplant what has become an established treatment for now quite a long time: the so-called CLEOPATRA regimen, which used the combined antibodies trastuzumab, pertuzumab with a taxane as first-line therapy. And then we've proceeded on with maintenance with ongoing HP for patients with responding or stable disease. And we'd seen long-term data showing, you know, at 8 years there was a group of patients whose cancers had never progressed and continued improved overall survival. So, T-DXd was studied in DESTINY-Breast09, either alone or in combination with pertuzumab compared to THP. The patient population had received a little bit more prior treatment, but interestingly, not a lot compared to CLEOPATRA. And they designed the trial to be T-DXd continued until progression with or without pertuzumab versus THP, which would go for six cycles and then stop around six cycles, and then stop and continue HP. Patients who had hormone receptor-positive disease could use hormone therapy, and this is one of the issues with this dataset because, surprisingly in this dataset and one other I'll mention, very few patients took hormone therapy. And even in the maintenance trial, the HER2CLIMB-05, less than 50% took hormone therapy as maintenance. This is kind of shocking to me and highlights an area of really important education, that outcome is improved when you add endocrine therapy for hormone receptor-positive HER2-positive metastatic disease in the maintenance phase, and it's a really important part of treatment. But suffice it to say, you know, you're kind of studying continued chemo versus stopping chemo in maintenance. And T-DXd, as we all expected, in combination with pertuzumab was superior to THP in terms of progression-free survival, really remarkably improved. And you could stop the chemo with toxicity, but most people continued it with T-DXd. Again, not a lot of people got hormone therapy, which is an issue, and you stop the chemo in the control arm. So, this has brought up a lot of interest in trying to use T-DXd as an induction and then go to maintenance, much as we do with the CLEOPATRA regimen with hormone therapy. But it brings up another issue. So first, T-DXd is superior; it's a great treatment. Not everybody needs to have it because we don't know whether it's better to give T-DXd first or second with progression - that we need a little bit longer follow-up. But just earlier this week, interestingly, the third week of December, the U.S. FDA approved T-DXd in the DESTINY-Breast09 approach with pertuzumab. So as I mentioned earlier, there was a T-DXd-alone arm; that arm has not yet reported. So very interesting, we don't know if you need pertuzumab or not. So what about the maintenance? That's the other area where we've made a huge advance here. So, we all want to stop chemo and we want to stop T-DXd. You don't want somebody being nauseated for two years while they're on treatment, and also there's a small number of patients with mostly de novo metastatic HER2-positive disease who are cured of their disease. We'd like to expand that, and I think these new drugs give us the opportunity to improve the number of patients who might be cured from metastatic disease. So the first maintenance study we saw was adding palbociclib, the CDK4/6 inhibitor, to endocrine therapy and HP, essentially. There, we had a remarkable improvement in progression-free survival difference of 15.2 months: 29 to 44 months, really huge. At San Antonio this year, we saw data with this oral tyrosine kinase inhibitor tucatinib, already showed it was great in a triplet, but as maintenance in combination with HP, it showed also a remarkable improvement in progression-free survival. But the numbers were all shifted down. So in PATINA, the control arm was in the 24-month range; here it was the tucatinib-HP arm that was in the 25 months and 16 months for control. So there was a differential benefit in ER-negative and ER-positive disease. So I think we're all thinking that our ideal approach moving forward would be to give T-DXd to most patients, we see how they do, and treat to best response. And then, stop the T-DXd, start HP, trastuzumab, pertuzumab for ER-negative, with tucatinib for ER-positive with palbociclib. We also have early data that suggests that both approaches may reduce the development of brain metastases, an issue in HER2-positive disease, and delay time to progression of brain metastases as seen in HER2CLIMB-05 in very early data - small numbers, but still quite intriguing that you might delay progression of brain metastases with tucatinib that clearly has efficacy in the brain.  So, I think that this is a hugely exciting advance for our patients, and these approaches are quickly moving into the early stage setting. T-DXd compared to standard chemo, essentially followed by THP, so a sequenced approach resulted in more pathologic complete responses than a standard THP-AC-type neoadjuvant therapy. T-DXd alone for eight cycles wasn't better, and that's interesting. We still need the sequenced non-cross-resistant chemo. But I think even more importantly, the data from DESTINY-Breast05 looking at T-DXd versus T-DM1 in patients with residual disease after neoadjuvant HER2-targeted therapy showed a remarkable improvement in invasive disease-free survival with T-DXd versus T-DM1, and quite early. It was a high-risk population, higher risk than the T-DM1 trial with KATHERINE, but earlier readout with a remarkable improvement in outcome. We expect to be FDA approved sometime in the first half of 2026. So then we'll get patients who've already had T-DXd who get metastatic disease. But my hope is that with T-DXd, maybe with tucatinib in the right group of patients or even sequenced in very high-risk disease, that we could cure many more patients with early-stage HER2-positive breast cancer and cure a subset, a greater subset of patients with de novo metastatic disease. Dr. Monty Pal: That's brilliant. And you tackled so many questions that I was going to follow up with there: brain metastases, etc. That was sort of looming in my mind. I mean, general thoughts on an ADC versus a TKI in the context of brain mets? Dr. Hope Rugo: Yeah, it's an interesting question because T-DXd has shown quite good efficacy in this setting. And tucatinib, of course, had a trial where they took patients with new brain mets, so a larger population than we've seen yet for the T-DXd trials, and saw that not only did they delay progression of brain metastases and result in shrinkage of existing untreated brain mets, but that patients who develop a new brain met, they could stay on the same assigned treatment. They got stereotactic radiation, and then the patients who were on tucatinib with trastuzumab and capecitabine had a further delay in progression of brain mets compared to those on the placebo arm, even after treatment of a new one that developed on treatment. So, I think it's hard. I think most of us for a lot of brain mets might start with the tucatinib approach, but T-DXd is also a very important treatment. You know, you're kind of trading off a diarrhea, some liver enzyme elevations with tucatinib versus nausea, which you really have to work on managing because it can be long-delayed nausea, and this risk of ILD, interstitial lung disease, that's about 12%, with most but not all trials showing a mortality rate from interstitial lung disease of just under 1 percent. In the early-stage setting, it was really interesting to see that with T-DXd getting four cycles in the neoadjuvant setting, a lot less ILD noted than the patients who got up to 14 cycles, as I think they got a median of 10 cycles in the post-surgical setting, there was a little bit more ILD. But I think we're going to be better and better at finding this earlier and preventing mortality by just stopping drug and treating earlier with steroids. Dr. Monty Pal: And this ILD issue, it always seems to resurface. There are drugs that I use in my kidney cancer clinic, everolimus, common to perhaps the breast cancer clinic as well, pembrolizumab, where I think the pattern of pneumonitis is quite different, right? What is your strategy for recognizing pneumonitis early in this context? Dr. Hope Rugo: Well, it is, and you know, having done the very early studies in everolimus where we gave it in the neoadjuvant setting and we're like, "Hmm, the patient came in with a cough. What's going on?" You know, we didn't know. And you have mouth sores, you know, we were learning about the drug as we were giving it. What we don't do with everolimus and CDK4/6 inhibitors, for example, is grade 1 changes like radiation pneumonitis, we don't stop, we don't treat it. We only treat for symptoms. But because of the mortality associated with T-DXd, albeit small, we stop drug for grade 1 imaging-only asymptomatic pneumonitis, and some of us treat with a half dose of steroids just to try and hasten recovery. We've actually now published or presented a couple of datasets from trials, a pooled analysis and a real-world analysis, that have looked at patients who were retreated after grade 1 pneumonitis or ILD and tolerated drug very well and none of them died of interstitial lung disease, which was really great to see because you can retreat safely and some of these patients stayed on for almost a year benefiting from treatment. So, there's a differential toxicity profile with these drugs and there are risk factors which clearly have identified those at higher risk: prior ILD, for example. A French group said smoking; other people haven't found that, maybe because they smoked more in France, I don't know. And being of Japanese descent is quite interesting. The studies just captured that you were treated in Japan, but I think it's probably being of Japanese descent with many drugs that increases your risk of ILD. And, you know, older patients, people who have hypoxia, those are the patients. So, how do we do this? With everolimus, we don't have specific monitoring. But for T-DXd we do; we do every nine weeks to start with and then every 12 weeks CT scans because most of the events occur relatively early. Somebody who's older and at higher risk now get the first CT at six weeks. Dr. Monty Pal: This is super helpful. And I have to tell you, a lot of these drugs are permeating the bladder cancer space which, you know, is ultimately going to be a component of my practice, so thank you for all this. We could probably stay on this topic of HER2-positive disease forever. I'm super interested in that space still. But let me shift gears a little bit and talk about triple-negative breast cancer and this evolving space of HR-positive, HER2-low breast cancer. I mean, tell us about ADCs in that very sort of other broad area. Dr. Hope Rugo: So triple-negative disease is the absolute hardest subset of disease that we have to treat because if you don't have a great response in the early stage setting, the median survival is very short, you know, under two years for the majority of TNBCs, with the exception of the small percentage of low proliferative disease subsets. The co-question is what do we do for these patients and how do we improve outcome? And sacituzumab govitecan has been one strategy in the later line setting that was shown to improve progression-free and overall survival, the Trop-2 ADC. We had recently three trials presented with the two ADCs, sacituzumab govitecan and the other Trop-2 ADC that's approved for HR-positive disease, datopotamab deruxtecan. And they were studied in the first-line setting. Two trials with SG, sacituzumab govitecan, those trials, one was PD-L1 positive, ASCENT-04. That showed that SG with a checkpoint inhibitor was superior, so pembrolizumab was superior to the standard KEYNOTE-355 type of treatment with either a taxane or gemcitabine and carboplatin with pembrolizumab for patients who have a combined positive score for PD-L1, 10 or greater. So, these are patients who are eligible for a checkpoint inhibitor, and SG resulted in an improved progression-free survival.  The interesting thing about that dataset is that few patients had received adjuvant or neoadjuvant checkpoint inhibitor, which is fascinating because we give it to everybody now. But access is an issue and timing of the study enrollment was an issue. The other thing which I think we've all really applauded Gilead for is that there was automatic crossover. So, you could get from the company, to try and overcome some of the enormous disparities worldwide in access to these life-saving drugs, you could get SG through the company for free once you had blinded independent central review confirmation of disease progression. Now, a lot of the people who got the SG got it through their insurance, they didn't bill the company, but 80 percent of patients in the control arm received SG in the second-line setting. So that impacts your ability to look at overall survival, but it's an incredibly important component of these trials. So then at ESMO, we saw the data from SG and Dato-DXd in the first-line metastatic setting for patients who either had PD-L1-negative disease or weren't eligible for an immunotherapy. For the Dato study, TROPION-Breast02, that was 10 percent of the patients who had PD-L1-positive disease but didn't get a checkpoint inhibitor, and for the ASCENT-03 trial population it was only 1 percent. Importantly, the trials allowed patients who relapsed within a year of receiving their treatment with curative intent, and the Dato study, TB-02, allowed patients who relapsed while on treatment or within the first six months, and that was 15 percent of the 20 percent of early relapsers. The ASCENT trial, ASCENT-03, had 20 percent who relapsed between 6 and 12 months. The drugs were better than standard of care chemotherapy, the ADCs in both trials, which is very nice. Different toxicity profiles, different dosing intervals, but better than standard of care chemotherapy in the disease that's hardest for us to treat. And importantly, when you looked at the subset of early relapsers, those patients also did better with the ADC versus chemotherapy, which is incredibly important. And we were really interested in that 15 percent of patients who had early relapse. I actually think that six months thing was totally contrived, invented, you know, categorization and doesn't make any sense, and we should drop it. But the early relapsers were 15 percent of TB-02 and Dato was superior to standard of care chemo. We like survival, but the ASCENT trial again allowed the crossover to an approved ADC that improved survival and 80 percent of patients crossed over. In the Dato trial, they did not allow crossover, they didn't provide Dato, which isn't approved for TNBC but is for HR-positive disease, and they didn't allow, of course, pay for SG. So very few patients actually crossed over in their post-treatment data and in that study, they were able to show a survival benefit. So actually, I think in the U.S. where we can use approved drugs already before there's a fixed FDA approval, that people are already switching to use SG or Dato in the first-line setting for metastatic TNBC that's both PD-L1 positive for SG and PD-L1 negative for both drugs. And I think understanding the toxicity profiles of the two drugs is really important as well as the dosing interval to try and figure out which drug to use. Dr. Monty Pal: Brilliant. Brilliant. Well, I'm going to shift gears a little bit. ADCs are a topic, again, just like HER2-positive disease we could stay on forever. Dr. Hope Rugo: Huge. Yes. Dr. Monty Pal: But we're going to shift gears to another massive topic, which is oral SERDs. In broad strokes, right, this utilization of CDK4/6 inhibitors in the context of HR-positive breast cancer is obviously, you know, a paradigm that's been well established at this point. Where do we sequence in oral SERDs? Where do they fit into this paradigm? Dr. Hope Rugo: Ha! This is a rapidly changing area; we keep changing what we're saying every other minute. And I think that there are three areas of great interest. So one is patients who develop ESR1 mutations that allow constitutive signaling through the estrogen receptor, even when there's not estrogen around, and that is a really important mutation that is subclonal; it develops under the pressure of treatment in about 40 percent of patients. And it doesn't happen when you first walk in the door. And what we've seen is that oral SERDs as single agents are better than standard single-agent endocrine therapy in that setting. The problem that we've had with that approach is that we're now really interested in giving targeted agents with our endocrine therapies, not just in the first-line setting where CDK4/6 inhibitors are our standard of care with survival benefit for ribociclib and, you know, survival benefit in subsets with other CDK4/6 inhibitors, and abemaciclib with a numeric improvement. So we give it first line. The question is, what do you do in the second-line setting? Because of the recent data, we now believe that oral SERDs should be really given with a targeted agent. And some datasets which were recently presented, which I think have helped us with that, have been EMBER-3 and then the most recently evERA BC, or evERA Breast Cancer, that looked at the oral SERD giredestrant with everolimus compared to standard of care endocrine therapy with everolimus, where 100 percent of patients received prior CDK4/6 inhibitor and showed a marked improvement in progression-free survival, including in the subsets of patients with a short response, 6-12 months of prior response to CDK4/6 inhibitor and in those who had a PIK3CA pathway mutation. The thing is that the benefit looks like it's much bigger in the ESR1 mutant population, although response was better, PFS wasn't better in the wild type. So, we're still trying to figure that out. We also saw EMBER-3 with imlunestrant and abemaciclib as a second line. Not everybody had had a prior CDK4/6 inhibitor; they compared it to imlunestrant alone, but still the data was quite striking and seemed to cross the need for ESR1 mutations. And then lastly, we saw data from the single arms of the ELEVATE trial looking at elacestrant with everolimus and abemaciclib and showed these really marked progression-free survival data, even though single-arm, that crossed the mutation status. At least for the everolimus combination, abemaciclib analysis is still to come in the mutated subgroups. But really remarkable PFS, much longer.  Single-agent fulvestrant after CDK4/6 inhibitor AI has a PFS in like the three-month range and in some studies, maybe close to five months. These are all at 10-plus months and really looking very good. And so those questions are, is it ESR1 mutation alone? Is it all comers? We'd like all comers, right? We believe in the combination approach and we're learning more about combinations with drugs like capivasertib and other drugs as we move forward. Everybody now wants to combine their targeted agent with an oral SERD because they're clearly here to stay with quite remarkable data. The other issue, so the second issue in the metastatic setting is, does it make a difference if we change to an oral SERD before radiographic imaging evidence of progression? And that was the question asked in the SERENA-6 trial where patients had serial monitoring for the presence of ESR1 mutations in ctDNA. And those who had them without progression on imaging could be randomized to switch to camizestrant with the same CDK4/6 inhibitor or stay on their same AI CDK4/6 inhibitor. And they showed a difference in progression-free survival that markedly favored camizestrant. But interestingly, the people who were on the standard control arm had an ESR1 mutation, we think AIs don't work, they stayed on for nine more months. The patients who were on the camizestrant stayed on for more than 16 months. And they presented some additional subset data which showed the same thing: follow-up PFS data, PFS2, all beneficial in SERENA-6 at the San Antonio [Breast Cancer Symposium]. So, we're still a little bit unclear about that. They did quality of life, and pain was markedly improved. They had a marked delayed time to progression of pain in the camizestrant arm. So this is all a work in progress, trying to understand who should we switch without progression to an oral SERD based on this development of this mutation that correlates with resistance. And, you know, it's interesting because the median time to having a mutation was 18 months and the median time to switch was almost 24 months. And then there were like more than 3,000 patients who hadn't gotten a mutation, hadn't switched, and were still okay. So screening everybody is the big question, and when you would start and who you would change on and how this affects outcome. Patients didn't have access to camizestrant in the control arm, something we can't fix but we have experimental drugs. We're actually planning a trial, I hope in collaboration with the French group Unicancer, and looking at this exact question. You know, if you switch and you change the CDK4/6 inhibitor and then you also allow crossover, what will we see? Dr. Monty Pal: We're coming right to the tail end of our time here, and I could probably go on for another couple of hours with you here. But if you could just give us maybe one or two big highlights from San Antonio, any thoughts to leave our audience with here based on this recent meeting? Dr. Hope Rugo: Yeah, I mean, I talked about a lot of those new data already from San Antonio, and the one that I'd really like to mention which I think was, you know, there were a lot of great presentations including personalized screening presented from the WISDOM trial by my colleague Laura Esserman, fascinating and really a big advance. But lidERA was the big highlight, I think, outside of the HER2CLIMB-05 which I talked about earlier in HER2-positive disease. And this study looked at giredestrant, the oral SERD versus standard of care endocrine therapy as treatment for medium and high-risk early-stage breast cancer. And what they showed, which I think was really remarkable with just about a three-year median follow-up, was an improvement in invasive disease-free survival with a hazard ratio of 0.7. I mean, really quite remarkable and so early. It looked as though this was all driven by the high-risk group, which makes sense, not the medium risk, it's too early. And also that there was a bigger benefit in patients who were on tamoxifen compared to giredestrant versus AI, but for both groups, the confidence intervals didn't cross 1. There's even a trend towards overall survival, even though it's way too early. I think that, you know, really well-tolerated oral drug that could improve outcome in early-stage disease, this is the first advance we've seen in over two decades in the treatment of early-stage hormone receptor-positive disease with just endocrine therapy. I think we think that we don't want to give up CDK4/6 inhibitors because we saw a survival benefit with abemaciclib and a trend with giving ribociclib in the NATALEE trial. So we're thinking that maybe one approach would be to give CDK4/6 inhibitors and then switch to an oral SERD or to have enough data to be able to give oral SERDs with these CDK4/6 inhibitors for early-stage disease. And that's all in the works, you know, lots of studies going on. We're going to see a lot of data with both switching 8,000 patients with an imlunestrant switching trial, an elacestrant trial going on, and safety data with giredestrant with abemaciclib and soon to come ribociclib. So, this is going to change everything for the treatment of early-stage breast cancer, and I hope cure more patients of the most common subset of the most common cancer diagnosed in women worldwide. Dr. Monty Pal: Super exciting. It's just remarkable to hear how this has evolved since 25 years ago, which is really the last time I sort of dabbled in breast cancer.  Thank you so much, Hope, for joining us today. These were fantastic insights. Appreciate you being on the ASCO Daily News Podcast and really want to thank you personally for your remarkable contribution to the field of breast cancer. Dr. Hope Rugo: Thank you very much, and thanks for talking with me today. Dr. Monty Pal: You got it. And thanks a lot to our listeners today as well. You'll find links to all the studies we discussed today in the transcript of this episode. Finally, if you value the insights that you hear today on the ASCO Daily News Podcast, please 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 opinion 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. Monty Pal @montypal Dr. Hope Rugo   @hoperugo Follow ASCO on social media:        ASCO on X  ASCO on Bluesky       ASCO on Facebook        ASCO on LinkedIn        Disclosures:     Dr. Monty Pal:    Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview   Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical   Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis   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. Lisa Hicks and Dr. Joseph Mikhael discuss the updated guideline from ASCO and Ontario Health (Cancer Care Ontario) on the treatment of multiple myeloma. They cover recommendations for therapeutic options across smoldering multiple myeloma, transplant eligible multiple myeloma, transplant ineligible multiple myeloma, and relapsed or refractory multiple myeloma. They highlight the importance of shared decision making and patient-centric care. They comment on the explosion of new treatment options in this space and the impetus for this guideline becoming a living guideline, which will be updated on an ongoing, regular basis. Read the full guideline, "Treatment of Multiple Myeloma: ASCO-Ontario Health (Cancer Care Ontario) Living Guideline" at www.asco.org/hematologic-malignancies-guidelines. TRANSCRIPT This guideline, clinical tools and resources are available at www.asco.org/hematologic-malignancies-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology,  https://ascopubs.org/doi/10.1200/JCO-25-02587   Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Lisa Hicks from St. Michael's Hospital and University of Toronto, and Dr. Joseph Mikhael from the Translational Genomics Research Institute, an affiliate of City of Hope Cancer Center, co-chairs on "Treatment of Multiple Myeloma: American Society of Clinical Oncology-Ontario Health (Cancer Care Ontario) Living Guideline." Thank you for being here today, Dr. Hicks and Dr. Mikhael. Dr. Lisa Hicks: Thanks so much. Dr. Joseph Mikhael: It is a pleasure to be with you, Brittany. Thank you. Brittany Harvey: Before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Hicks and Dr. Mikhael who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into what we are here today to talk about, Dr. Mikhael, I would like to start by recognizing that this guideline updates the 2019 ASCO-CCO Guideline on the Treatment of Multiple Myeloma. So what prompted this update and what is the scope of this updated guideline? Dr. Joseph Mikhael: It is amazing when we think back in myeloma years, 2019 actually seems a very, very long time ago because really so much has changed in myeloma over these last six to seven years. Indeed, there have been over 150 randomized controlled trials that we didn't have at the prior guideline that we reviewed for this. Myeloma is a disease that has really changed so dramatically over these last several years. Multiple new agents have been introduced. We now have CAR-T cell therapy, bispecific antibodies, and multiple other agents that were not available at the time. Furthermore, with this growing complexity, it is becoming more important than ever to be able to provide practical advice and guidelines to the oncology community. For most oncologists, they have less than 5% of their time dedicated to multiple myeloma. It is important to bring a clarity to them that allows them to care for their patients. And the scope of these guidelines, furthermore, really cover the whole spectrum of myeloma. They go further than our prior guideline where now we have included smoldering multiple myeloma along with frontline therapy and relapsed multiple myeloma. So, we have really tried to provide the full spectrum to our colleagues in oncology to ensure that they have the tools they need to provide the best care possible for their patients. Dr. Lisa Hicks: That is a really terrific summary. And maybe one thing I will just add is it is really unique to have this much literature. I can't think of another guideline that I have ever been involved with that has seen a field move so quickly and develop so many advancements in a period of just over four or five years. Brittany Harvey: Certainly, there is a large volume of evidence that you all had to review for this guideline update. I think to your point probably one of the greater volumes of literature for a guideline update that you both mentioned. Based on that, I would like to review the key recommendations that are updated in this guideline. So Dr. Hicks, that new patient population that Dr. Mikhael mentioned earlier, what are the key recommendations for patients with smoldering multiple myeloma? Dr. Lisa Hicks: So this is the first time that an ASCO guideline is addressing this branch of multiple myeloma care. It is an area where I think some guidance is needed, and smoldering myeloma is not an active cancer. And so one thing that I really want to highlight is that the panel felt very strongly that to recommend any therapy in this space we needed a higher level of evidentiary certainty, of evidentiary confidence, to make recommendations for active therapy. The panel really made two very important recommendations. First of all, the panel did not recommend treatment for low or intermediate risk smoldering myeloma. That is important. And then the area where I think for the first time we have recommended consideration of treatment is patients with high risk smoldering myeloma. And for patients with high risk smoldering myeloma, the panel recommended that it was appropriate to consider either treatment with daratumumab or careful observation. Dr. Joseph Mikhael: And I think that move forward as you have mentioned, Dr. Hicks, is particularly important because it is an area to some degree still of equipoise and many trials are going on in the area. But we do now have a strong phase III trial that supports the use of daratumumab monotherapy for three years when compared to close observation. But of course, that is not for everyone. And one of the key themes of all of our recommendations are going to be now that more and more choices are available, that we have discussions with our patients to ensure that we match the right treatment with the preference of the patient. And I think that is particularly important here in smoldering myeloma. Dr. Lisa Hicks: Multiple myeloma care and the multiple myeloma evidence is really so nuanced, and one of the nuances that readers will appreciate if they read the guideline is that how smoldering myeloma is risk stratified has been different across different trials. And that really adds to the complexity of this recommendation and is one of the reasons that the panel felt that it was appropriate to recommend either observation or treatment. Brittany Harvey: It is great to have these new recommendations for this unique patient population. And as you both mentioned, that individualized patient care is really important across this entire guideline. So then following those recommendations, Dr. Mikhael, what is recommended for initial therapy, autologous stem cell transplantation, post transplant therapy, and measurement of response for patients with transplant eligible multiple myeloma? Dr. Joseph Mikhael: Well, that is an area that has really considerably also grown since the last guideline. Obviously one would have to consult the guidelines to get every last detail, but in essence, we want to assess whether or not patients are transplant eligible or ineligible. And that assessment is not based on age or renal function alone, but indeed on a careful assessment of that patient. When that assessment is made and deemed that a patient is transplant eligible, our recommendation is that a patient typically would receive a quadruplet. That is to say, a monoclonal antibody directed against CD38, a proteasome inhibitor, an immunomodulatory drug, and dexamethasone to be given for approximately four to six cycles followed by the stem cell transplant, followed by potentially another two cycles of consolidation, and then maintenance therapy. A couple of important caveats. One, we do have two different CD38 antibodies that can be used, either daratumumab or isatuximab. Although typically bortezomib is the preferred proteasome inhibitor, consideration can be given to carfilzomib by virtue of the potential toxicity from bortezomib. And then lastly in the maintenance setting, we are typically recommending at least lenalidomide alone, but consideration can be given to dual maintenance therapy as the data is emerging to either add to that daratumumab or carfilzomib. All the while using the IMWG criteria for response. The goal of course is to achieve the deepest response possible and to maintain that response until such time as patients would relapse. Finally, the length of maintenance therapy continues to be an area of equipoise and study in multiple myeloma. And so at minimum, patients would receive two to three years of maintenance therapy, and based on risk status and depth of response it can be considered that patients would potentially come off maintenance therapy, of course always with the caveat that toxicity would influence length of therapy as well. Brittany Harvey: Yes, as you mentioned, evaluating which patients are eligible is extremely important for considering what is recommended in the guideline for both transplant eligible and transplant ineligible patients. So then Dr. Hicks, following those recommendations for transplant eligible multiple myeloma, what are the recommended treatments, goals of therapy, and measurement of response for patients with transplant ineligible multiple myeloma? Dr. Lisa Hicks: You know, I really can't emphasize enough how important an individualized patient assessment is. When we are thinking about the range of patients that are included in this category of transplant ineligible patients, it is a huge range. You may have fairly fit patients in their late 70s all the way to patients in their 90s. And we really want to see that treatments are tailored both to the fitness of the patient, their individual circumstances, and their preferences. And it is a wonderful thing to have lots of options for patients in this circumstance. What the guidelines have recommended for most patients who are transplant ineligible but fit enough for a stronger therapy is quadruplet therapy. So actually therapy that is very similar to what is being recommended in the transplant eligible population but for a longer period of time. And then for those patients who for whatever reason, be it their fitness or their preference, are not appropriate for that quadruplet therapy, the recommendation is for triplet therapy with a combination of lenalidomide, bortezomib, dexamethasone, or very often, more often in most cases, an antibody based approach with an anti-CD38 plus lenalidomide plus dexamethasone. Dr. Joseph Mikhael: The only thing I would add to that, I think we have to also, as we do mention in our recommendations, be particularly cautious with the dosing of these medications. Because even though we think of them as a single agent or a particular class, there can be quite a variation within the dosing regimen that can affect a patient's side effects and their quality of life. And so being very careful with dose modifications, and particularly in the transplant ineligible patient, is an important part of the recommendation as well. Dr. Lisa Hicks: Yeah, this is a podcast so no one can see me nodding vigorously that dose modification is so important particularly with those older and frailer patients, and with particular attention to trying to reduce dexamethasone doses and favoring weekly administration of bortezomib when that drug is used. Brittany Harvey: Absolutely. Considering the risks and benefits and patient preferences is really key to selecting therapy for these patients. So then Dr. Mikhael, for the final overarching patient population addressed in this guideline, for patients with relapsed or refractory multiple myeloma, what treatment options are recommended? Dr. Joseph Mikhael: This of course is, if you will, the biggest part of the guideline because there has been so much done in the relapse setting. And I think we start the guideline by saying a decision has to be made as to when to institute therapy. That there may be some patients with slow biochemical relapse that may be monitored for a period of time. But when the decision is made to initiate treatment, instead of a simple algorithm, the guideline emphasizes the fact that there are multiple choices that can be given to a patient that are going to match what comorbidities the patient has, what they have been treated with before, and of course what their preferences are. I think we highlight two particular areas. That now that CAR-T cell therapy is available as early as first relapse, it should be a consideration by virtue of the fact that it has resulted in such deep and durable responses. But that triplets should also be considered in that earlier relapse setting because we do have multiple classes of agents that can be used. We know that in later relapse options exist including bispecific antibodies for which we have four different choices. And that in general, patients will ultimately receive either a triplet or CAR-T cell therapy in earlier relapse, but there are some patients who may be eligible only for a doublet by virtue of their comorbidities and of their prior therapies. Lastly, it really does emphasize the point as we have mentioned a few times in this podcast, and I am so glad it keeps coming up, is that as I often say we don't treat myeloma, we treat people. And engaging the patient in that conversation to ensure that the right treatment gets matched to the right patients is particularly important because with all the new classes that we have with antibody drug conjugates, with XPO1 inhibitors, the traditional three classes of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, along with as we have already mentioned CAR-T and bispecific antibodies, it really is an incredible laundry list of choice. And making that choice specific to the patient becomes absolutely critical. I should also lastly note that there are patients who may defer their initial transplant. There may be patients who may be eligible for a second transplant. So autologous stem cell transplant, although primarily used in the frontline setting, may still be a consideration for a smaller subset of patients in the relapse setting. Dr. Lisa Hicks: I think maybe one thing that I would add is an overarching principle which is actually similar to a principle in the first guideline, and that is that in the relapsed or refractory setting, there are many different treatment options. And in fact, the number of treatment options feels like it is evolving every day. But an overarching principle for clinicians to consider is to try and choose combinations of drugs that the patient has either not been exposed to in the past or certainly that they are not refractory to. We really want to be pulling new options out of the toolbox as much as we can. Dr. Joseph Mikhael: Very often we do see where someone may be on a triplet and they are progressing on it and someone just changes out one drug. We have suggested not to take that approach but to take the approach of completely introducing a new therapy when someone is progressing on their current therapy. I think that point is particularly important and the consensus panel was very clear. Brittany Harvey: Understood. That is very helpful when thinking about what options to offer to patients in the relapsed and refractory setting. And as you mentioned earlier, the figures in this guideline provide an outline of options and then the tables really go into some of the details and outcomes of the trials, and those are very helpful for clinicians to refer to. So then Dr. Hicks, we have talked a little bit about some of the nuances of the guideline, but what should clinicians know as they implement these new and updated recommendations? Dr. Lisa Hicks: I think they should feel comfortable that these are trustworthy guidelines. So these are evidence-based guidelines that have been rigorously developed after a very thorough evidence review and put together by a panel of experts who were extremely thoughtful in their review of the evidence. And so all of this contributes to the trustworthiness of the guidance. And then I would also encourage people to take a deep look at the guidelines because of the importance of nuance that is addressed in them, and then to also explore some of the tools that ASCO is developing that helps with implementation including the flow charts that are contained within the guidelines and some additional tools that are available online. Brittany Harvey: Absolutely. The tools and resources for this guideline are available online with the publication and we will provide links to that in the show notes of the episode. So then following that, Dr. Mikhael, how does this guideline update affect patients with multiple myeloma? Dr. Joseph Mikhael: As we sort of intimated earlier, I like to say I don't treat myeloma, I treat people. I think we should always be patient-centric and patient-focused. And I think in the discussion we always were. We always wanted to ensure that multiple factors go into a decision-making process. We are not just looking at the biology of the disease, we are looking at patient factors. Those patient factors include their frailty as we commented in a frailty assessment, their preferences, their comorbidities. And I think, in a day where we have so many choices, we emphasize in the guideline the importance of that conversation with the patient. That, if you will, shared decision-making model where options are laid out and based on the patient factors and the treatment factors they can then be meshed together in the best way so that patients can make the right choice. And of course in conjunction with the guidelines, we have patient friendly summaries of them. And we involved, of course, patients in the development of these guidelines. And I think that is one of the greatest strengths of the ASCO guidelines is that there is a patient with us at the table who is giving their perspective on the guideline as we go forward. So I am very thankful that we have created a product that is, if you will, not only for the providers, the practitioners that are prescribing these agents and that are directly giving the care, but indeed for the very patients who of course have the most at stake here. Dr. Lisa Hicks: Yeah Joe, I am so glad you called out the participation of patient partners in the guideline. It is such an important part and they were really- the patient partner was such an important part of this panel in helping us understand the patient perspective as we developed this guidance. Brittany Harvey: Definitely. It is a hugely important role for the panel and for all of the panel including the patient partners and the experts in the disease to review the evidence and come up with comprehensive recommendations. And yes, as you mentioned, the individualized treatment and the shared decision-making is really paramount to this guideline. Finally, Dr. Hicks, you alluded to earlier the vast number of treatment options that is really exploding in multiple myeloma. And so this guideline is becoming a living guideline continuously updated by ASCO. So what are the outstanding questions regarding this topic and what evidence is the panel looking forward to for future updates? Dr. Lisa Hicks: I am really excited about this. This is one of the first guidelines that will be a living guideline for ASCO and it is such a good fit. You have heard Joe and I say a few times how quickly this field is moving, how complex the field is. I think everyone on the panel knew that no matter how quickly we did it and how deeply we reviewed the evidence, it was inevitable that more evidence would be generated as we were putting out the guideline. In a field like that, it is really important that we find a way to provide evidence-based guidelines quickly to the community. You know, waiting another five years, letting another 150 trials accrue before we do another guideline is not what the community needs. And so ASCO has really risen to this challenge and is committed to living guidelines. And so a living guideline is a guideline that commits to reviewing the evolving evidence on an ongoing basis, watching for practice changing trials, and having a standing panel that will review evidence and update recommendations on a regularly scheduled basis. So that is what a living guideline is, and that is what this guideline is becoming. That is just the first thing in terms of what a living guideline is. And then what are we watching? Well, honestly what aren't we watching? There is so much happening in multiple myeloma. We knew as we put the guideline out that there were trials in process, some trials that had been released at conferences but not yet published. We will be waiting for those and if they are practice changing they will be addressed in upcoming updates. There is new evidence just recently presented around combined anti-CD38 and bispecific antibodies. I don't know yet whether that will be addressed but I wouldn't be surprised if it was. There are so many things coming down the pipeline and it is just wonderful that there is going to be a way to try and address them in a robust fashion. Dr. Joseph Mikhael: Yeah I agree with you, Lisa. I can't think of another disease that would be more relevant for a living guideline. I mean we had difficulty because new data kept coming in as we were making recommendations. And so at some point we had to draw a line and say this is where we will stop and produce this guideline and have it ongoing. And I really look forward to seeing the updates because we know as you mentioned that there are so many things that are on the verge of approval and on the verge of changing the way we manage this terrible disease. And before I close, I would love to remind all of our listeners that as we commented from the start, patient engagement is critical at ASCO and in our guidelines process. Unfortunately we lost a very dear patient during the guidelines process, and that is Jack Aiello. Jack Aiello had been a patient and a patient advocate for many, many years in the myeloma community. And indeed we have actually dedicated these guidelines to his honor. And so I thought it would be valuable for us to mention that today. And we miss you Jack, but we are very grateful that we have been able to dedicate this excellent body of work to your memory. Brittany Harvey: Absolutely. This guideline and your dedication to him is an honor to his memory and we really recognize him in thinking about this guideline. We will look forward to those future trial results that you mentioned, Dr. Hicks, to update this guideline and continue to provide options for patients with multiple myeloma and improve upon those options and shared decision-making with patients. So I want to thank you both for all of your work to develop this guideline and for your time today, Dr. Hicks and Dr. Mikhael. Dr. Lisa Hicks: You are so welcome. Thanks for featuring this guideline. Dr. Joseph Mikhael: Thank you so much, Brittany. It has been a privilege. Brittany Harvey: Finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/hematologic-malignancies-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App, which is available in the  Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 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.  

"We proposed a concept to the American Society of Clinical Oncology (ASCO), recognizing that extravasation management requires significant interdisciplinary collaboration and rapid action. There can occasionally be uncertainty or lack of clear guidance when an extravasation event occurs, and our objective was to look at this evidence with the expert panel to create a resource to support oncology teams overall. We hope that the guideline can help mitigate harm and improve patient outcomes," Caroline Clark, MSN, APRN, AGCNS-BC, OCN®, EBP-C, director of guidelines and quality at ONS, told Chelsea Backler, MSN, APRN, AGCNS-BC, AOCNS®, VA-BC, oncology clinical specialist at ONS, during a conversation about the ONS/ASCO Guideline on the Management of Antineoplastic Extravasation. Music Credit: "Fireflies and Stardust" by Kevin MacLeod Licensed under Creative Commons by Attribution 3.0  Earn 0.5 contact hours of nursing continuing professional development (NCPD) by listening to the full recording and completing an evaluation at courses.ons.org by January 2, 2027. The planners and faculty for this episode have no relevant financial relationships with ineligible companies to disclose. ONS is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation. Learning outcome: Learners will report an increase in knowledge related to the management of antineoplastic extravasation. Episode Notes  Complete this evaluation for free NCPD. ONS/ASCO Guideline on the Management of Antineoplastic Extravasation ONS Podcast™ episodes: Episode 391: Pharmacology 101: Antibody–Drug Conjugates Episode 335: Ultrasound-Guided IV Placement in the Oncology Setting Episode 145: Administer Taxane Chemotherapies With Confidence Episode 127: Reduce and Manage Extravasations When Administering Cancer Treatments ONS Voice articles: Access Devices and Central Lines: New Evidence and Innovations Are Changing Practice, but Individual Patient Needs Always Come First New Extravasation Guidelines Provide Recommendations for Protecting Patients and Standardizing Care Standardizing Venous Access Assessment and Validating Safe Chemo Administration Drastically Lowers Rates of Adverse Venous Events This Organization's Program Trains Non-Oncology Nurses to Deliver Antineoplastic Agents Safely ONS books: Access Device Guidelines: Recommendations for Nursing Practice and Education (fourth edition) Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice (second edition) Clinical Guide to Antineoplastic Therapy: A Chemotherapy Handbook (fourth edition) ONS courses: Complications of Vascular Access Devices (VAD) and IV Therapy ONS Fundamentals of Chemotherapy and Immunotherapy Administration™ ONS Oncology Treatment Modalities Clinical Journal of Oncology Nursing articles: Chemotherapy Extravasation: Incidence of and Factors Associated With Events in a Community Cancer Center Standardized Venous Access Assessment and Safe Chemotherapy Administration to Reduce Adverse Venous Events Oncology Nursing Forum article: Management of Extravasation of Antineoplastic Agents in Patients Undergoing Treatment for Cancer: A Systematic Review ONS huddle cards: Antineoplastic Administration Chemotherapy Immunotherapy Implanted Venous Port ONS position statements: Administration (Infusion and Injection) of Antineoplastic Therapies in the Home Education of the Nurse Who Administers and Cares for the Individual Receiving Antineoplastic Therapies ONS Guidelines™ for Extravasation Management ONS Oncologic Emergencies Learning Library ONS/ASCO Algorithm on the Management of Antineoplastic Extravasation of Vesicant or Irritant With Vesicant Properties in Adults American Society of Clinical Oncology (ASCO) Podcast: Management of Antineoplastic Extravasation: ONS-ASCO Guideline To discuss the information in this episode with other oncology nurses, visit the ONS Communities.  To find resources for creating an ONS Podcast club in your chapter or nursing community, visit the ONS Podcast Library. To provide feedback or otherwise reach ONS about the podcast, email pubONSVoice@ons.org. Highlights From This Episode "The focus of this guideline was specifically on intravenous antineoplastic extravasation or when a vesicant or an irritant with vesicant properties leaks out of the vascular space. This can cause an injury to the patient that's influenced by several factors including the specific drug that was involved in the extravasation, whether it was DNA binding, how much extravasated, the affected area, and individual patient characteristics." TS 1:48 "The panel identified and ranked outcomes that mattered most with extravasation. Not surprising, one of the first was tissue necrosis. Like, 'How are we going to prevent tissue necrosis and preserve tissue?' The next were pain, quality of life, delays in cancer treatment: How is an extravasation going to delay cancer treatment that's vital to the patient? Is an extravasation also going to result in hospitalization or additional surgical interventions that would be burdensome to the patient? ... We had a systematic review team that then went in and summarized the data, and the panel applied the grading of recommendations, assessment, development, and evaluation (GRADE) criteria, grading quality of evidence and weighing factors like patient preferences, cost, and feasibility of an intervention. From there, they developed their recommendations." TS 7:35 "The panel, from the onset, wanted to make sure we had something visual for our readers to reference. They combined evidence from the systematic review, other scholarly sources, and their real-world clinical experience to make this one-page supplementary algorithm. They wanted it to be comprehensive and easy to follow, and they included not only those acute management steps but also guidance on 'How do I document this and what are the objective and subjective assessment factors to look at? What am I going to tell the patient?' In practice, for use of that, I would compare it to your current processes and identify any gaps to inform policies in your individual organizations." TS 16:34 "The guidelines don't take place of clinician expertise; they're not intended to cover every situation, but a situation that keeps coming up that we should talk about as a limitation, is we're seeing these case reports of tissue injury with antibody–drug conjugate extravasation. There's still not enough evidence to inform care around the use of antidotes with those agents, so this still needs to be addressed on a case-by-case basis. We still need publication of those case studies, what was done, and outcomes to help inform direction." TS 19:24 "Beyond the acute management is to ensure thorough documentation regarding extravasation. Whether you're on electronic documentation or on paper, are the prompts there for the nurse to capture all of the factors that should be captured regarding that extravasation? The size, the measurement, the patient's complaints. Is there redness? Things like that. And then within the teams, everyone should know where to find that initial extravasation assessment so that later on, if they're in a different clinic, they have something to go by to see how the extravasation is healing or progressing. ... I think there's an importance here, too, to our novice oncology nurses and their preceptors. This could be anxiety-provoking for the whole team and the patient, so we want to increase confidence in management. So, I think using these resources for onboarding novice oncology nurses is important." TS 22:34

Send us a textYou listened and you LOVED this episode, which is exactly why this is THE NUMBER ONE EPISODE of TheOncoPT Podcast for 2025!In case you missed it, the most important cancer rehab research since the PAL trial debuted at ASCO 2025.Today on the podcast, I'm joined by Scott Capozza, PT, who recently attended and presented at ASCO 2025. Scott breaks down what ASCO is, how it compares to APTA CSM, and why oncology rehab professionals need to be paying attention.We dive into some of the key themes from this year's conference, including the game-changing findings from the CHALLENGE trial and the growing emphasis on structured exercise as a critical part of cancer care. But more importantly, we talk about how OncoPTs are perfectly positioned to take this research and turn it into action.It's not just about being at the table. It's about putting research into practice, starting now—because our patients can't wait.Listen now!Follow TheOncoPT on Instagram.Follow TheOncoPT on LinkedIn.

Since the first immunotherapy agent for lung cancer was approved in 2015, this class of drugs has captured the imagination and the narrative for the treatment of driver negative lung cancer. Immunotherapy is now the standard of care for most patients with lung cancer in some form. And while not all patients benefit, those that do, have the chance for transformative benefit. In today's episode, we focus not on the benefit of immunotherapy, which can be massive, but on the toxicity of immunotherapy. Guest: Dr. Jarushka Naidoo, a consultant medical oncologist at Beaumont Hospital Dublin and a Professor in the Royal College of Surgeons in Ireland. She currently serves as national lung cancer lead for Cancer Trials Ireland and serves on several international guideline panels including ASCO and SITC

Listen to JCO's Art of Oncology article, "Final Silence" by Dr. Ju Won Kim, who is an Assistant Professor at Korea University College of Medicine, Medical Oncology. The article is followed by an interview with Kim and host Dr. Mikkael Sekeres. Dr Kim explores the burden of silence when caring for dying patients. TRANSCRIPT Narrator: Final Silence, by Ju Won Kim  Dr. Mikkael Sekeres: Welcome back to JCO's Cancer Stories: The Art of Oncology. This ASCO podcast features intimate narratives and perspectives from authors exploring their experiences in oncology. I'm your host, Mikkael Sekeres. I am a Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. We are so thrilled to have joining us today, Dr. Ju Won Kim. She is Assistant Professor at Korea University College of Medicine, and she is here to discuss her Journal of Clinical Oncology article, "Final Silence." Ju Won, thank you for contributing to the Journal of Clinical Oncology and for joining us today to discuss your article. Dr. Ju Won Kim: Hello, Mikkael. It's really nice to be here. Thanks so much for inviting me. Dr. Mikkael Sekeres: It's so nice to have you here today also. Thank you for also taking time so late in the evening because our time difference is so huge. Dr. Ju Won Kim: Yeah, it's not that late. It's 9 o'clock in Seoul. 9:00 PM. Dr. Mikkael Sekeres: I wonder if I could start by asking you if you can tell us about yourself. Could you walk us through your career so far? Dr. Ju Won Kim: Yes. I am Ju Won Kim from Korea University in Seoul. I was born and also raised here and never really left from Seoul. I did my residency in internal medicine and fellowship in oncology at the same hospital, and now I'm an assistant professor there. So you could say I've spent my whole life on the same campus, just moving from one side of the hallway to another. Dr. Mikkael Sekeres: That's a beautiful way of describing it. Is that common in Korea for somebody to remain at the same institution for training and then to continue through your career? Dr. Ju Won Kim: It used to be common about a decade ago, but nowadays it is not that common. Most of my colleagues are from another campus or another hospital. Dr. Mikkael Sekeres: Well, I'm so curious, what is a typical week like for you? How many days do you spend seeing patients and how much time do you spend doing research or writing or have other responsibilities? Dr. Ju Won Kim: Usually, I spend four times for my outpatient clinic, but in Korea, there are so many cancer patients and so little number of medical oncologists. I usually treat so many patients in one clinic, like maybe 20 to 30 in one time. Dr. Mikkael Sekeres: Wow. Dr. Ju Won Kim: Yeah, that's a burden. Most of the time I spend treating my patients, and rest of them I use to spend for my research with my lab students, and maybe with my colleagues, and I have to write something like documents or some kind of medical articles. That is about 10 or 20% of my working time, I think. Dr. Mikkael Sekeres: Okay, okay. That makes sense. So, and do you specialize within oncology, or do you see any person who has cancer? Dr. Ju Won Kim: I'm a medical oncologist, and I used to treat breast cancer or biliary pancreatic cancer or some kind of liver cancer or rare cancer, maybe, also. Dr. Mikkael Sekeres: Okay, okay. It's such a long trip. Are you able to make it to the ASCO Annual Meeting in Chicago? Dr. Ju Won Kim: Actually, I've been Chicago for ASCO meeting just one time in this year. Actually, I gave birth to my son in March, and I was in the long vacation for my birth, and the last part of my birth vacation, I went to Chicago to participate in ASCO. It was a really good time. Dr. Mikkael Sekeres: Oh, fantastic. That's great. How about your own story as a writer? How long have you been writing narrative pieces and when did you start? Dr. Ju Won Kim: Actually, I've always thought of myself more as a reader than a writer. Reading was my comfort zone from childhood. Then I started a small book club with friends about 10 years ago, and we began writing short reflections after each meeting. That's how writing slowly became part of my routine. When reading feels heavy, I write. When writing feels tiring, I read. It's a rhythm that keeps me balanced. At first, it was only academic writing like medical articles, but a few years ago, I challenged myself to post one short reflection a month on my Instagram, usually a quote from a book and a few sentences on why it mattered to me. It was my life about writing. Dr. Mikkael Sekeres: That is really remarkable. So, did you take any formal writing classes at university? Dr. Ju Won Kim: Not really. It was just a hobby of my own. Dr. Mikkael Sekeres: It always impresses me when people come into writing organically like this, where they just discover it and start and don't have formal teaching because your writing is very, very good. Dr. Ju Won Kim: Oh, thank you. Dr. Mikkael Sekeres: And how do you find the time to read and write when you have a busy career, academic career, and you have a child? Dr. Ju Won Kim: It was my old routine that I used to read it before going to bed, from my bedside with a small light, I used to read some novels and get to sleep easily. But after I started to work as a medical oncologist, it was a very busy job as you know. I used to sleep more and not have time for reading. I try to read more when I get some free time. Dr. Mikkael Sekeres: I love how you talk about alternating reading and writing and how when one gets too heavy, you go to the other, and then you switch back. One of the most common pieces of advice I've heard from writers is to read more. Dr. Ju Won Kim: Yeah. Dr. Mikkael Sekeres: You can see how other people put thoughts together and the cadence of their writing, and also it inspires your mind to develop new ideas for writing. Dr. Ju Won Kim: Actually, the new idea also comes from the book, I think, when I came into a new book and the idea bangs up with me, so I started to write and that's an easy way to have some idea about writing. Dr. Mikkael Sekeres: I'm always impressed by people who are facile with languages and bilingual or trilingual. I think I'm unfortunately a hopeless monoglot. Dr. Ju Won Kim: Maybe you can try Korean. Dr. Mikkael Sekeres: I'd be embarrassed to even attempt it. When you read, do you read in Korean or do you read in English or other languages? Dr. Ju Won Kim: Definitely in Korean. Dr. Mikkael Sekeres: Okay, okay. And when do you find the space to write? Do you need to be alone at home in a special room or at a special desk, or do you write at work, or do you just find any time to write? Dr. Ju Won Kim: I usually don't have much time on my own because I have my baby now and some family gathers frequently. So, I always write every free time I'm trying to, any short free time in my work maybe. Dr. Mikkael Sekeres: If you feel comfortable doing so - this is a very heavy piece, and a lot of us have dealt with deaths of our own patients, of course, we see this unfortunately commonly in oncology, but many of us, myself included, have also dealt with patients or their family members who've committed suicide - can you tell us what prompted you to write this piece? Dr. Ju Won Kim: As an oncologist treating biliary and pancreatic cancers, I've witnessed many deaths, as you know. Most fade with time because I treat so many patients, but just one family stayed with me, I think. It was early in my career, just months after I started this specialty, and even 5 years later, I still think about them, the family I wrote about in the "Final Silence." The story eventually became the piece I wrote. Dr. Mikkael Sekeres: And what is it about them that caused you to think about them so much even years later? Dr. Ju Won Kim: I'm not sure. That's the only experience I came into someone's suicide so closely in my life, I think, and also it happened in my very early career. That's the impact. Dr. Mikkael Sekeres: It is amazing how certain patients stick with us even years or decades later, particularly when they're tied to an emotional response to illness, and that can be our patients' emotional response or our own. Can you talk some about Korean culture and how cancer is viewed? Is it discussed openly? Dr. Ju Won Kim: In Korea, death is still a quiet topic. Cancer equals death in many people's minds, and death equals grief. Even today, some families ask doctors not to tell their patients about the diagnosis, but Korea is aging so fast, so I see more older patients now, but culturally, we are still learning how to talk about dying openly. That's the big problem as a medical oncologist, especially treating biliary and pancreatic cancers. Dr. Mikkael Sekeres: I can just imagine. When you first meet a patient and their family is in the room, do you tell them that they have cancer, or do you need to check in with the family and with the patient how much they know about their diagnosis first? Dr. Ju Won Kim: Actually, I usually try to tell them there is a cancer, which can never be treated perfectly, because I used to treat patients with stage four, which is incurable, but I'm not sure is it okay to tell them that your life is about 3 months or 6 months or 1 year. It is not that okay for the Korean patients, especially the first time when they meet me in the clinic. I try to tell them about the truth just a few times later. Dr. Mikkael Sekeres: I think that's common. I think we do that in the United States also. We may not mention a number to patients during that very first meeting because when you're talking to somebody and once you mention that number, often people will shut down. They won't hear anything else that you say. And you need to build up a relationship and some trust with somebody and also get the sense how much they want to know about their cancer and their prognosis before entering that conversation. I've certainly had instances when I'm in a room with a patient, and that patient's spouse or children, and someone else in the room will say, "How long does Dad have to live?" And I've turned to my patient, "Dad", and said, "Is this a number that you want to know?" And the patient has said, "No, I don't." Dr. Ju Won Kim: Yeah, that happens. Dr. Mikkael Sekeres: So sometimes we have to be careful and check in and remind ourselves in the high emotions around a cancer diagnosis that our first responsibility is always to our patient and what they want to know about their diagnosis and their prognosis. Dr. Ju Won Kim: Do you have any opposite cases where patients really want to know the numbers? Dr. Mikkael Sekeres: Yeah, I do. And, you know, you can almost predict who that's going to be depending on what they did during their lives. Dr. Ju Won Kim: Yes. Dr. Mikkael Sekeres: So I have patients who are engineers or who have a math-based career like they're accountants and they'll come in and they write every number down and they want to know the number about their prognosis. I have other patients who are English professors and they want descriptively to know what the prognosis is but maybe don't want a number. So... Dr. Ju Won Kim: I think most Koreans want the number, the specific number. Yeah. Dr. Mikkael Sekeres: I'm curious, is cancer in a father or a son dealt with differently than cancer in a mother or a daughter? Dr. Ju Won Kim: I don't think there's much difference between sons and daughters, or maybe moms and dad, because every child is very precious in Korea now, but between husband and wives, I think the dynamic stands out. People often say when a husband gets cancer, the wife becomes his main caregiver, but when the wife gets cancer, sometimes the husband disappears. I've heard that from my colleagues, though not often in my own clinic. Now, what I do see is many middle-aged women who have been diagnosed with breast cancer, women coming to treatment alone, strong and very independent. Dr. Mikkael Sekeres: Interesting. So I was going to follow up by asking if you've seen that in your own clinic. Have you seen- is it more likely that your female patients who have a cancer diagnosis come to clinic alone but the male patients come with their spouse and with family support? Dr. Ju Won Kim: Yeah, it is not just because of their sex, but most of the breast cancer patients who are female are in good condition, but biliary pancreatic cancer male patients have very poor condition, so... Dr. Mikkael Sekeres: Ah... Dr. Ju Won Kim: Maybe, I think that's the problem. Dr. Mikkael Sekeres: Interesting. The part of your essay in which you describe the attempted suicide of your patient's daughter is absolutely chilling. How did that affect you? Have you ever had a patient attempt suicide before? Dr. Ju Won Kim: Yes, the event I wrote in my essay was extremely shocking for me, but it's the only experience I have. It wasn't my patient, but I've heard a few cases where someone in the hospital tried to take their own life. I haven't had that happen directly, but I've seen patients fall into deep depression or break down in tears. In those moments, I always suggest psychiatry nowadays. That used to be taboo in here, but the stigma is fading, and many patients actually feel better afterwards. I also check in with close family members because their mental state affects the patients, too. It's something I hope never to experience again. Dr. Mikkael Sekeres: It's so unsettling when that happens, and as I mentioned, I've had a patient who took his own life, and you go back and back and back to it to wonder if there's something you could have done to intervene quicker or to get that psychosocial support in place to help that patient so that you avoid it in the future. And, you know, you protect your patients and yourself. Dr. Ju Won Kim: Yeah, I try to. Dr. Mikkael Sekeres: Speaking of protecting, you write, and I'm going to quote you to you, "I told myself I was protecting her, that to burden her in her final hours with such unthinkable news would be cruel. But a deeper truth is that I was protecting myself. I didn't know how to say it. I didn't know how to bear the weight of her devastation on top of my own shock and helplessness, so I avoided it." Do we owe it to ourselves sometimes to protect ourselves from the pain we sometimes impart to our patients? Dr. Ju Won Kim: That reflection came from realizing how doctors sometimes say we are protecting patients from pain, but really, we are protecting ourselves, I think. It's human. We can't hold every piece of suffering we see. Setting emotional boundaries isn't weakness. It's survival. What matters is recognizing when it's self-protection and being honest about it later. Dr. Mikkael Sekeres: Well, I think something that really helps with that is being able to talk to our colleagues about times when this happens and recognize we're in a shared experience and that we have the support of our colleagues, and they recognize how hard it is to be the bearer of bad news to other people and to bring pain to them sometimes. Dr. Ju Won Kim: That really works. Dr. Mikkael Sekeres: Dr. Ju Won Kim, it has been such a pleasure having you on this show. Dr. Kim has written just a fabulous essay called "Final Silence" for JCO Art of Oncology. Thank you so much for sharing your article with us and for joining us today. Dr. Ju Won Kim: Yeah, thank you so much for the conversation. It was a pleasure talking with you. Dr. Mikkael Sekeres: If you've enjoyed this episode, consider sharing it with a friend or a colleague or leave us a review. Your feedback and support helps us continue to have these important conversations. If you're looking for more episodes and context, follow our show on Apple, Spotify, or wherever you listen and explore more from ASCO at asco.org/podcasts. Until next time, this has been Mikkael Sekeres for Cancer Stories. 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. Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio:Dr Ju Won Kim is an Assistant Professor at Korea University College of Medicine, Medical Oncology.

JCO PO author Dr. Shilpa Gupta at Cleveland Clinic Children's Hospital shares insights into her article, "Fibroblast Growth Factor Receptor 3 (FGFR3) Alteration Status and Outcomes on Immune Checkpoint Inhibitors (ICPI) in Patients with Metastatic Urothelial Carcinoma". Host Dr. Rafeh Naqash and Dr. Gupta discuss how FGFR3 combined with TMB emerged as a biomarker that may be predictive for response to ICPI in mUC. 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 Associate Professor at the OU Health Stephenson Cancer Center. Today I am excited to be joined by Dr. Shilpa Gupta, Director of Genitourinary Medical Oncology at the Cancer Institute and co-leader of the GU Oncology Program at the Cleveland Clinic, and also lead author of the JCO PO article titled "Fibroblast Growth Factor Receptor 3 Alteration Status and Outcomes on Immune Checkpoint Inhibitors in Patients With Metastatic Urothelial Carcinoma." At the time of this recording, our guest's disclosures will be linked in the transcript. Shilpa, welcome again to the podcast. Thank you for joining us today. Dr. Shilpa Gupta: Thank you, Rafeh. Honor to be here with you again. Dr. Rafeh Naqash: It is nice to connect with you again after two years, approximately. I think we were in our infancy of our JCO PO podcast when we had you first time, and it has been an interesting journey since then. Dr. Shilpa Gupta: Absolutely. Dr. Rafeh Naqash: Well, excited to talk to you about this article that you published. Wanted to first understand what is the genomic landscape of urothelial cancer in general, and why should we be interested in FGFR3 alterations specifically? Dr. Shilpa Gupta: Bladder cancer or urothelial cancer is a very heterogeneous cancer. And while we find there is a lot of mutations can be there, you know, like BRCA1, 2, in HER2, in FGFR, we never really understood what is driving the cancer. Like a lot of old studies with targeted therapies did not really work. For example, we think VEGF can be upregulated, but VEGF inhibitors have not really shown definite promise so far. Now, FGFR3 receptor is the only therapeutic target so far that has an FDA approved therapy for treating metastatic urothelial cancer patients, and erdafitinib was approved in 2019 for patients whose tumors overexpressed FGFR3 mutations, alterations, or fusions. And in the landscape of bladder cancer, it is important because in patients with non-muscle invasive bladder cancer, about 70 to 80% patients can have this FGFR3. But as patients become metastatic, the alterations are seen in, you know, only about 10% of patients. So the clinical trials that got the erdafitinib approved actually used archival tumor from local cancer. So when in the real world, we don't see a lot of patients if we are trying to do metastatic lesion biopsies. And why it is important to know this is because that is the only targeted therapy available for our patients right now. Dr. Rafeh Naqash: Thank you for giving us that overview. Now, on the clinical side, there is obviously some interesting data for FGFR3 on the mutation side and the fusion side. In your clinical practice, do you tend to approach these patients differently when you have a mutation versus when you have a fusion? Dr. Shilpa Gupta: We can use the treatment regardless of that. Dr. Rafeh Naqash: I recently remember I had a patient with lung cancer, squamous lung cancer, who also had a synchronous bladder mass. And the first thought from multiple colleagues was that this is metastatic lung. And interestingly, the liquid biopsy ended up showing an FGFR3-TACC fusion, which we generally don't see in squamous lung cancers. And then eventually, I was able to convince our GU colleagues, urologists, to get a biopsy. They did a transurethral resection of this tumor, ended up being primary urothelial and synchronous lung, which again, going back to the FGFR3 story, I saw in your paper there is a mention of FGFR3-TACC fusions. Anything interesting that you find with these fusions as far as biology or tumor behavior is concerned? Dr. Shilpa Gupta: We found in our paper of all the patients that were sequenced that 20% had the pathognomonic FGFR3 alteration, and the most common were the S249C, and the FGFR3-TACC3 fusion was in 45 patients. And basically I will say that we didn't want to generate too much as to fusion or the differences in that. The key aspect of this paper was that historically there were these anecdotal reports saying that patients who have FGFR alterations or mutations, they may not respond well to checkpoint inhibitors because they have the luminal subtype. And these were backed by some preclinical data and small anecdotal reports. But since then, we have seen that, and that's why a lot of people would say that if somebody's tumor has FGFR3, don't give them immunotherapy, give them erdafitinib first, right? So then we had this Phase 3 trial called the THOR trial, which actually showed that giving erdafitinib before pembrolizumab was not better. That debunked that myth, and we are actually reiterating that because in our work we found that patients who had FGFR3 alterations or fusions, and if they also have TMB-high, they actually respond very well to single agent immunotherapy. And that is, I think, very important because it tells us that we are not really seeing that so-called potential of resistance to immunotherapy in these patients. So to answer your question, yeah, we did see those differences, but I wouldn't say that any one marker is more prominent. Dr. Rafeh Naqash: The analogy is kind of similar to what we see in lung cancer with these mutations called STK11/KEAP1, which are also present in some other tumors. And one of the questions that I don't think has been answered is when you have in lung cancer, if you extrapolate this, where doublet or single agent immunotherapy doesn't do as well in tumors that are STK11 mutated. But then if you have a high TMB, question is does that TMB supersede or trump the actual mutation? Could that be one reason why you see the TMB-high but FGFR3 altered tumors in your dataset responding or having better outcomes to immunotherapy where potentially there is just more neoantigens and that results in a more durable or perhaps better response to checkpoint therapy? Dr. Shilpa Gupta: It could be. But you know, the patients who have FGFR alterations are not that many, right? So we have already seen that just patients with TMB-high respond very well to immunotherapy. Our last podcast was actually on that, regardless of PD-L1 that was a better predictor of response to immunotherapy. So I think it's not clear if this is adding more chances of response or not, because either way they would respond. But what we didn't see, which was good, that if they had FGFR3, it's not really downplaying the fact that they have TMB-high and that patients are not responding to immunotherapy. So we saw that regardless, and that was very reassuring. Dr. Rafeh Naqash: So if tomorrow in your clinic you had an individual with an FGFR3 alteration but TMB-high, I guess one could be comfortable just going ahead with immunotherapy, which is what the THOR trial as you mentioned. Dr. Shilpa Gupta: Yes, absolutely. And you know, when you look at the toxicity profiles of pembrolizumab and erdafitinib, really patients really struggle with using the FGFR3 inhibitors. And of course, if they have to use it, we have to, and we reserve it for patients. But it's not an easy drug to tolerate. Currently the landscape is such that, you know, frontline therapy has now evolved with an ADC and immunotherapy combinations. So really if patients progress and have FGFR3 alterations, we are using erdafitinib. But let's say if there were a situation where a patient has had chemotherapy, no immunotherapy, and they have FGFR3 upregulation and TMB-high, yes, I would be comfortable with using only pembrolizumab. And that really ties well together what we saw in the THOR trial as well. Dr. Rafeh Naqash: Going to the clinical applications, you mentioned a little bit of this in the manuscript, is combination therapies. You alluded to it a second back. Everything tends to get combined with checkpoint therapy these days, as you've seen with the frontline urothelial, pembrolizumab with an ADC. What is the landscape like as far as some of these FGFR alterations are concerned? Is it reasonable to combine some of those drugs with immune checkpoint therapy? And what are some of the toxicity patterns that you've potentially seen in your experience? Dr. Shilpa Gupta: So there was indeed a trial called the NORSE trial. It was a randomized trial but not a comparative cohort, where they looked at FGFR altered patients. And when they combined erdafitinib plus cetrelimab, that did numerically the response rates were much higher than those who got just erdafitinib. So yeah, the combination is definitely doable. There is no overlapping toxicities. But unfortunately that combination has not really moved forward to a Phase 3 trial because it's so challenging to enroll patients with such kind of rare mutations on large trials, especially to do registration trials. And since then the frontline therapy has evolved to enfortumab vedotin and pembrolizumab. I know there is an early phase trial looking at a next generation FGFR inhibitor. There is a triplet combination looking in Phase 1 setting with a next generation FGFR inhibitor with EV-pembro. However, it's not a randomized trial. So you know, I worry about such kinds of combinations where we don't have a path for registration. And in the four patients that have been treated, four or five patients in the early phase as a part of basket trial, the toxicities were a lot, you know, when you combine the EV-pembro and an FGFR3 inhibitor, we see more and more toxicity. So the big question is do we really need the "kitchen sink" approach when we have a very good doublet, or unless the bar is so high with the doublet, like what are we trying to add at the expense of patient toxicity and quality of life is the big question in my mind. Dr. Rafeh Naqash: Going back to your manuscript specifically, there could be a composite biomarker. You point out like FGFR in addition to FGFR TMB ends up being predictive prognostic there. So that could potentially be used as an approach to stratify patients as far as treatment, whether it's a single agent versus combination. Maybe the TMB-low/FGFR3 mutated require a combination, but the TMB-high/FGFR mutated don't require a combination, right? Dr. Shilpa Gupta: No, that's a great point, yeah. Dr. Rafeh Naqash: But again, very interesting, intriguing concepts that you've alluded to and described in this manuscript. Now, a quick take on how things have changed in the bladder cancer space in the last two years. We did a podcast with you regarding some biomarkers as you mentioned two years back. So I really would like to spend the next minute to two to understand how have things changed in the bladder cancer space? What are some of the exciting things that were not there two years back that are in practice now? And how do you anticipate the next two years to be like? Maybe we'll have another podcast with you in another two years when the space will have changed even more. Dr. Shilpa Gupta: Certainly a lot has happened in the two years, you know. EV-pembro became the universal frontline standard, right? We have really moved away from cisplatin eligibility in metastatic setting because anybody would benefit from EV-pembro regardless of whether they are candidates for cisplatin or not, which historically was relevant. And just two days ago, we saw that EV-pembro has now been approved for localized bladder cancer for patients who are cisplatin ineligible or refusing. So, you know, this very effective regimen moving into earlier setting, we now have to really think of good treatment options in the metastatic setting, right? So I think that's where a lot of these novel combinations may come up. And what else we've seen is in a tumor agnostic trial called the DESTINY-PanTumor trial, patients who had HER2 3+ on immunohistochemistry, we saw the drug approval for T-DXd, and I think that has kind of reinvigorated the interest in HER2 in bladder cancer, because in the past targeting HER2 really didn't work. And we still don't know if HER2 is a driver or not. And at ESMO this year, we saw an excellent study coming out of China with DV which is targeting HER2, and toripalimab, which is a Chinese checkpoint inhibitor, showing pretty much similar results to what we saw with EV-pembro. Now, you know, not to do cross-trial comparisons, but that was really an amazing, amazing study. It was in the presidential session. And I think the big question is: does that really tell us that HER2-low patients will not benefit? Because that included 1+, 2+, 3+. So that part we really don't know, and I think we want to study from the EV-302 how the HER2 positive patients did with EV and pembro. So that's an additional option, at least in China, and hopefully if it gets approved here, there is a trial going on with DV and pembro. And lastly, we've seen a very promising biomarker, like ctDNA, for the first time in bladder cancer in the adjuvant setting guiding treatment with adjuvant atezolizumab. So patients who were ctDNA positive derived overall survival and recurrence-free survival benefit. So that could help us select moving forward with more studies. We can spare unnecessary checkpoint inhibitors in patients who are not going to benefit. So I think there is a lot happening in our field, and this will help do more studies because we already have the next generation FGFR inhibitors which don't have the toxicities that erdafitinib comes with. And combining those with these novel ADCs and checkpoint inhibitors, you know, using maybe TMB as a biomarker, because we really need to move away from PD-L1 in bladder cancer. It's shown no utility whatsoever, but TMB has. Dr. Rafeh Naqash: Well, thank you so much, Shilpa, for that tour de force of how things have changed in bladder cancer. There used to be a time when lung and melanoma used to lead this space in terms of the number of approvals, the biomarker development. It looks like bladder cancer is shifting the trend at this stage. So definitely exciting to see all the new changes that are coming up. I'd like to spend another minute and a half on your career. You've obviously been a leader and example for many people in the GU space and beyond. Could you, for the sake of our early career especially, the trainees and other listeners, describe how you focused on things that you're currently leading as a leader, and how you shaped your career trajectory over the last 10 years? Dr. Shilpa Gupta: That's a really important question, Rafeh, and you and I have had these discussions before, you know, being an IMG on visas like you, and being in different places. I think I try to make the most of it, you know, instead of focusing on the setbacks or the negative things. Like tried to grab the opportunities that came along. When I was at Moffitt, got to get involved with the Phase 1 trial of pembrolizumab in different tumor types. And just keeping my options open, you know, getting into the bladder cancer at that time when I wanted to really do only prostate, but it was a good idea for me to keep my options open and got all these opportunities that I made use of. I think an important thing is to, like you said, you know, have a focus. So I am trying to focus more on biomarkers that, you know, we know that 70% patients will respond to EV-pembro, right? But what about the remaining 30%? Like, so I'm really trying to understand what determines hyperprogressors with such effective regimens who we really struggle with in the clinic. They really don't do well with anything we give them after that. So we are doing some work with that and also trying to focus on PROs and kind of patient-reported outcomes. And a special interest that I've now developed and working on it is young-onset bladder cancer. You know, the colorectal cancer world has made a lot of progress and we are really far behind. And bladder cancer has historically been a disease of the elderly, which is not the case anymore. We are seeing patients in their 30s and 40s. So we launched this young-onset bladder cancer initiative at a Bladder Cancer Advocacy Network meeting and now looking at more deep dive and creating a working group around that. But yeah, you know, I would say that my philosophy has been to just take the best out of the situation I'm in, no matter where I am. And it has just helped shape my career where I am, despite everything. Dr. Rafeh Naqash: Well, thank you again. It is always a pleasure to learn from your experiences and things that you have helped lead. Appreciate all your insights, and thank you for publishing with JCO PO. Hopefully we will see more of your biomarker work being published and perhaps bring you for another podcast in a couple of years. Dr. Shilpa Gupta: Yeah, thank you, Rafeh, for the opportunity. And thanks to JCO PO for making these podcasts for our readers. So thanks a lot. Dr. Rafeh Naqash: 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. DISCLOSURES Dr. Shilpa Gupta Stock and Other Ownership Interests: Company: BioNTech SE,  Nektar Consulting or Advisory Role: Company: Gilead Sciences, Pfizer, Merck, Foundation Medicine, Bristol-Myers Squibb/Medarex, Natera, Astellas Pharma, AstraZeneca, Novartis, Johnson & Johnson/Janssen Research Funding: Recipient: Your Institution Company: Bristol Myers Squibb Foundation, Merck, Roche/Genentech, EMD Serono, Exelixis, Novartis, Tyra Biosciences, Pfizer, Convergent Therapeutics, Acrivon Therapeutics, Flare Therapeutics, Amgen Travel, Accommodations, Expenses: Company: Pfizer, Astellas Pharma, Merck    

In this special episode of Lung Cancer Considered, Dr. Narjust Florez and Dr. Stephen Liu discuss highlights from the IASLC | ASCO 2025 North America Conference on Lung Cancer. Dr. Igor Odintsov discusses updates in diagnostic pathology, including the integration of next-gen sequencing into the patient's journey. Dr. Byoung Chul Cho shares data from the phase 3 trial of gotistobart vs. docetaxel in patients with metastatic squamous cell lung cancer. Dr. Sulin Wu shares insights on the role of family history in lung cancer among women and low-exposure smokers.

Dr. Alison Loren and Dr. Ann Partridge share the latest guideline from ASCO on the management of cancer during pregnancy. They highlight the importance of this multidisciplinary, evidence-based guideline and overarching principles for the management of cancer during pregnancy. Drs. Loren and Partridge discuss key recommendations from each section of the guideline, including diagnostic evaluation, oncologic management, obstetrical management, and psychological and social support. They also touch on the importance of this guideline and accompanying tools for clinicians and how this serves as a framework for pregnant patients with cancer. The conversation wraps up with a discussion on the unanswered questions and how future evidence will inform guideline updates.  Read the full guideline, "Management of Cancer During Pregnancy: ASCO Guideline" at www.asco.org/survivorship-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-02115   Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Alison Loren from the Perelman School of Medicine of the University of Pennsylvania and Dr. Ann Partridge from Dana-Farber Cancer Institute, co-chairs on "Management of Cancer During Pregnancy: ASCO Guideline." Thank you for being here today, Dr. Loren and Dr. Partridge. Dr. Alison Loren: Thanks for having us. Dr. Ann Partridge: It's a pleasure. Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Partridge and Dr. Loren who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into the meat of this guideline, to start us off, Dr. Loren, could you provide an overview of the scope and purpose of this new guideline on the optimal management of cancer during pregnancy? Dr. Alison Loren: Sure, thanks, Brittany. So this was really born out of I think a lot of passion and concern for this really vulnerable patient population. We have observed, and I am sure it is not any surprise to your audience, that the incidence of cancer in young people is increasing. And simultaneously, people are choosing to become pregnant at older ages, and so we are seeing more and more people with a cancer diagnosis during their pregnancy. And for probably obvious reasons, there is really no way to do randomized clinical trials in this population. And so really trying to assemble and articulate the best evidence for safely managing the diagnosis of cancer, the management of cancer once it is confirmed, being thoughtful about obviously the health of the mom, but also attending to potential risks to the developing fetus, and really just trying to be really comprehensive and balanced about all the choices for these patients when they are facing some really challenging decisions in a very emotionally fraught environment. And I think it is really emotionally fraught for the providers, too. You know, this is obviously an extremely intense, very emotional set of decisions, and so trying to provide a rudder essentially to sort of help people frame the questions and trying to make as evidence-based a set of recommendations as possible. Dr. Ann Partridge: And I would just add that "evidence-based" is a strong word here because typically our, as you just heard, our gold standard evidence is a randomized trial, but you can't do that in this setting, in general. And so, what we were able to do with the support of the phenomenal ASCO staff was to pull together kind of the world's literature on the safety and outcomes of treatments during pregnancy, as well as consensus opinion. And I think that is a really, really critical difference about this particular guideline compared to many of the other ones that ASCO does, where consensus and good judgment needed to kind of rule the day when evidence is not available. So, there is a lot of that in our recommendations. Dr. Alison Loren: That is such a good point. And I just, before we move forward, I just want to reflect that the composition of the panel was really broad and wide-ranging. We had maternal medicine specialists, we had legal and ethical experts, we had representatives who understand pharmaceutical industries' perspectives, and then medical oncologists representing the full spectrum of oncology diagnoses. And so it was a really diverse, in terms of expertise, panel, internationally composed to try to really get the best consensus that we could in the absence of gold standard evidence. Brittany Harvey: Absolutely. That multidisciplinary panel is really key to developing this guideline and, as you said, looking at the evidence and even though it does not reach the level of randomized trials, still critically evaluating it and reviewing that along with consensus to come up with optimal management for diagnosis and management of cancer during pregnancy. So then to follow that up, I would like to next review the key recommendations of the guideline across the main sections that the expert panel provided. First, I will throw this out to either of you, but what are the important general principles for the management of cancer during pregnancy? Dr. Ann Partridge: I think there were three major principles that we hammer home in the guidelines. One is that this is a team sport. It is multidisciplinary care that is necessary in order to optimize outcomes for the patient and potentially for the fetus. And that you really need to, from the beginning, bring in a coordinated team, including not just oncologists but obstetricians, maternal-fetal medicine specialists, neonatologists, ethics consultants, and obviously the patient and potentially her family. So that, I think, is one of the most important things. Second would be that obviously in a pregnancy, there are two potential patients and that the nuances of safety and risk from treatment is really wrapped up in where in the trimester of the pregnancy the patient is diagnosed, along with the kind of cancer that it is, both the urgency of treatment and the risk of the cancer, as well as the potential risks of any given intervention across the cancer continuum. It is a broad guideline in that regard. And then finally, and this is particularly timely given what is going on from a sociopolitical standpoint in the U.S., really thinking about informed consent and potential ethical as well as legal implications of some of the choices that patients might have when they are thinking about, in particular, continuing a pregnancy or potential termination. Dr. Alison Loren: And I will just add that I think that the key to all of this guidance is nuance and individualization and also making sure that patients and their care providers understand all the choices that are available to them and also the consequences of those choices. You know, nobody would choose to receive chemotherapy during pregnancy if that wasn't necessary. So there are risks to treatment, but there are also risks to not treatment. And making sure that in a suboptimal situation where you do not have a lot of evidence, trying to weigh, the best you can, the risks and benefits of all of the choices so that the patient can come to a decision about the treatment plan that is right for her. Brittany Harvey: Definitely. And those core concepts really set the stage for individualized care on what is necessary for appropriate multidisciplinary care, prioritizing both patient autonomy and informed decision making. With those core concepts and key principles in mind, I would like to move into the recommendations section of the guideline. So what are the key recommendations regarding diagnostic evaluation for pregnant patients with signs or symptoms of cancer? Dr. Alison Loren: I think the most important thing is to not delay, that there are very careful and well-thought-out recommendations for how to evaluate a potential cancer. And while there are certain things that we know can be harmful, particularly when certain dose thresholds are exceeded - for instance, abdominal imaging, there are certain radiographic thresholds that you don't want to exceed because of risk of harm to the embryo or fetus - there are still lots of options for diagnosing cancer during pregnancy. And again, thinking about the costs of not doing versus the cost of doing, right? It is really important to make the diagnosis of cancer if that is a consideration or a concern. And sometimes going directly to biopsies or getting definitive studies, even if there is a small risk to the developing fetus, is really essential because if the mom does not survive, of course, the fetus is also not going to survive. And so we need to be thinking first about the patient who is sitting in front of us, the woman who needs to know what is going on in her body so she can make good decisions about her health. So, I think that is a key principle in thinking about this. Brittany Harvey: Absolutely. So, following that diagnosis of a new or recurrent cancer, what is recommended for oncologic management of patients who are diagnosed with cancer during their pregnancy? Dr. Ann Partridge: So, I think the general principle is, again, cancer is such a wide number of diseases and even within diseases, a range of stages and risks and associated opportunities for risk reduction and/or treatment depending on the type of cancer. Just by example, in the work that I do, which is breast cancer, once someone has had a surgery in the early-stage setting, a lot of our treatment is about risk reduction. And that is very different than from what Alison does, which is treating people with leukemia, where it is kind of binary. If you do not treat, including with cytotoxic drugs, the patient and an unborn fetus will die, especially early in the pregnancy, obviously. So this is where cancers are very, very different. So I think taking the approach of what would you do if the patient were not pregnant? And what is the best treatment for that particular patient with that particular kind of cancer? And then applying the pregnancy and where the patient is in that pregnancy in terms of the trimester of the pregnancy, and what is safe and what is unsafe from the options that you would give her if she were not pregnant. And then if the patient is choosing to keep the pregnancy, which in my practice, many people come and they come to me because they want to hold onto their pregnancy and want to figure out how to make it work, coming up with a regimen that tries to give them kind of the best bang for the buck, the best possible breast cancer therapy with the least harm, when possible, to the fetus. It is a bit of a balance, right? And then we cannot always give people the best approach. And sometimes it comes down to making a decision to give up something that may improve their survival so as not to harm the fetus. And sometimes it goes the opposite direction where a patient will say, "Oh, that is going to improve my survival by 5% and you can't give it to me now? I am going to choose to terminate." Even though that is obviously a very, very difficult and challenging decision to make in this setting because they want to optimize their survival and ideally live on to potentially have another pregnancy in the future if that is something that is of interest to her. So these are really, really hard conversations as you can imagine, but that is kind of where we go. Dr. Alison Loren: Yeah, and I think this is where the need for more research and understanding is really key because sometimes questions come up. I guess I am thinking about like HER2-directed agents, which we know are contraindicated in pregnancy. But what about sequencing? Does it matter when you get it? Can you get it later? I think that is something that we don't really fully understand. And similarly, again, this is obviously like a breast cancer and blood cancer focused discussion because that is what we do, but thinking about managing blood cancers, certainly with acute lymphoblastic leukemia, there is actually a lot of options now that, you know, you could potentially use to temporize or sort of get somebody through a pregnancy relatively safely. I am focusing on the word "relatively" because we do not know what the long-term impact might be of potentially not optimal therapy in the long run. And then thinking about other things like timing of a bone marrow transplant relative to either delivery or termination. I mean, again, we really do not know what are the right sets of sort of timing considerations for those. So there are just a lot of unknowns. And I think trying to be sort of self-aware and humble and honest about those unknowns so that the patient can engage in the conversation in a way that is meaningful to her and make the decisions that make the most sense for her. I think the most important thing is to make sure that the patient feels supported and safe to make those decisions with as little regret as possible. Brittany Harvey: Yes, I think it is really important that you mentioned that there is a wide range of cancers here, and that means that care really needs to be individualized for each patient. I will also note, just in this section, that I found really informative while reading through the guideline the list of oncologic agents that may be offered in each individual trimester, whether it is contraindicated or it can be used with caution, or if there is relatively good safety data on it for prioritizing maternal treatment needs and balancing fetal safety at the same time. I think that is, that is really key. And I think readers will really like that section of the guideline to provide concrete information for them and their patients. Dr. Alison Loren: Thank you. We actually spent a lot of time on that table and just thinking about what it should look like, what the format ought to be, what the language ought to be. Because of course, at the end of the day, everything should be used with caution. So what does that actually mean? And we sort of tried to explicate that a little bit in like the footnotes. We really tried to leverage what we know from clinical experience, from package labels, from mechanism of action to try to be as clear and definitive as we could be without overstating or understating what we know. Dr. Ann Partridge: Yeah, and I think we are focusing on breast and leukemia because that is what we do. But the truth is much of the data comes from those two areas. Leukemia, not because it is so common, but because you do not really have choices to treat or not treat. And so for decades, they have been treating and saying, "We hope the progeny comes out okay." And for many agents it does. The babies are okay. And so, we have reasonable observational data. And then in breast cancer, there have been actually some prospective registry-type studies where people have been followed and treated when pregnant, and the progeny have been accounted for, and so we have some good experience in that way too. Again, not randomized trials, but at least data that suggests certain agents are safe. And increasingly, because of that, when we have had to treat patients, we have said, "Okay, let us do it on this registry so that we can at least learn from every patient that comes in in this situation." And so, I think we will have more and more data given the growing number of young adults with cancer and the delays in childbearing that are happening around the world, and particularly in Westernized countries. I wish we did not. We wish we did not see this problem, but of course, when we do, we have to make sure that we learn from it and try and get patients enrolled in these registries and any kinds of studies that are available. Dr. Alison Loren: Yeah, I will just underscore that to say that, you know, there is outcomes of pregnancy and then there is outcomes of pregnancy, right? So there is like, "Okay, the baby was born with 10 fingers and 10 toes, and they passed their Apgar, and they are doing all their developmental processes along the way." But what happens when they are 10 or 15 or 20? Are they maturing normally? Are they cognitively intact? And then, of course, it is really inseparable from what is the impact on a family of having the mom with cancer? And how does that impact childhood development and intellectual development? And so these are really, really important questions that are very difficult to answer given the longitudinal information that you need, but it is a really critical question that, you know, patients ask and we do not know the answer. Dr. Ann Partridge: Yeah, that actually leads me to one of the important principles in the guideline that is a little bit of a change from when I first started practicing, which is we have learned from the wider neonatology literature, as they have followed up on the children that were born prematurely, that it is actually better not to be premature and to keep the baby in utero as long as it is safe for the fetus and the mother as long as possible, ideally to term rather than delivering early and then giving the chemo after that or separating the chemo from before and after. We used to try and deliver early and then give agents, but now we typically will give agents that are safe to be given at the end of pregnancy, ideally close to term, a couple weeks out, to allow for the ability of count recovery, and you do not want to go into preterm labor with chemotherapy on board, but we used to go much earlier and have an argument with our maternal-fetal medicine doctors. "How early can you get them out?" And they would say, "How long can they stay in?" And increasingly, we have been able to try and compromise to go even later and allow the fetus to go to term because of the neonatal outcomes that in longer term there is a suggestion that the children are developing better in the long run if they are kept in utero for as long as possible. Dr. Alison Loren: Yeah, that is such a great point. I think that is probably the most important thing for people to take away. For anyone who sort of does this, I mean, no one does this regularly because it is a rare event, although I think it is increasing as I mentioned. But this idea that the third trimester is, most of us know, is primarily a time for growth. Most of the critical development has already occurred, and so administering most chemotherapy agents towards the end of the third trimester seems to be preferable long term than delivering them early. So that is a really big change. I think we used to try to sort of, "Oh, get them to 30 or 32 weeks and then deliver," but we really are trying to get them closer to term, 37 weeks or more, and then coordinating the treatment so that they are not nadiring, as Ann said, at the time of planned delivery. Brittany Harvey: Yes, and that is a really important point related to evidence-based care and why we have changed that practice. And so then that actually leads nicely into my next question. But as you both mentioned, this is an important collaboration between oncologists and obstetricians. So the next section of the guideline addresses obstetrical practice. And so beyond what is standard, what additional recommendations are there in obstetrical management for pregnant patients with cancer? Dr. Alison Loren: That is a great question. So I will say we were really struggling with like how much do we cover? Like this is an oncology guideline. We are not obstetricians. We certainly had great representation from our maternal-fetal medicine colleagues on the panel. But really trying to sort of give useful information without overstepping. And so I think that the main recommendations are to increase the frequency of fetal monitoring, make sure that there is close attention to blood counts in the patient. But I think there is really still a gap in terms of what we know about optimal management of a pregnant person who is receiving therapy and how to handle the pregnancy itself. The delivery should be a usual delivery. Our colleagues did not recommend a planned C-section. They recommended usual care in terms of planning for the delivery. Obviously, if a C-section is indicated, then it should be done, but it should not be planned this way because of the cancer diagnosis. And I guess the other thing that we mentioned in the guideline, although we were reluctant to push it too hard because of access to these specialized services, was evaluating the placenta after birth to ensure that there were no metastases in the placenta itself. Dr. Ann Partridge: Those are the main things, and judicious and prudent obstetrical care, as I think, you know, is trying to be practiced regularly with MFM. Typically these patients should be followed not by your average OB/GYN, but a maternal-fetal medicine specialist because these patients will have special concerns, especially if they are sick. So oftentimes, especially Alison's patients, are actually sick with leukemia. And so you are monitoring them a lot, whereas, you know, a breast cancer patient typically isn't sick, although they could get sick with their chemotherapy. And so we really want to hand-in-hand manage these patients with our MFM colleagues. Dr. Alison Loren: I think we also highlighted in the guideline just for the refresher purposes of the oncology community, generally which drugs that would be given in a normal oncology setting are safe to be given to a pregnant person. So we talked a little bit about what kinds of steroids are recommended, antiemetics, DVT prophylaxis, peripartum. These are things that we think about a lot in oncology, but just want to make sure that it sort of intersected appropriately with the care of a pregnant patient. Brittany Harvey: Definitely. That specialized care is really important for patients who are pregnant and have cancer. And then the last section of the recommendations addresses psychological and social support. As you both mentioned before, this is a highly emotional time and it can be difficult and challenging to make decisions. So what is recommended for the psychological and social support of pregnant patients with cancer? Dr. Ann Partridge: Well, as I said, it is really something that needs to be considered at the beginning, through the diagnostic period, all the way into survivorship. Ironically, even though it is a highly fraught, emotional situation, I find that my pregnant patients actually are extraordinarily resilient, and what they are really focused on often is the safety of the fetus, because again, many of the people that come to me, it is a highly wanted pregnancy. They are also focused on their own health, of course, and often you need to bring in social work, sometimes a psychologist, professionals who are there just to help manage their emotions while we are focusing on what do they need medically to be as healthy as possible, both for the again, the mother, the patient, and the fetus. It is very tricky, and I will say also bringing in sometimes people on the ethics team in the hospital to help, both from the "Are you recommending and giving something that is safe?" That is number one. And then number two, sometimes patients want to be treated with drugs that we do not have any safety data for in pregnancy. What are our obligations? I think most of us would say we would not treat someone if we do not have safety data and there is suspicion for concern. But where is that line in terms of the right thing to do by that patient? And so we are all beholden to our ethics colleagues to help us when we make decisions like that. You know, we all want to do right by the patient, but we have to uphold our oaths and legal obligations. I don't know if you have to add on that because it's very tricky. Dr. Alison Loren: It is, it is very hard. I mean, I think, you know, there is a lot of emotion, obviously any cancer diagnosis is extremely charged and people are already at sort of a heightened, you know, they are anticipating a new baby and planning around that. And so it is just an extremely disruptive is the smallest word I can think of to describe it. And I think that often there is a co-parent, there might be parents and in-laws and other siblings, and then there is care after delivery. And so it is just a very complex set of dynamics. And having both our ethics colleagues and our psychology and social work colleagues to sort of just pitch in and make sure that the patient is being supported. I think there are sometimes really difficult situations where maybe what the patient wants is different from what the father of the baby wants or what the rest of the family wants. And so that can be really challenging. And you never really know where those landmines are going to pop up. So it is good to have the team on board early and often. Dr. Ann Partridge: Yeah, I would add to that, the other thing here that I think is really important, like in all of medicine but especially in situations like this, this is where we have to be very careful as professionals not to impose our own ethical, moral, emotional, personal views on the patient and to try to reserve judgment as much as possible. We are their navigator with the most important evidence and information that we can provide in the current situation. And that is where this guideline is extraordinarily helpful, we hope, for clinicians in the years to come. And at the same time, we cannot necessarily impose our own views and what we would do on a patient or what we tell our daughters, sisters, friends, family members. It is very tricky in that way. And so sometimes not just support for the patient, but support for the care team may be warranted in some of these very fraught situations. Dr. Alison Loren: Yeah, that is such a great point. And I was sort of thinking that too. I mean, it is, of course, the patient is front and center, but these are really difficult situations to navigate. And I will just add also that a lot of times these patients end up in academic centers, which I think is that's where the expertise or even just the experience may be. But the downside of that is that, you know, the teams are constantly changing. You have a new resident, you have a new intern, you have a new attending, a new fellow. And so, you know, the patients may be subjected to lots of different ways of communicating and sometimes those perceived differences can be really challenging. So sort of team huddles to sort of make sure that everybody is reading from the same script and everyone is comfortable with how the information is being presented so that the patient does not feel more confused or more overwhelmed, that they are kind of getting a consistent message from the whole team that, "This is what we know, this is what we are recommending, here are your other choices, and here are the pros and cons of each of these options." Brittany Harvey: Yes, I think you have both touched on this and that bringing in appropriate experts to support both clinicians and patients and their decision-making and their mental health is really important for this section of the guideline. We have already discussed this a fair bit throughout our conversation, but in your view, what is the importance of this guideline and how will it impact both clinicians and pregnant patients diagnosed with cancer? Dr. Ann Partridge: I could start with that. We just talked about experts and having them all around, but the fact is most people do not have the experts all around when they are dealing with this. And I think this is, you know, an expert-based, evidence-based guideline where having this in one's back pocket, whether you are in rural Montana or at a major cancer center on either coast, you will be armed with the latest and the greatest in terms of what we know and what we do not know, and some very helpful algorithms for how to think through the process of dealing with a patient who is diagnosed during pregnancy, whichever type of cancer it is. We could not cover every single specific thing about every cancer, although it is a pretty long guideline and there is a lot of nuance in there. So you might find a lot about specific cancers. And I think that that will be very, very helpful for people who are faced with this situation in the clinics just to frame it out, think through. Sometimes there is no answer that is the perfect answer and then, you know, using this as kind of a scaffolding and phoning a friend who may have more experience to help guide you and guide the patient, most importantly. I think it will be very helpful in that regard. Dr. Alison Loren: Yeah, I think so too. And I have talked about that we are working on this guideline and the anecdotal feedback has been, "This is so helpful." Like there really has not been, I think, an all-in-one place, diagnostic considerations, radiographic considerations, staging, treatment, all the modalities, surgical, radiation, systemic chemotherapy. We tried to include, when we could, novel agents including targeted agents and monoclonal antibodies and bispecifics and cellular immunotherapies and non-cellular immunotherapies. We really, really tried to cover in 2025 what are people using to treat cancer and to try to give the most balanced view of what we think is is safe or reasonably safe and what we think is either unproven or known to be risky, really to have it be kind of a go-to, like all-in-one, as much information as we have about these really challenging cases. We tried to include, Ann mentioned, you know, specific cancers, and I think when there were specific things to shout out with specific cancers, we really tried to highlight that. Like, "Okay, lots of young patients with cancer have Hodgkin's lymphoma, so what is safe and what is not for that specific case?" Or, "What is safe or what is not when you are thinking about colon cancers?" And we have a shout-out in here about considering checking for DPD deficiencies in patients who are pregnant. And I know it is generally recommended nowadays, but certainly for people who are pregnant, you know, you really want to avoid excess toxicity. So I think just really trying to be attentive to specifics about certain cancers in young patients and what would be valuable for a practicing oncologist and obstetrician to know when you are faced with this situation. Dr. Ann Partridge: Yeah, and I think the other critical thing that is great about this guideline is it's a starting place. And I anticipate that we will be building on this guideline for many years to come. And remember that when first, I was not around then, but probably three or four decades ago, when chemotherapy was just coming out and patients were coming in pregnant, there was a feeling I am sure that was, "We cannot give this to this person because it is purposefully going to destroy cells. And when you destroy cells in a growing fetus, you are going to destroy or harm that fetus." And yet, people did not have great choices. It was get treated or die, especially with things like leukemia early on. And bold patients along with their oncologist said, "Bring it on." And that is how some of this literature has been born. And so moving forward, there will be either purposeful exposures or inadvertent exposures of some of our therapies where we will learn ultimately. And this is a place where we can update these guidelines. That is the beautiful thing about the ASCO guidelines is that they are constantly being thought about to be updated. And then when there is enough of a change in practice, they will be updated such that they will continue to inform how we do this in the years to come for patients who come in pregnant. Dr. Allison Loren: Yeah, and I will say I have been doing this long enough now, we were just talking about a different guideline, the fertility guideline earlier today, and over the 20 years that the fertility guidelines have been out, just the amount of research has really skyrocketed. And you can see as you look at each guideline how much we have learned, what we can say, "Yes, this is working," "No, this is not working." Like, it is stuff that we used to say, "Oh, we do not really know," and now we have answers.  I think I speak for both of us when I say that we are hopeful that this will serve as, as Ann said, as a starting off point and really inspire people to ask the questions and do the research so that we can give better guidance moving forward, really trying to think about, you know, mechanisms and leaning on our colleagues in pharma and in the government who sort of think about safety and efficacy, to sort of make sure that they are contemplating not just non-pregnant patients, but also pregnant patients or as they are thinking about marking the package inserts with safety guidelines around this. Brittany Harvey: Yes, this is a critically important first guideline on the management of cancer during pregnancy, and we will look forward to continuing to build on that. I think as you mentioned, this guideline is far-reaching and has a lot of recommendations in it. And so both the full text of the guideline and those at-a-glance algorithms, figures, and tables will be really useful for clinicians in their clinic. Finally, to wrap us up, we have just been discussing this a little bit, but specifically, what are the outstanding questions on the management of pregnant patients with cancer, and where is this further research needed? Dr. Alison Loren: There are lots and lots and lots of unanswered questions. And I think if you look at the table, most of what we say is, "We are pretty sure this is okay, we are not so sure about this." I am paraphrasing, but we really just are operating in a paucity of what we would normally consider gold-standard evidence. It is hard to imagine, of course, there would ever be, as we mentioned in the beginning, randomized trials. But I think that preclinical data, mechanistic data, trying to think about including as we go through animal data, making sure that we are looking at female animals and pregnant animals so that we can sort of fully understand what the impact may be. And then I think thinking about more localized therapies around sort of radiation, you know, we are now moving into really hyper-focused radiation treatments like protons. Is that better because there is less scatter? Like I think those are real considerations that we just do not know the answer to. What do you think? Dr. Ann Partridge: I think so many unanswered questions, and this is a call to action to continue to and increase the documentation of the experiences and outcomes for patients diagnosed during pregnancy. Dr. Alison Loren: Yeah, and I think the long-term outcomes too are really going to be critical. Brittany Harvey: Yes, we will look forward to learning about more evidence across the spectrum of care to inform future updates to this guideline. So I want to thank you both so much for your work to develop this guideline, to review the extensive amounts of literature that you did, and work to create this guideline. And thank you also for your time today, Dr. Loren and Dr. Partridge. Dr. Alison Loren: Thanks. It was fun. Dr. Ann Partridge: Yeah, thank you. Brittany Harvey: And finally, thank you to all of our listeners for tuning into the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 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. 

Guests Dr. Andrea Necchi, Dr. Ashish Kamat and host Dr. Davide Soldato discuss JCO article "End Points for the Next-Generation Bladder-Sparing Perioperative Trials for Patients With Muscle-Invasive Bladder Cancer," focusing on the evolving treatment landscape of MIBC (muscle-invasive bladder cancer) and the need to properly design novel trials investigating non-operative management while including the incorporation of biomarkers and patient perspectives in clinical trials. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy. Today we are joined by JCO authors Andrea Necchi, Associate Professor of Medical Oncology at University San Raffaele and Medical Oncology at Ospedale San Raffaele in Milan, Italy, and Ashish Kamat, Professor of Urologic Oncology and Cancer Research at University of Texas MD Anderson Cancer Center. Both Professor Necchi and Professor Kamat are internationally recognized experts in the field of genitourinary malignancy and particularly in bladder cancer. Today we will be discussing the article titled "Endpoints for the Next Generation Bladder-Sparing Perioperative Trials for Patients with Muscle-Invasive Bladder Cancer." So thank you for speaking with us, Professor Necchi and Professor Kamat. Dr. Andrea Necchi: Thank you, Davide, and thank you JCO for the opportunity. Dr. Ashish Kamat: Yeah, absolutely. It is a great honor and privilege to be discussing this very important article with you. So thank you for the invitation. Dr. Davide Soldato: The article that you just published in JCO reports the results of a consensus meeting that was held among experts in the field of genitourinary malignancy and particularly for bladder cancer. So the objective was really to define endpoints for a novel generation of trials among patients diagnosed with muscle-invasive bladder cancer. So my first question would be: what is the change in clinical practice and in clinical evidence that we have right now that prompted the start of such consensus in 2025? Dr. Andrea Necchi: So, we are living so many changes in the treatment paradigm of patients with muscle-invasive bladder cancer. In general, patients diagnosed with bladder cancer or urothelial cancer today, thanks to the advent of immunotherapy or immunotherapy combinations, and today thanks to the advent of novel antibody-drug conjugates like enfortumab vedotin in combination with immunotherapy that are actually changing the landscape of treatment of patients with metastatic disease and also are entering quite fast into the treatment paradigm of patients with organ-confined disease with a lot of clinical trials testing these combination therapies, neoadjuvantly or adjuvantly, before or after radical cystectomy. Having said that, by potentiating the efficacy of systemic therapy, an increasing number of patients that receive neoadjuvant therapy of any kind, at a certain point in time, result to have achieved a deep response to systemic therapy, evaluated radiologically with conventional imaging, CT scan or MRI, or with cystoscopy or with other urology-based techniques, urinary cytology, and so. And based on the fact that they achieve a complete response, so no residual viable disease after systemic therapy, they raise concern about the fact that they have to undergo surgery like radical cystectomy that is quite impactful for their quality of life and for the future of their lives after the surgery. So the point that the patients are raising, and the patients are raising this point, is primarily due to the efficacy of systemic therapy. And we have seen so many cases fortunately achieving a deep response. So the question about what to do with the patient that at a certain point, at the start with the commitment to radical cystectomy, but at a certain point in time change their mind towards something else if possible, depending on the fact that they have achieved a deep response, is something that is a question and is a need to which we have to provide data, information, and guidance in general to the patients. Dr. Davide Soldato: If we look at the population that the recommendations were formulated for, we are mainly speaking about patients who would be fit for cystectomy, and this is a very distinct population compared to those who are not fit for cystectomy, both from a medical oncology point of view but also from a urologic point of view in terms of surgery. So, can you explain a little bit to our listeners why you think that this distinction is critical and why you developed this recommendation especially for this population? Dr. Ashish Kamat: That is a very important distinction that you made. To build upon what Professor Necchi mentioned earlier, this question that we get from patients after neoadjuvant therapy or systemic therapy is not a new question. It has been something that they have been asking us for the last 20 or 30 years. "Do I really need to have my bladder taken out?" And patients who are especially not fit for surgery will sometimes say, "Do I need to have my bladder taken out? And if I cannot have my bladder taken out, am I going to just not have anything done?" Because the eligibility for radical cystectomy is also a moving target. Over the years with improvement in surgical technique, improvement in perioperative therapy, ERAS protocols, et cetera, it is really unusual for us to deny a patient the opportunity to have major surgery unless clearly they have very significant comorbid conditions. So I think this endeavor is more broadly encompassing of the patient population than what was evident in previous years. And I really want to give a shout out to Professor Necchi because what we did was, as part of the International Bladder Cancer Group and Professor Necchi is an integral part of the scientific advisory board, we broached this topic broadly during one of our discussions. And of course, Andrea always does this, he picks on a topic and then he says, "Okay, we need to discuss this really in detail," put together a multinational, multicenter collaborative group, but the driving force was our patients. Because our patients are constantly asking, "Do I need to lose my organ? Do I need to have radiation therapy?" which again, also, has a lot of side effects. So this was really to answer the question in today's day and age as to do we need to do local consolidation, and if so, in what way? It is not a new question, but we have newer therapies, newer technology, and better ways to answer this. So it is a much needed question that needs to be answered. And I think the distinction between non-surgical candidates and surgical candidates is a little bit blurred in today's day and age. Dr. Davide Soldato: What about the eligibility, for example, for cisplatin-based chemotherapy? Because I think that that is a very fundamental part of this type of strategy that we apply to patients with muscle-invasive bladder cancer. So we know that there are some caveats for proposing such treatment. And also this population was specifically defined inside this recommendation. Dr. Andrea Necchi: I think that the focus of our work is just to analyze what is happening after any type of systemic therapy the patient may get neoadjuvantly. So it is not actually a question of treatment eligibility or including cisplatin eligibility. This is an old question of today's practice and clinical trials. But regardless of what the patient received neoadjuvantly, the point that we have addressed in our consensus meeting was what to do next as a further step after systemic therapy or not. So basically we are- the consensus guidance includes all-comers, so patients to get any type of systemic therapy. So really non-selected based on specific features that determine a special eligibility to a special or a particular therapy. But an all-comer approach is always the winning approach for the translation to be in practice, an all-comer approach just focusing on what has happened after treatment and that we are assessing by the use of conventional imaging, MRI or CT, cystoscopy, urinary cytology, and trying to merge all together this information, all these features in a unique, shared, reliable definition of clinical complete response that could be used as a biomarker for the selection of newer therapies instead of pathological response that has been historically used, and maybe surrogate for the outcome, the long-term outcome and survival of these patients. Dr. Davide Soldato: A very specific point of the consensus was actually the definition of clinical complete response. As you were saying, this is actually a combination of several parameters including urinary cytology, the use of cross-sectional imaging, for example CT scan, but also the evaluation in cystoscopy of the bladder. Do you foresee any potential problems when applying this type of recommendation, not inside clinical trials, but in the context of routine clinical practice? Dr. Ashish Kamat: Absolutely. And that was the whole reason we had this consensus meeting. What happens nowadays in daily practice, and we see this every day at our center, we see patients referred to us. This definition or this sort of attempt to define clinical complete response is an ongoing issue. And urologists, medical oncologists, radiation oncologists are always looking to see, does my patient have a complete response? That definition and those paradigms have changed and evolved over the years. The FDA had a workshop many years ago looking at this very question. And it was to address the proposal that complete clinical response, which is a clinical definition, a clinical state, does this correlate with pathologic response? And with the technology and the systemic therapies we had then, the answer was 'no'. In fact, more patients got recurrent disease than did not get recurrent disease. And that is why, of course in the paper we mention the trials that looked at this question, the trials that evolved around this question. And I think the distinction between a clinical trial and daily practice is extremely important when we are looking at this definition per se. Because essentially what happens with this issue is that if the patient is not appropriately counseled, and if the physician does not do the appropriate clinical complete response assessment as Professor Necchi mentioned, right, cystoscopy, cytology, imaging, use of markers that are still in evolvement, we risk doing harm to the patient. So we caution in the paper too that this definition is not ready for prime time use. It is something that needs to be studied. It is a rigorous definition and currently we are recommending it for clinical trials. I am sure eventually it will trickle down into clinical practice, but that guidance was not the purpose of this consensus meeting. Dr. Davide Soldato: There are several parameters that are potentially evolving and could potentially enter inside of clinical practice. For example, you mentioned pelvic MRI and we have now very specific criteria, the VI-RADS criteria, we're able actually to diagnose and also to provide information. So along with these novel imaging techniques, we also know that there are novel biomarkers that could be explored, for example ctDNA and urinary DNA. So what I was wondering is, why were not these included inside the definition that you provide for clinical complete response? And do you think that, as we are designing these trials to potentially spare cystectomy for this patient, we should include these biomarkers very early so that we can actually provide better stratification for our patients and really propose this type of cystectomy-sparing strategy only to those where we are very confident that we have obtained a clinical complete response? Dr. Andrea Necchi: I would say you have just to wait. So a follow-up is ongoing and hard work is ongoing. At the time we met, at the time we established the meeting in mid-December last year, we had no information on the ctDNA data from major trials, with only a few exceptions. So we were just at the beginning of a story that was more than likely to change but still without numbers and without data from clinical trials. Now in just nine months or 10 months time, we have accumulated important data and newer data will be presented during just a few weeks and a few days regarding the ctDNA, circulating tumor DNA in particular, as a prognostic marker assessed baseline or assessed after neoadjuvant therapy. So the point is certainly well made and ctDNA is certainly well shaped to be incorporated in a future definition of clinical complete response. But you have to consider the fact that most of the data that we are accumulating related to ctDNA are about the post-cystectomy field or the metastatic field. So regarding neoadjuvant therapy, you know, we have neoadjuvant therapy in the context of bladder-sparing approach, basically we have no information. And the point that is emerging in our daily practice when using these biomarkers or in clinical trials, and the impression in general, is that it is a very strong biomarker associated with survival, but we absolutely do not know what is the performance of the test in the prediction of superficial bladder relapses, high-grade pTa relapse in the bladder that is left untouched in the patient. We are considering, and maybe it will be just a matter of further discussion, not just what is happening within the immediate endpoint of clinical CR, but also what is happening later with other survival endpoints. And for example, when looking at the type of events that we may see in this kind of bladder-sparing approaches, most of the events, also in the trials that have been published including the RETAIN study published in JCO, most of the events are related to superficial high-grade superficial non-muscle invasive relapses. So the ability to predict these types of events with ctDNA is completely unknown. Maybe, maybe other liquid biomarkers like urinary tumor DNA, utDNA, could be a bit better shaped in the prediction of this kind of events, you know. But we have still to build the story. So the question is good. The answer is yes, we will likely, more than likely incorporate liquid biomarkers in the definition, but we have to wait at least more data and more robust data in order to translate this information in routine practice, you know. Another consensus meeting is organized by IBCG and the same folks for November. This meeting will be primarily focused on the liquid biomarkers, the interpretation and use and approval and so of liquid biomarkers including bladder cancer. And we will likely be able to address all these, most of these open issues, so most of these points in the next meetings. Dr. Davide Soldato: In the consensus you say that probably clinical complete response is now ready to be included in early phase trials, so actually to test what is the efficacy of the regimens that is being evaluated inside of these trials. But you actually do very in-depth work of defining what are the most appropriate endpoints for later phase trials. So to be very specific, the phase three registrational trials that bring new regimens inside of this space. So I just wanted to hear a little bit about what was the definition for event-free survival, which you define as the most appropriate one for this type of trials. And as you were mentioning before, Professor Necchi, there is a very specific interest on the type of events that we observe, especially when we look at these superficial relapses inside of the bladder. So was this a very urgent matter of debate as we define which type of events should actually trigger event-free survival? And did you make a very thoughtful decision about why using this type of endpoint instead of others, for example metastasis-free survival? Dr. Ashish Kamat: Yeah, this was a matter of intense debate as you might imagine. And again, this is a moving target. So as Professor Necchi mentioned, we tend to partner with each other, our organizations, on having definitions of clinical complete response, biomarker, retreats, and then using that as a marker, and you might imagine this definition of what is appropriate event-free survival, what events matter to the patient, is something we have been talking about for two years. It was not just something that came up at the retreat. But at the retreat there was intense discussion. One of the things that we talked about was bladder-intact event-free survival because we are trying to spare the patient's bladder. And do we count bladder-intact event-free survival as something that is relevant? The patient advocates absolutely liked that, right? They wanted that. But then we also learned from some of the studies, for example from the RETAIN study, that the non-muscle invasive recurrences can actually lead to metastatic disease. It is not as benign when you have a patient with muscle-invasive bladder cancer that then develops a non-invasive tumor because maybe there is cancer growing underneath the surface that we don't detect when we look in the bladder. So a lot of those discussions were held, debated. It was a consensus. I have to say it was not 100% agreement on that particular definition, but it was broad consensus. And Andrea, do you want to clarify a little bit as to how we came about that consensus? Because I think this is a very important point we need to make. Dr. Andrea Necchi: We focused on a bit different definition of BI-EFS, Bladder-Intact Event-Free survival. Just stating EFS as an all-inclusive parameter including all type of high-grade relapse or progression or death that may happen to the patient. So that we were counting high-grade pTa, pT1, CIS relapses to the bladder and of course more deeper involvement in the muscle layer and so, and metastatic disease as a relapse. But the point is that as compared to the classical bladder-intact EFS definition of chemoradiation bladder-sparing approaches that is including muscle-invasive relapses only or death as events, we tried to be as inclusive as possible in order to be as much conservative as possible and to raise as higher the bar as possible for the success. And this is actually what the patients are asking us. So they are asking, "Okay, I can save my bladder, sparing radical cystectomy, but at which cost?" So in order to provide an answer, we have to be very, very cautious and be on the right shape, on the right position to say, "Okay, we have accomplished the most, the safest points, you know, by which you can proceed with the bladder-sparing." This is the first point. The other point is related to the MFS, metastasis-free survival that you have mentioned. For sure, it was recognized as a very important point for sure. But in the discussion was clear that our focus was in saving patients, curing the patient, and saving the bladder. Any single event, superficial event that may occur in the bladder-saving approaches of this kind may expose the patient to an extra risk of developing distant metastases, as it happened for example in the RETAIN study. So EFS defined as we have agreed and published, is actually a way of including or anticipating in a safest position the MFS. Because most or if not the entirety of the events of metastasis development in patients undergoing bladder-sparing after neoadjuvant systemic therapy were preceded by a superficial phase of disease relapse, you know. So I remember very, very few, or we can count just on the finger of one hand, the cases that have been reported in the literature developing de novo metastatic disease in the similar bladder-sparing approaches, in particular when using a maintenance immunotherapy strategy, you know, after they reach TURBT. So this is the reason why with all the limitation that Ashish has mentioned, with all the uncertainties that are still there, the nervousness that is still there, EFS, as defined in the protocol, as put in the paper, is to us at the moment is the safest way to use a primary endpoint in potentially registration trials of this kind with perioperative systemic therapy and response-adapted surgery. Dr. Ashish Kamat: And David, just to be absolutely clear for our listeners, right, so what was the event-free survival that we defined? Essentially it was a very inclusive definition. Event was defined as high-grade tumor persistence, recurrence, or progression during or after perioperative therapy, and receipt of any additional standard of care treatment including radical cystectomy, radiotherapy or even intravesical therapy. So this was done at the behest of our patient advocates because we really wanted to make a very robust definition that could be utilized appropriately as an adequate primary endpoint for both early and late phase bladder preservation trials. Dr. Davide Soldato: I think that it really highlights one of the points that I liked the most about this consensus is that it really incorporated the patient vision and a sort of shared decision making process when we are deciding how we want to design these trials that will explore this bladder-sparing surgery. And Professor Necchi mentioned something that I think will be also a very interesting question for trials that will be developed considering the activity of this combination that we are seeing right now, which is maintenance. Because right now our approach in the few cases where patients do not do any type of treatments after an induction with neoadjuvant treatments is basically represented by observation. So I was wondering if you think that the field will actually evolve to a sort of maintenance strategy even in patients that will achieve a complete clinical response? Dr. Andrea Necchi: We just mentioned briefly in the paper, this is a very important point that was touched during the discussion, and in particular was raised and discussed by FDA people participating in the meeting. And when looking at the data from the trials that were available and are still available thus far, we could provide a suggestion that maintenance immune therapy is the preferred approach in this kind of approach as it currently stands, as the data currently stand. Because the cleanest data towards the successful part of this journey is related to the studies that provided a kind of maintenance therapy, like the study with nivolumab or the RETAIN-2 study with maintenance immune therapy instead of RETAIN study that was just stopping treatment until surgery with MVAC chemotherapy. So in general the impression is that maintenance therapy may help in reducing the type of events, including the events that we incorporate in the EFS definition that we mentioned in the paper. The point that you mentioned is very important because on the other side we have a problem, a big problem of affordability and cost of the treatment. The de-escalation trials are an urgent need and represent a call for the studies. Unfortunately, as you mentioned, this is something that moves beyond the possibilities of this type of consensus because we don't have data and we have to accumulate data from clinical trials prior to saying, "Okay, certain patients could de-escalate therapy and stop therapy and some other not." So we are still at the very beginning. So we can do- we can discuss about this in the radical cystectomy paradigm but not in the bladder-sparing paradigm, you know. But this is for sure a point, a discussion point that will be taken, pretty well taken in one year or two year projection. Dr. Davide Soldato: I was wondering if in the consensus, considering that patient advocates and patient associations were also involved, did you decide to actually suggest the inclusion of patient-reported outcomes or the evaluation of shared decision-making in the development of this trial really as endpoints that should matter as much or as much as possible as event-free survival and clinical complete response? Dr. Ashish Kamat: Oh yeah, absolutely. We had patient advocates, we had the World Bladder Cancer Patient Coalition, Bladder Cancer Advocacy Network, patient representatives. And we always consider this. Shared decision-making is actually the impetus behind why these efforts have been launched, right? So it is the shared decision-making that is very, very important. It is the driving force behind what we do. And it is worth noting, for example, for the design of such studies, regulatory agencies consider response-based endpoints or overall survival as primary endpoints. But the patient advocates consider quality of life to be just as important, if not more important sometimes than overall survival numbers. Because patient advocates will say, "Well if I live longer but I'm miserable living longer, yes that works for regulatory agencies but doesn't work for us." So PROs clearly are very, very important. And, in fact, we just literally had a meeting in Houston, the IBCG meeting where PROs were a main point of what we discussed. So incorporating PROs in everything we do, not just this but everything we do, Dr. Necchi, myself, everybody involved in these fields realizes it is very, very important. So absolutely. Dr. Davide Soldato: I want to thank again Professor Necchi and Professor Kamat for joining us today. Dr. Andrea Necchi: Thank you. Dr. Ashish Kamat: It is our pleasure. Dr. Davide Soldato: Thanks again and we appreciate you sharing more on your JCO article titled "Endpoints for the Next Generation Bladder-Sparing Perioperative Trials for Patients with Muscle-Invasive Bladder Cancer." If you enjoy our show, please leave us a rating and review and be sure to come back for another 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.

Cada mañana me despierto con el ardiente deseo de escuchar y leer las noticias, a ser posible todo a la vez. En este momento, aparte de la extrema derecha mundial y porque quieren dominar el planeta, los únicos seres humanos que tienen esperanza colectiva son los sirios. Y de una guerra civil que ha generado no pocos bandos enfrentados e intrusiones ajenas. Da bastante asco pertenecer a una parte del mundo que observa con complacencia el avance de la ley del más fuerte.

Listen to JCO's Art of Oncology article, "Smell," by Dr. Alice Cusick, who is a Hematology Section Chief at Veterans Affairs Ann Arbor Health System and Assistant Professor at the University of Michigan Division of Hematology and Oncology. The article is followed by an interview with Cusick and host Dr. Mikkael Sekeres. Dr Cusick shares a connection to a cancer patient manifested as a scent. TRANSCRIPT Narrator: Smell, by Alice Cusick, MD  Dr. Mikkael Sekeres: Welcome back to JCO's Cancer Stories: The Art of Oncology. This ASCO podcast features intimate narratives and perspectives from authors exploring their experiences in oncology. I'm your host, Mikkael Sekeres. I'm Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. Joining us today is Alice Cusick, Hematology Section Chief at the Veterans Affairs Ann Arbor Healthcare System and Assistant Professor at the University of Michigan, Division of Hematology and Oncology, to discuss her Journal of Clinical Oncology article, "Smell." Alice, thank you for contributing to Journal of Clinical Oncology and for joining us to discuss your article. Dr. Alice Cusick: Thank you so much for having me, Mikkael. I appreciate it. Dr. Mikkael Sekeres: It's really a pleasure, and as usual, Alice and I discussed this beforehand and agreed to call each other by first names. I always love to hear your story first. Can you tell us about yourself? Where are you from, and walk us through your career, if you could. Dr. Alice Cusick: I'm a Midwesterner. I grew up in Iowa and Illinois and went to a small college in Illinois, played basketball, Division lll, and was an English Literature major. I took one science class and was going to be an English professor. And then my father's a physician. My senior year, I realized I don't think I could spend all my time in a library. I didn't feel like I was helping anyone. And so I talked to my dad, and he said, "Yeah, I think you could be a doctor." So I thought I would help people by being a physician. So I moved to Iowa City and spent two years working in a lab and doing science classes and took the MCAT, which was the first year they had the essay on there, and I rocked that. That was my highest score. I got into the University of Iowa and then went on to residency and fellowship at the University of Wisconsin, just in hematology. I didn't do solid tumors. And then went on, spent a couple years there, worked in Pennsylvania in more of a group practice, and then came back to academics at the University of Michigan about 10 years ago. And then five years ago, I became the Hematology Section Chief at the VA in Ann Arbor. So I work there full time now. Dr. Mikkael Sekeres: I love that story. I served on the admissions committee at Cleveland Clinic and Case Western when I was also a Midwesterner for 18 years. And I always wondered if instead of searching for science majors, we should be searching for English majors because I think there's a core element of medicine that is actually storytelling. Dr. Alice Cusick: Oh, very much so. My father was a country doctor for many, many years in rural Iowa in the fifties and sixties. So he did house calls, and he talked about how you really got to know people by going to their house. And I'll never forget the first time that I did a full history and physical, I think I was maybe a second-year medical student, and I was telling him, "Oh, I'm so excited. I'm going to do my first history and physical." And he said, "Alice, don't talk to them about medicine right away or about their problems right away. Talk to them about something else. Get to know them because you know about sports, talk about sports." I said, "Dad, that's called establishing rapport." You know, that's what they had taught us. But it was intuitive to him. I'll never forget that he just said their story is important and how they live and where they live and who they live with is so important. It really helps you figure out their medical issues as well. And I've always tried to carry that through. Dr. Mikkael Sekeres: It's funny what we glean from our parents. My dad was a journalist for the Providence Journal-Bulletin. He was a reporter for a couple of decades, and I almost feel like some of what I'm doing is acting as a reporter. It's my job to get the story and get the story right and solicit enough details from a patient that I really have a sense that I'm with them on the journey of their illness, so I can understand it completely. Dr. Alice Cusick: Oh, very much so. And that's one of the things I really harp about with the fellows because sometimes I remember more of the social history than I do sometimes the medical history when I'm seeing a patient. I remind them, you need to know who they live with and how they live. It helps you take care of them. Dr. Mikkael Sekeres: Well, and that must be particularly germane with your patient population. When I was a medical student, my first rotation on internal medicine was at the Philadelphia VA, and it's actually what convinced me to specialize within internal medicine. What is it like caring for veterans? Dr. Alice Cusick: This is the best job I've ever had in my life. And I think because it speaks to my sense of duty that I got from my parents, particularly from my father, and I really feel I got back to my original focus, which is helping people. So that sense of duty and serving those who served, which is our core mission, this job is the most rewarding I've ever had because you really feel like you're helping people. Dr. Mikkael Sekeres: How much do you learn about your patients' military history when you first interact with them? Dr. Alice Cusick: It can come up in conversation. It sort of depends on what the context is and how much you ask and how much of that is incorporated into what's going on with their medical history. It comes up a lot in terms of, particularly cancer, because a lot of cancers that veterans develop can be related to their military exposures. So it can come up certainly in that context. Dr. Mikkael Sekeres: You write about how your patient and his wife brought in photographs of his younger self. Can you describe some of those photos? Dr. Alice Cusick: So a lot of it was about the sports he was doing at the time. He was kind of almost like a bodybuilder and doing like martial arts. So there were some pictures of him in his shirt and shorts, showing how healthy he was. He was much younger, but it was such a contrast to how he was at that time as he was nearing death. But it really rounded out my understanding of him because, as we all know, when we meet people, we see them when they're at that particular age, and we may not have that context of what they were 20, 30 years ago. But that still informs how they think about themselves. I mean, I still think of myself as an athlete even though I'm much older. So that's important to understand how the patient thinks about himself or herself. Dr. Mikkael Sekeres: You know, it's funny you mentioned those two photographs. I- immediately flashed into my mind, I had a patient who also was a martial arts expert, and I remember he was in his early seventies and hospitalized, but he made sure to put up that photo of him when he was in his prime, in his martial arts outfit in a pose. And I've had another patient who was a boxer, and all he wanted to talk about whenever he saw me was his first experience boxing in Madison Square Garden and what that moment felt like of climbing into the ring, squeezing in between the ropes, and facing off in front of what must have been some massive crowd. Dr. Alice Cusick: Yeah. Dr. Mikkael Sekeres: Why do you think it was important to them to bring in those photos to show you? Dr. Alice Cusick: I think it was to help me understand what he had been. I think it was important for him, and because we had a relationship, it wasn't just transactional in terms of his medical problems. It was really conversations every day about what he was doing and how his life was going. And I think he really wanted me to understand what he had been. And so I felt really honored because I think that was important. It told me that his relationship with me was very important to him. I found that very, very humbling. Dr. Mikkael Sekeres: Yeah, I find it fascinating the details that patients offer to us about themselves as opposed to the ones that we solicit. I think it speaks to also the closeness of the relationship we have with patients when they want to share that aspect of them. They want to show you who they were before they were ill. And it's not a point of bragging. It's not flexing for them. I think it's really to remind themselves and us of the vitality of the person who's sitting in front of us or lying in front of us in the hospital johnny or sitting on an exam table. Dr. Alice Cusick: Oh, very much so. And I've experienced that even with my own parents as they got older and were in the medical system. I remember vividly, my father had had a stroke, and the people taking care of him didn't understand what he had been. They didn't understand that his voice was very different. We kept asking, you know, "His voice is different." They had no concept of him beforehand. So that also really hit home to me how important it is to understand patients in the whole context of their lives. Dr. Mikkael Sekeres: And as a family member, do you think it's equally important to share that story of who somebody was before they were ill as a reminder to yourself and to the people taking care of a relative? Dr. Alice Cusick: Oh, very much so. I think it's very helpful because it also makes you feel like you're supporting the loved one as well by, if they can't speak for themselves, particularly when they're very ill, to help people understand, it may help the physicians or any provider understand their illness better, especially if there's a diagnostic dilemma, thinking about going home, what are they going to need at home, those sorts of things. I think it's always important to try to provide that context. Dr. Mikkael Sekeres: Patients will often talk about their deaths or transitions to hospice as an abstract future. Do you think they rely on us to make the decision about a concrete transition to hospice, or do you think they know it's time and are looking for us to verbalize it for their family and friends? Dr. Alice Cusick: I think it depends on how much groundwork you've done beforehand. So when you talk about end of life with people well before that transition it's almost mandatory, I think it's very important. It makes the transition much smoother because then they understand what hospice is, and they can prepare themselves. When they're not prepared, I think it's much more of a very clear transition. So it's almost like you're shutting one door, disease treatment, and moving on to, "I'm just going home to die," versus when you're laying the groundwork and you make sure that it's about how you live. I always try to emphasize, it's how you want to spend your time. It's how you want to live. Hospice is helping people live the best they can for as long as they can. And if you haven't prepared people, I think then they think much more you're closing the door and you're just sending me home to die. Dr. Mikkael Sekeres: It's tricky though, isn't it? Because as an oncologist or hematologist-oncologist, in our case, people look to us for that hope that there's still something to do and there's still life ahead of them. But at a certain point, we all realize that we need to transition our focus. But once we say that out loud, do you ever feel like it almost shuts a door for our patients? Dr. Alice Cusick: Again, it depends on the situation, and it depends on the support they have. It's different when you're dealing with somebody who's out in an outpatient world who has good family support and you've developed a relationship versus the patient who's taken a very sudden turn for the worse, and maybe is in the hospital, and things are more chaotic, and maybe they've been on very active treatment beforehand, but suddenly things have changed. So in my mind, it depends on the context that you're dealing with and what the relationship you have prior to. Maybe you're covering for your colleague, and you don't have a relationship with that particular family or that particular patient, but yet you have to talk to them. Somebody gets transferred from another hospital and you have a very brief relationship. And so I think the relationship kind of dictates sometimes how patients feel. But as long as you can help people understand the process of end of life as best as you can, I think that sometimes helps the transition. Some people are going to be angry no matter what. And that's totally understandable, angry about their family member dying, angry about what's happening to them if they're the patient. I think that's always part of the process, but it's hard to make things smooth all of the time. We do the best we can. Dr. Mikkael Sekeres: I was going to ask, has anyone ever been shocked when you start to talk about palliative care or hospice and never really did see it coming? Dr. Alice Cusick: Oh, of course. I think, especially if you've been doing this for a while, you sometimes see the future. You know what's, well, I mean, not exactly, but you have a good sense of what's going to happen. And there can be times when you start talking about end of life and palliative care or hospice and people are shocked, particularly family members, family members who may not be there all the time, who may not have seen their loved one frequently and haven't just understood what the disease course has been. And that certainly can be shocking. And again, totally understandable, but it's my responsibility to try to smooth that over and help people understand what's going on and make it a conversation. Dr. Mikkael Sekeres: It's a nice description of what we do. We make it a conversation. When talking about what you smelled that day when you saw your patient, you write, "Did I suddenly have a gift? Could I float through the hospital wards and smell the future? Or maybe I could only smell inevitability." It's a beautiful sentence. "Could I only smell inevitability?" What do you think it was that led you to know that his time had come? And I wonder, was it a distinct odor or what I refer to as a Malcolm Gladwell "blink" moment, you know, in which your 25 years of experience allowed you to synthesize a hundred different sensory and cognitive inputs in a split second to realize this was the time? Dr. Alice Cusick: I think I knew it was time because I had been seeing him so frequently and I knew him very well. The smell was very real to me. My husband and I disagree because I've talked to my husband about this. He thinks it was a real smell and that I did smell something. I think it was more that amalgamation of my experience and, as I said in the piece, a scent took the place of a thought. Dr. Mikkael Sekeres: Huh. Dr. Alice Cusick: But it bothered me so much, and that's when I talk about, "Did I have a gift?" You know, there are people who can smell diseases. There's a report of a woman who could smell Parkinson's disease. I thought, "Have I suddenly developed some sort of gift?" But in my mind, I thought, "You know, it was inevitability." I mean, it was inevitable that this gentleman was going to die of this disease. So that was my thought. I don't think I had a gift. I think it was smelling the inevitability that I understood through experience and knowing this patient so well. Dr. Mikkael Sekeres: Why do you think that smell haunted you so much afterwards? I mean, you really think about it and really dwell on it. I think in a way that any one of us would. Dr. Alice Cusick: I think because I thought there was something wrong with me. As I said in the piece, I thought it made my experience of that patient, my memory of that visit in particular and the whole relationship with him, I was thinking more about myself instead of thinking about him and his experience and his family's experience. And you know, you always grieve for patients, and it was interfering with my normal process. And so it really bothered me. In the end, it was more, "What was wrong with me?" This was weird, and it just sort of played with my usual understanding of how these things were supposed to go. And that's what really bothered me. Dr. Mikkael Sekeres: It is true. We really feel acutely our patients' loss, and it's so much more, I don't know if "acute" is the right word, or so much more meaningful when it's someone we've gotten to know over years, isn't it? Dr. Alice Cusick: Oh, very much so. You grieve for them, you miss them. At the same time, you also, you know, especially with this patient, his death was how he wanted it. So helping someone with the, quote unquote, "good death", the death surrounded by family, the death where there is no suffering or as minimal suffering as possible, you do find that helps with the grief, I think, instead of thinking, "Oh, what did I do wrong? What did I miss?" You can make it somewhat helpful in processing the grief. Dr. Mikkael Sekeres: It's perhaps one of the more exquisite aspects of the art of medicine is helping people with that transition in their final days and sharing in the emotions of that. It has been such a pleasure to have Alice Cusick, who is Hematology Section Chief at Veterans Affairs Ann Arbor Health System and Assistant Professor at the University of Michigan, Division of Hematology and Oncology to discuss "Smell." Alice, thank you so much for submitting your article and for joining us today. Dr. Alice Cusick: Oh, thank you so much. I really appreciate it. Dr. Mikkael Sekeres: If you've enjoyed this episode, consider sharing it with a friend or colleague or leave us a review. Your feedback and support helps us continue to have these important conversations. If you're looking for more episodes and context, follow our show on Apple, Spotify, or wherever you listen and explore more from ASCO at asco.org/podcasts. Until next time, this has been Mikkael Sekeres for Cancer Stories. 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. Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio: Dr Alice Cusick is Hematology Section Chief at Veterans Affairs Ann Arbor Health System and Assistant Professor at the University of Michigan Division of Hematology and Oncology.

JCO Editor-in-Chief Dr. Jonathan Friedberg is joined by colleagues Dr. Jennifer Woyach, Dr. Wojciech Jurczak, and Dr. Matthew Davids to discuss simultaneous publications presented at ASH 2025 on pertibrutinib, a new upfront treatment option for patients with chronic lymphocytic leukemia. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Jonathan Friedberg: I'm Jonathan Friedberg, editor of Journal of Clinical Oncology, and welcome to JCO After Hours, where we are covering two manuscripts that were presented at the American Society of Hematology meeting 2025 in Orlando, Florida. I am delighted to be joined by colleagues on this call to discuss these pivotal manuscripts which cover the topic of pirtobrutinib, a new upfront treatment option for patients with chronic lymphocytic leukemia. I will first just introduce our guests, Dr. Woyach. Dr. Jennifer Woyach: Hi, my name is Jennifer Woyach. I am from the Ohio State University. Dr. Wojciech Jurczak: Hello, I am Wojciech Jurczak, working at the National Research Institute of Oncology in Krakow, Poland. Dr. Matthew Davids: Hi, I am Matthew Davids from Dana-Farber Cancer Institute in Boston. Dr. Jonathan Friedberg: We are going to start by just learning a little bit about these two trials that were both large, randomized phase 3 studies that I think answered some definitive questions. We will start with your study, Jennifer. If you could just describe the design of your study and the patient population. Dr. Jennifer Woyach: Absolutely. So this is the BRUIN CLL-314 study, and this is a phase 3 randomized trial of pirtobrutinib versus ibrutinib in patients with CLL or SLL who had not previously been treated with a covalent BTK inhibitor. The patients were both treatment-naive and relapsed/refractory, about one-third of the patients treatment-naive, the rest relapsed/refractory, and they were stratified based upon 17p deletion and the number of prior lines of therapy. The primary objective was looking at non-inferiority of overall response rate over the entire treated population as well as the relapsed/refractory patient population. Key secondary objectives included progression-free survival in the intention-to-treat and the smaller relapsed/refractory and treatment-naive populations. Dr. Jonathan Friedberg: And just comment a little bit on the risk of the patients. Dr. Jennifer Woyach: This study was fairly typical of this cohort of patients. Within the relapsed/refractory patient population, there was a median of one prior line of therapy in each of the groups, up to nine prior lines of therapy in the patients included on the study. For the overall cohort, about two-thirds of the patients were IGHV unmutated, about 15% had 17p deletion, 30% had TP53 mutations, and about 35% to 40% had a complex karyotype, which is three or more abnormalities. Dr. Jonathan Friedberg: And what were your findings? Dr. Jennifer Woyach: Regarding the primary outcome, which is the focus of the publication, we did find that pirtobrutinib was indeed non-inferior and actually superior to ibrutinib for overall response rate throughout the entire patient population and in both the relapsed/refractory and treatment-naive cohorts. PFS is a little bit immature at this time but is trending towards also being significantly better in pirtobrutinib-treated patients compared with ibrutinib-treated patients. Probably most significantly, we found this to be the case in the treatment-naive cohort where there was a striking trend to an advantage of pirtobrutinib versus ibrutinib. Dr. Jonathan Friedberg: And the follow-up that you have on that progression-free survival? Dr. Jennifer Woyach: So we have about 18 months follow-up on progression-free survival. Dr. Jonathan Friedberg: The second study, Wojciech, can you just go through the design and patient population that you treated? Dr. Wojciech Jurczak: Thank you, Dr. Friedberg, for this question. So the BRUIN CLL-313 study was, in fact, the first phase 3 study with pirtobrutinib in exclusively untreated CLL patients. It was a randomized study where we challenged pirtobrutinib versus bendamustine-rituximab. At the time we designed the protocol, bendamustine-rituximab was an option as a standard of care, and Bruton tyrosine kinase monotherapy was used far more commonly than nowadays. The primary target of the study was progression-free survival. We took all untreated patients except for those with 17p deletions. Therefore, it is a good representation for intermediate risk. We had about 60% of the population, 56 to be precise, which was unmutated, evenly distributed into two treatment arms. 17p deleted cases were excluded, but we had about 7% and 8% of TP53 mutated patients as well as about 11% and 7%, respectively, in the pirtobrutinib and bendamustine-rituximab arm of patients with complex karyotype. The progression-free survival was in favor of pirtobrutinib and was assessed by an independent review committee. What is important is that the progression-free survival of the bendamustine-rituximab arm was actually similar to the other studies addressing the same questions, like the comparison with ibrutinib in the ALLIANCE study or zanubrutinib in the SEQUOIA study. What was different was the hazard ratio. In our study, it was 0.20. It was one of the longest effect sizes noted in the frontline BTK study. It represented an 80% reduction in progression-free survival or death. If we compare it to ibrutinib or zanubrutinib, it was 0.39 and 0.42 respectively. Presumably, this great effect contributed towards a trend of overall survival difference. Although survival data are not mature enough, there is a clear trend represented by three patients we lost in the pirtobrutinib arm versus 10 patients lost in the bendamustine-rituximab arm. This trend in overall survival is becoming statistically significant despite the fact that there was a possibility of crossover, and effectively 52.9 patients, which means 18 out of 34 patients relapsing in the bendamustine-rituximab arm, were treated by pirtobrutinib. Dr. Jonathan Friedberg: I am going to turn it over to Matt. The question is: why study pirtobrutinib in this patient population? And then with these two studies, how do you find the patients that were treated, are they representative of people who you see? And do you see this maybe being approved and more widely available? Dr. Matthew Davids: I think in terms of the first question, why study this in a frontline population, we have seen very impressive data with pirtobrutinib in a very difficult-to-treat population of CLL patients. This was from the original BRUIN phase 1/2 study where most of the patients had at least two or three lines of therapy, often both a covalent BTK inhibitor and the BCL2 inhibitor venetoclax, and yet they were still responding to pirtobrutinib. The drug was also very well tolerated in that early phase experience. And actually, we have seen phase 3 data from the BRUIN 321 study comparing pirtobrutinib to bendamustine and rituximab in a relapse population as well. So I think that really motivated these studies to look at pirtobrutinib as a first therapy. You know, often in other cancers of course, we want to use our best therapy first, and I think these studies are an initial step at looking at that. In terms of the second question around the patient population, these are pretty representative patient populations, I would say, for most frontline CLL studies. We see patients who are a bit younger and fitter than sort of the general population of CLL patients who are treated in clinical practice, and I think that is true here as well. Median age in the sort of mid-60s here is a bit younger than the typical patients we are treating in practice. But that is not different from other CLL frontline studies that we have seen recently, so I think it makes it a little bit easier as we kind of think across studies to feel comfortable that these are relatively similar populations. Dr. Jonathan Friedberg: How do you see this either getting regulatory approval or potentially being used compared to current standard of care options? Dr. Matthew Davids: So my understanding is that both of these trials were designed with registrational intent in the frontline setting, and they are both positive studies. That is certainly very encouraging in terms of the potential for an approval here. We have seen in terms of the FDA recently some concerns around the proportion of patients who are coming from North America, and my understanding is that is relatively low on these two studies. But nonetheless, the datasets are very impressive, and so I think it is certainly supportive of regulatory approval for frontline pirtobrutinib. Dr. Jonathan Friedberg: I will ask Jennifer a question. The control arm in your study was ibrutinib, and I think many in the audience may recognize that newer, second-generation BTK inhibitors like acalabrutinib and zanubrutinib are more frequently used now if monotherapy is decided. How do you respond to that, and how would you put your results in your pirtobrutinib arm in context with what has been observed with those agents? Dr. Jennifer Woyach: Yeah, that is a great question. Even though in the United States we are predominantly using acalabrutinib or zanubrutinib when choosing a monotherapy BTK inhibitor, this is actually not the case throughout the entire world where ibrutinib is still used very frequently. The head-to-head studies of both acalabrutinib and zanubrutinib compared to ibrutinib have shown us pretty well what the safety profile and efficacy profile of the second-generation BTK inhibitors is. So even though we do not have a head-to-head study of acalabrutinib or zanubrutinib versus pirtobrutinib, I think, given the entirety of data that we have with all of the covalent BTK inhibitors, I think we can safely look at the pirtobrutinib arm here, how the ibrutinib arm compares or performs in context with those other clinical trials. And though we really can not say anything about pirtobrutinib versus acalabrutinib or zanubrutinib, I think we can still get a good idea of what might be the clinical scenarios in which you might want to choose pirtobrutinib. Dr. Jonathan Friedberg: And Wojciech, do you agree with that? Obviously, I think you have acknowledged that chemoimmunotherapy is rarely used anymore as part of upfront treatment for CLL. So, I guess a similar question. If you were to put the pirtobrutinib result in your study in context with, I guess, more contemporary type controls, would you agree that it is competitive? Dr. Wojciech Jurczak: Well, I think that that was the last study ever where bendamustine-rituximab was used as a comparator arm. So we should notice that smashing difference. Because if we look at the progression-free survival at two years, we have 93.4% in pirtobrutinib arm versus 70.7% in bendamustine-rituximab arm. Bendamustine-rituximab arm did the same as in the other trials, like ALLIANCE or SEQUOIA. Pirtobrutinib did exceptionally well, as pirto is not just the very best BTK inhibitor overcoming the resistance, but perhaps even more important for the first line, it is very well tolerated and is a very selective drug. Now, if we look at treatment-related adverse events, the discontinuation rate, they were hardly ever seen. If we compared the adverse events in exposure-adjusted incidence, literally all adverse events were two or three times higher in bendamustine-rituximab arm except for the bleeding tendency, which however was predominantly in CTCAE grade 1 and 2 with just 0.7% of grade 3 hemorrhage. Therefore, I think that we should actually put the best and the safest drugs upfront if we may, and pirtobrutinib is, or should be, the first choice if we choose monotherapy. Now, I understand that we are not presenting you the data of pirtobrutinib in combination with anti-CD20 or with BCL2 inhibitors, but that is to come. Dr. Jonathan Friedberg: Matt, how would you envision, were regulatory approval granted and this were an option, using this in the upfront patient population? Is there anybody who you would preferentially use this or start on this treatment? Or would this be something that you would tend to reserve for second line? Dr. Matthew Davids: So I would say that in general for most of my patients who would want to start with a continuous BTK inhibitor, I would still use a covalent BTK inhibitor, and I say that for a couple of reasons despite the very promising data from these studies. The first is that the follow-up for both of these phase 3 trials is still quite short, in the range of a median 18 to 24 months. And we know that CLL is a marathon, not a sprint, and these patients are going to probably be living for a very long time. And we do have much longer follow-up from the covalent BTK inhibitors, median of 10-year follow-up with ibrutinib and five to six years with zanubrutinib and acalabrutinib respectively. And you know, I do not think that the pirtobrutinib is going to fall off a cliff after two years, but on the other hand, I think there is a lot of value to long-term data in this disease, and that is why I think for most of my patients I would stick with covalent BTK inhibitors. But the other important factor that we need to consider is patients who are younger and may have many different CLL treatments over the years. We have to be very careful, I think, about how we sequence these drugs. We know right now that we can start with covalent BTK inhibitors and then subsequently patients will respond well to the non-covalent inhibitor pirtobrutinib in later lines of therapy. But right now we do not have prospective data the other way around. So how will the patients on these studies who progress on pirtobrutinib respond to covalent BTK inhibitors? We do not know yet. There have not been a lot of progression events, which is great, but we would like to see some data in that respect to feel more comfortable with that sequence. Now, I do think that particularly for older patients and those who have significant cardiovascular comorbidities, if they wanted to go on a continuous BTK inhibitor, I do think these data really strongly support using pirtobrutinib as the BTK inhibitor of choice in that population. In particular, the cardiovascular risks with pirtobrutinib seem to be quite low. I was very struck in the comparison with BR that the rate of AFib was equivalent between the two arms of the study. And that is really the first time we have seen that with any of these BTK inhibitors, no elevated risk of AFib in a randomized study. I think that is the population where it will get the most traction first, is the upfront, sort of older patient with significant cardiovascular comorbidities. And as the data from these studies mature, I think that we will start to see more widespread use of pirtobrutinib in the frontline setting. Dr. Jonathan Friedberg: Jennifer, I am just curious if you have any personal experience or heard anecdotally about after progression on pirtobrutinib the use of other BTK inhibitors and whether there is a growing experience there. Dr. Jennifer Woyach: I do not think that there is much clinical experience, you know, as Matt alluded to, it certainly has not been tested yet. There has been some data in relapsed CLL suggesting that in people who have resistance mutations to covalent BTK inhibitors after treatment with pirtobrutinib, sometimes those mutations go away. I think most of us are concerned that they are probably not actually gone but maybe in compartments that we just have not sampled, suggesting that sort of approach where you might sequence a covalent inhibitor after a non-covalent in somebody who had already been resistant probably would not work that well. But, you know, in this setting where people had never been exposed to a covalent BTK inhibitor before, we really have no idea what the resistance patterns are going to be like. We assume they will be the same as what we have seen in relapsed CLL, but I think we just need some longer follow-up to know for sure. Dr. Wojciech Jurczak: If I may confront Dr. Davids about the use of covalent BTK inhibitors upfront, well, I think that we should abandon the idea of using the first and the second and the third generation, at least if we don't have medical lines. If we endlessly block the same pathway, it is not going to be effective. So if pirtobrutinib gets approval in first, second line, we do not necessarily have to use it in the first line. I am not here in a position to defend that we should treat patients with pirtobrutinib upfront and not BCL2 time-limited regimen. However, the way I look at CLL patients when choosing therapy is not just how should I treat them now, but what would be the best regimen in 5, 10 years if I have to re-treat them. And in some instances, the idea may be that in this setting we would like to have a BTK inhibitor upfront to have a BCL2 inhibitor later to make it time-limited. Although I understand and I agree with Matthew that if we have an elderly, fragile population, then the charm of having a drug taken once a day in a tablet with literally few cardiovascular adverse events might be an option. Dr. Jonathan Friedberg: And I will give Matt the last word whether he wants to respond to that, and also just as a forward-looking issue, I know both investigators have implied that there will be future studies looking at combinations with pirtobrutinib, and if you have any sense as to what you would be looking for there. Dr. Matthew Davids: The field really is heading toward time-limited therapy for most patients, I would say. There is a bit of a discrepancy right now in the field between sort of what we are doing in academic practice and what is done sort of more widely in community practice. And so right now we are going to see evolving datasets comparing these approaches. We are already seeing data now from the CLL17 study with ibrutinib comparing continuous to time-limited venetoclax-based therapy, and we are seeing similar efficacy benefits from these time-limited therapies without the need for continuous treatment. And so that is where I think some of the future studies with pirtobrutinib combining it with venetoclax and other partners are so important. Fortunately, several of these studies are already ongoing, including a phase 3 trial called CLL18, which is looking at pirtobrutinib with venetoclax, comparing that to venetoclax and obinutuzumab. So I am optimistic that we are going to be developing these very robust datasets where we can actually use pirtobrutinib in the frontline setting as a time-limited therapy as a component of a multi-drug regimen. So far, those early data are very promising. Dr. Wojciech Jurczak: Perhaps last but not least, in a single center we have treated over 300 patients with pirtobrutinib. So eventually some of them relapsed. And I must say that our experience on BCL2 inhibitors, not just venetoclax but including sonrotoclax, are appealingly good. Therefore, by using pirtobrutinib even earlier, we do not block the efficacy of other compounds. Dr. Jonathan Friedberg: All right. Well, I want to thank all of our speakers. I also want to congratulate our two guests who presented these very influential papers at the ASH Annual Meeting, and chose to publish them in JCO, so we thank you for that, and Dr. Davids for your commentary - really appreciated. That is this episode of JCO After Hours. Thank you for your attention. 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. Wojciech Jurczak Consulting or Advisory Role: BeiGene, Lilly, Abbvie/Genentech, Takeda, Roche, AstraZeneca Research Funding: Roche, Takeda, Janssen-Cilag, BeiGene, AstraZeneca, Lilly, Abbvie/Genentech Dr. Jennifer Woyach Consulting or Advisory Role: Pharmacyclics, Janssen, AstraZeneca, Beigene, Loxo, Newave Pharmaceutical, Genentech, Abbvie, Merck Research Funding: Company name: Janssen, Schrodinger, beone, Abbvie, Merck, Loxo/Lilly Dr. Matthew Davids Honoraria: Curio Science, Aptitude Health, Bio Ascend, PlatformQ Health, Plexus Consulting or Advisory Role: Genentech, Janssen, Abbvie, AstraZeneca, Adaptive Biotechnologies, Ascentage Pharma, BeiGene, Lilly, Bristol-Myers Squibb, Genmab, Merck, MEI Pharma, Nuvalent, Inc., Galapagos NV, Schroedinger Research Funding: Ascentage Pharma, Novartis, MEI Pharma, AstraZeneca  

Dr. Pedro Barata and Dr. Ravin Garg discuss strategies to increase trial representation, including leveraging trial navigators and prioritizing pragmatic trial models, as featured in the ASCO Educational Book article, "Practical Guide to Clinical Trial Accessibility: Making Trial Participation a Standard of Care." TRANSCRIPT Dr. Pedro Barata: Hello, and welcome to By the Book, a podcast from ASCO featuring compelling perspectives from authors and editors of the ASCO Educational Book. I'm Dr. Pedro Barata. I am a medical oncologist at University Hospital Seidman Cancer Center and an associate professor of medicine at Case Western Reserve University in Cleveland, Ohio. I am also the associate editor of the ASCO Educational Book. We know that in recent years, the oncology community has increasingly prioritized the need to modernize clinical trial eligibility, reduce patient burden, and enhance diversity in trial participation. On that note, today we will be speaking about ways to enhance access to clinical trials with Dr. Ravin Garg. He is a hematologist oncologist at Maryland Oncology Hematology and also an assistant professor of oncology at Johns Hopkins Hospital in Baltimore. Dr. Garg is also the co-author of a fantastic paper in the ASCO Educational Book titled, "Practical Guide to Clinical Trial Accessibility: Making Trial Participation a Standard of Care."  Dr. Garg, welcome. Thanks for being here, and congrats on your paper. Dr. Ravin Garg: Thank you for having me, Pedro. I am excited to be here. Dr. Pedro Barata: [KI1]  Your paper is a wonderful, multidisciplinary piece that actually features perspectives from the different stakeholders, right? The patient advocacy, industry, community practice, and academia about these challenges in making trials more available. This podcast is a wonderful platform. It reaches out to a lot of folks within our community. So, I will start by asking you the obvious. Why do you think it is a must read for our community, for our listeners? Dr. Ravin Garg: So Pedro, thanks again for inviting me. You do a great job with these podcasts.  So, I think first and foremost, oncologists right now are under a lot of stress, just in terms of clinical volume. There is concern for research money, and how we get the best care for our patients. So I think this article is very important because it helps bring together, as you had mentioned, the stakeholders throughout academic to community practice and everywhere in between, and try to find how, as a team with different oncologists who partake in different aspects of oncology, can come together to streamline the process to try to get our patients on trials, or certainly have them have availability of trials, just if they are interested in going on them. Being in practice, we have had several challenges that we can talk about throughout this podcast, but I think it is a very important paper because it recognizes that at the end of the day, it takes a team effort for all of us in academics, community, industry, and pharmaceuticals to really come together as a team to really help put forth the trials for our patients. Dr. Pedro Barata: So, from the perspective of a community oncologist, how do you put together, or maybe you can describe some of the challenges that you see to increase trial participation in the community? Dr. Ravin Garg: Yes, Pedro, that is a great question, and it is something that I keep on thinking about and trying to find ways to be better at it myself. But I will say some of the challenges as a community doctor that I have seen for myself and talking to other colleagues. Number one, I do think there is a lot of stress on doctors in the community in general, Pedro. Oftentimes we are tasked to see a wide smorgasbord of patients, so we may not have the luxury of being a specialist in any particular tumor subtype. Like oftentimes, we will have to see lung cancer, the next one will be breast cancer, the next one could be CML, the next one could be thrombocytopenia. And as you know better than I do, Pedro, the field in each one of these disciplines is changing so rapidly: molecular genomics, radioligand treatments, different imaging tests, MRD testing for some of our hematologic malignancies. And I think one challenge we have in community is just keeping up with the basics of Oncology 101. In the process of doing that, it can be very difficult to sometimes remember that we have very exciting trials available for our patients. So, I think a lot of it is the day in and day out of being an oncologist is so taxing at times that oftentimes a research trial is not the first thing in our head space when we see a patient. I think number two, Pedro, at least in the community, and perhaps this is with academics too, is that we are bombarded, I would say, by a lot of messaging these days. We have in-baskets to go through, labs to go through, things of that nature. And in the process of a patient visit, seeing them, doing an exam, taking a history, trying to go over the NCCN guidelines on best practice for how to manage their care, at least for me at times, it is very hard to remember, "Hey, there might be a great trial available, whether within our network or maybe partnering with an academic center." So getting through a day can be fraught with a lot of peril and just difficulties, I would say. And I would say number three, Pedro, at least as, you know, I am in a private practice where I do see a wide range of benign and malignant hematology and solid tumors, so I would not call myself a specialist. And I think the challenge with that, at least for trials, Pedro, is that when you are a specialist or perhaps you are focusing on a couple of disease subtypes, you become more of an authoritative voice in those types of tumors, and you might be more aware of the trials within your network or perhaps in proxy with an academic center that you can offer your patient. So I think when sometimes we spread ourselves too thin, it can be very hard to be a thought leader, if you will, in a particular subtype of a malignancy, let's say, and maybe not be aware of a trial that could be really well-suited for your patient. In terms of ideas that myself and colleagues have had in terms of helping mitigate against some of these, I would say, setbacks or issues in the practice for trial enrollment, some of the things we have talked about, Pedro, is, number one, is we do partner with academic centers. So we live here in Maryland. We have several really fantastic academic centers. So, you know, oftentimes, not just within our practice of Maryland Oncology Hematology, we have a lot of great trials available here too, for certain, but in addition to that, we will often times work with doctors at Georgetown, Johns Hopkins, and Maryland if they have a compelling trial that we do not have within our network. It is really of the patient's interest, Pedro, to reach out to them in a collaborative manner to see if they have a trial that might be really compelling for your patient. So I do find myself collaborating a lot with colleagues in, like talented like yourself in academics. You know, I think you do a lot of GU malignancies. So as an example, like partnering with colleagues who are GU experts and say, "Hey, we have a patient with stage IV renal cell. These are the standard options I know, but are there any trials that you might have available?" I think the other thing that has been very helpful for us is having navigators within research, Pedro. Like as an example, what has really helped the uptake of trial enrollment for our center in Annapolis is having a research navigator because often times what they can do is, a priori, Pedro, before you see the patient and you are kind of formulating a standard of care treatment plan perhaps, they might tug you on the shirt and say, "Hey, we have a great trial here through Sarah Cannon, or there might be something else out there." And being aware of that when you go into a patient's room really provides a nice arena, if you will, to go and say, "The standard of care is here, but hey, we have a trial option that might be well suited for you, maybe perhaps even better, that we can talk about, too." So having research support in the community is really a huge boon, I think, Pedro, for us to really increase our enrollment for patients onto trials. Dr. Pedro Barata: Yes, I really love that, Ravin. So, let me switch gears a bit. I would love for you to talk a little bit about patient advocacy because they do play a huge role in cancer, and they address many barriers. How do you think we should leverage the patient advocacy groups to reduce patient burden and maybe have them really leverage patient advocacies to improve representation in clinical trials? What do we think we can do more? Dr. Ravin Garg: Oh, Pedro, I think they are very critically important. As a clinical oncologist now, and I would say this is for anyone in the field of medicine, you are exactly right. I think patients are bombarded by information. There are a lot of things online, whether it be TikTok, Facebook, Google, Yahoo, and people really just have a lot of information given to them. And some of it is fact driven, and some of it is not, Pedro. And oftentimes, I do think there can be at times a mistrust with some medical personnel. I think we are in an era where we are seeing that to some degree with some attributes of medicine. And I think of it as an opportunity for education for the patient and for myself as a physician. And I think patient advocates, to your point, which was well taken, serve as a bridge to both. And what I mean is that, you know, patient advocates are wonderful. They are, I think, outstanding communicators. They almost are a neutral party, Pedro, where many patients feel that they are an independent source of information that is free of bias, if you will. They are there to provide support, emotional support, scientific support for patients so they can make an informed decision. So, in terms of our practice right now, patient advocates is something that we are evolving in that capacity, I would say, Pedro. I think now more than ever, having more people as bridges of communication with care providers along with patients is of critical importance. And I would venture a guess, and I think this has been published, where patient advocates really can help tremendously in familiarizing patients with trials and what they are all about and maybe clear up some misconceptions of what trials, what the mission of trials are. Because I do think some patients, at least I have had a few over the years, where when they hear the term trial, they almost think they are being experimented upon, when, in point of fact, they could really help advance their care. That messaging along the way for some can may be mixed up a little bit. And so I think patient advocates is a really great way to offer more information for patients with a source they find very independent and trustworthy, if you will. And it can really help expedite, and I think make a more fruitful conversation for care providers, whether academic or community, and they might be more open-minded in terms of enrolling onto a trial. Dr. Pedro Barata: Wonderful. Yes, I agree. I agree with you completely.  So let's focus a little bit now on the folks designing the studies. We usually call them the sponsors. It might be an academic sponsorship, if you will, but we can also have pharma being the sponsor of a study. The angle from an academic design, it is not necessarily the same as what happens when we have pharma. And from that angle, how do you think a more inclusive research can be promoted? Dr. Ravin Garg: Oftentimes with trials, I think keeping them simple, as simple as we can. And what I mean by that is, often times for trials, Pedro, even for care providers who are enrolling, it can be daunting when there are a lot of different things involved, particularly, let's say, for investigator sponsored, which are incredibly brilliant science, incredible, but it can be a little bit daunting for patients and even the referring physician to talk about getting translational specimens, imaging, traveling to certain centers to get scans and biopsies and even different diagnostic testing like PSMA testing for, you know, prostate cancer. And it can, I think, be very intimidating for patients in terms of what might be required of him or her to enter onto a trial. Like, "This is not what I signed up for. This is laborious. This is a full time job for me. Do I have to pay for parking to go to a city? Do I have to pay for these imaging tests? And do I have to stay in a place for my family to enroll onto a trial?" So I think keeping trials as simple as possible, but yet cull the data we need as investigators where we can really advance the care, hopefully get approval for a drug, but also learn more about the medication and how it works for our patients. So I think simplifying language for trial is very important. I know when I have gone over studies for patients, Pedro, if it is a voluminous amount of information, they can right away get very intimidated. "Like, oh my goodness, this is like a term paper for college again," you know? I am joking, but you know, keeping language simplified is very important, I think, number one. And I feel that sometimes when they are asked to do a lot of different diagnostic testing, which is very important for translational work, I 100% understand, but I do think sometimes patients can get a little bit off put, if you will, and frustrated with the whole process of doing it. The second thing for our patients, Pedro, that they have mentioned to us when we put them on trials, not just within our own site but elsewhere, is that it takes a lot of time in terms of collecting information, perhaps a washout period from their last standard of treatment prior to enrollment onto a study. Many patients, Pedro, as you know better than I do, are in maybe crisis in terms of their health and their cancer might be growing, promulgating out of control, and they worry about not being able to expeditiously start onto a treatment, onto a trial. So that can lead to a lot of frustration. And one thing that you brought up, which was outstanding for me, is the enrollment criterion for some of our patients is felt to be somewhat strict. We have had some patients who may have had a remote history of a stage I malignancy that was by all accounts in remission, you know, let's say 4 or 5 years in the past, and the risk of recurrence at this point would be incredibly low, but they may not be able to enter onto a study because of some stringent criterion put forth. And that can be a little bit frustrating. In fact, I have had one or two patients who, as an example, with kidney issues, but the GFR was about 60, like right near a cutoff that oftentimes, as you know, we use where you can get into trial or not. And you know, if they are at 58, as an example, and otherwise they are a picture of health, a great candidate for a trial that will likely advance their care, and if the entry criterion is too stringent, that might be a lost opportunity for all parties involved, all stakeholders, if you will. I do appreciate the criterion for entry onto studies cannot be too liberalized. You have to have a certain baseline, but there is a little bit of a gray area and tension, of sorts, if you will, where the patient has a comorbid illness that is a disqualifying offense, but in practicality, perhaps it shouldn't be, especially if they are motivated and there is an opportunity to really advance their care. We have run into, not often, but sometimes in the past, I should say, where patients have been very off put because we try to get them onto a study and there may have been a particular feature or attribute in their underlying care that they couldn't get onto it. So I think having a little bit more thoughtfulness, perhaps, in terms of entry criterion and practicality, if you will, I think would really help enrollment onto studies. Dr. Pedro Barata: Really well said. Is there anything else that you would like to tell our listeners before we wrap up the podcast today? Dr. Ravin Garg: I would say just macroscopically speaking, it is really an honor to be an oncologist. I think I speak for both of us. Anyone listening who is thinking about the field, it is tremendous. Just the research, the bravery of our patients, and the thoughtfulness of our scientists like Pedro and translationalists and clinical trialists is really awe inspiring. So I have really loved this field. I will say from a trial perspective, we really need to enter as many patients as we can onto trials because the science is so brilliant now, the genomic underpinnings of the tumor, we are making great strides as a team of clinicians and scientists, translationalists. So the more that we can get people onto trials and get approved drugs, it is going to help them out in the end. So I think it is such an important time for all of us to come together as a community, find the best way to help our patients out. And clinical trials have to be at the forefront of how we can continue to advance care for our patients. Dr. Pedro Barata: Yeah, no Ravin, I really agree with you. We really need to increase access to clinical studies, and actually your paper is a great step in that direction by raising awareness, bringing up solutions, and again, collaboration, collaboration, collaboration is really a multidisciplinary effort to accomplish that.  Thank you so much for sharing your fantastic thoughts and insights with us. Dr. Ravin Garg: Thank you, Pedro. I am- you do a wonderful job with these podcasts. I am really honored to meet you and to be part of this. Dr. Pedro Barata: And thank you to our listeners for your time today. I encourage you to check out Dr. Garg's article in the 2025 ASCO Educational Book. We will post a link to the paper in our show notes. And please join us again next month on By the Book for more insights on key advances and innovations that are shaping modern oncology. Thank you for your attention. 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. Pedro Barata   @PBarataMD    Dr. Ravin Garg Follow ASCO on social media:          @ASCO on X      ASCO on Bluesky     ASCO on Facebook       ASCO on LinkedIn       Disclosures:       Dr. Pedro Barata:   Stock and Other Ownership Interests: Luminate Medical   Honoraria: UroToday   Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Merck, Ipson, Astellas Medivation, Novartis, Dendreon   Speakers' Bureau: AstraZeneca, Merck, Caris Life Sciences, Bayer, Pfizer/Astellas   Research Funding (Inst.): Exelixis, Blue Earth, AVEO, Pfizer, Merck    Dr. Ravin Garg: Patents, Royalties, Other Intellectual Property: Creator, editor, and writer of hemeoncquestions.com  

JCO Editorial Fellow Peter Li and author Dr. Jahanzaib Khwaja discuss the  ASH 2025 Simultaneous Publication article, "A New Validated Staging System for AL Amyloidosis With Stage lllC Defining Ultra-Poor Risk: AL International Staging System." TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Peter Li: Welcome to this episode of JCO Article Insights. I am Dr. Peter Li, JCO's Editorial Fellow, and today, I am joined by Dr. Jahanzaib Khwaja on a new validated staging system on AL amyloidosis with stage lllC defining ultra-poor risk, AL International Staging System. This is a simultaneous publication that will be presented at this year's ASH Conference.  At the time of this recording, our guest has disclosures that will be linked in the transcript.  So, Dr. Khwaja, let's start off first: What would you say is the significance of your study? Dr. Jahanzaib Khwaja: Thank you very much. This is an important study in that, in the current treatment era, we have really improved outcomes of patients with systemic AL amyloidosis. Traditionally, the staging systems that have been employed, which are the Mayo 2012 and the European modification 2016, have been founded in eras where there were historic treatment protocols. So the significance of this new staging system is looking at outcomes of patients in the modern treatment era. That is patients who are treated with daratumumab-based treatments in the first line. And this is kind of the largest study which is externally validating a new prognostic model in the current treatment era with modern outcomes. Dr. Peter Li: Can you tell our listeners what is different about your new staging system? Dr. Jahanzaib Khwaja: The traditional staging systems, the Mayo 2012 and the European modification of 2016, looked at outcomes of patients with systemic AL amyloidosis with historic treatment protocols. And we know that they looked at outcomes according to an NT-proBNP and troponin, and in the Mayo 2012, they looked at it with the addition of the dFLC, which is the difference in the involved and uninvolved free light chain. Over the years, we have seen that outcomes have improved, and over decades, actually, outcomes are much better when we compare them to the previous decade. If we look at current treatment approaches, those traditional staging systems inadequately determine the poorest prognostic risk. So they are unable to tell us those who are going to perform poorly. Our current new validated staging system looks at the traditional NT-proBNP and troponin but uses the addition of the longitudinal strain. This is an echocardiographic parameter, and it is used widely in treatment centers who treat amyloidosis. This really identifies those ultra-high risk patients, and these are the patients who will perform poorly in current treatment protocols. And why is that important? Well, we need a robust staging system in the current treatment era which can stratify patients who will do well but also stratify those patients who do not do well. Because that is important for counseling patients, for risk stratification, for treatment approaches, and in the future, for designing clinical trials. Dr. Peter Li: And that is referring to the longitudinal strain greater than  -9% and NT-proBNP greater than 8,500 and then the high-sensitivity troponins greater than 50, which will define the new staging system. Can you talk more about how you picked these cutoffs and also what that alludes to in terms of the outcomes that you have discovered in this age of daratumumab-based therapy? Dr. Jahanzaib Khwaja: Yeah, that is a really excellent question because we have aimed to build upon traditional staging systems. So clinicians have used these traditional models for many, many years, and they have robustly underpinned our stratification of patients and how we counsel patients. So we didn't want to change some of these well-established thresholds, but we wanted to test them in the current treatment era. So the NT-proBNP of 8,500 and the high-sensitivity troponin of 50 were the traditionally used thresholds. And they actually stand the test of time. But we found that longitudinal strain additionally and independently predicts outcome independent of these other biomarkers. It is independent actually as a continuous variable, so you can cut this at a number of different stratification points and find independence. But we wanted to determine and discriminate those with the poorest outcomes. So we validated a longitudinal strain threshold of greater than  -9% by deriving this from a dataset of patients with the traditionally highest risk. Those are with European stage lllB. And looked at the optimal threshold with time-dependent ROC analysis. So we did this in our derivation cohort and then validated this externally in our external validation cohort amongst a number of centers in Europe, in the US, and in the UK. And it is important to note because longitudinal strain is an echocardiographic parameter, and traditionally the limitations are considered to be inter-vendor and inter-operator variability and intra-operator variability, and there are challenges with reproducibility of some of these measurements. So that is often cited as a limitation. But we found, when we have externally validated this across different centers using different platforms, actually the threshold of -9% is independently predictive of poorer outcomes independent of the traditional NT-proBNP and troponin thresholds, and it is robustly predictive of poorest outcomes. We know that those with stage lllC have a median overall survival of 4 to 7 months in the modern treatment era. And if we sub-stratify these by patients treated with daratumumab, outcomes have improved, but still, even if we look at daratumumab-treated patients, one-year overall survival is still only around 50 percent. So these are a poor risk group in the modern treatment era. Dr. Peter Li: Which kind of makes sense in a way because this kind of predicts whether they have amyloid-related cardiomyopathy. So I think this all tracks with our listeners. But given the poor outcomes even with daratumumab-based therapies, do you think this new staging system would change practice, if at all? Dr. Jahanzaib Khwaja: Yeah, I think that is a really good point because I think it comes to the question of why we use a staging system. What are its applications? I think one of the key things we think about in the clinic is how do we counsel patients when we first talk to them about their diagnosis. So there is a lot of information, but predominantly people want to know, what is my outlook going to look like? And as I say, in the bortezomib treatment era, 2010 to 2020, we used to say you have stage lllB, you have very poor outcomes, median survival maybe around six months. We have shown here that actually those with lllB have much better outcomes definitely over 12 months, up to 24 months in those with daratumumab-based therapies. So we need to counsel them in a different way. We then also need to say, "Well, who are the ultra-high risk?" So we said those with the longitudinal strain of greater than -9% with the traditional NT-proBNP and troponin cutoffs. And those patients will have poor outcomes. We need to talk about palliation. We need to talk about alternate treatment approaches. And then importantly for the community is about treatment and clinical trial design. So again, traditionally the traditional high-risk group lllB used to be considered an exclusion for all major trials. So these were excluded in the ANDROMEDA study, which led to the approval of daratumumab-based therapy, and multiple other trials. And we show here that actually patients with lllB should not be excluded from these studies because they do have good outcomes. And I think we make the important point that those with lllC, who do have poor outcomes, they need a different treatment approach, and we need to think about stratifying these patients differently. So perhaps the next modality of treatment will be the anti-fibril antibodies or a mode of treatment which can clear antibodies or clear the amyloid fibrils from the organs and reduce the organ toxicity early on. We know that those with lllC have poor outcomes particularly within the first year, and organ dysfunction really predominates here. So a different treatment approach is required, and we need to design trials specifically for these patients which look beyond anti-plasma cell clone therapy but also look at clearing the amyloid fibrils and improving organ function as this is predominantly the cause of death in these patients. Dr. Peter Li: That's an excellent point right there.  Do you foresee any limitations to this new staging system, or can you comment on is there potentially a better way to refine this staging criteria in the future? Dr. Jahanzaib Khwaja: Yeah, I think that is a really excellent point to consider, that staging systems always need refining across treatment eras. So we have looked at the bortezomib era, and then we have validated this in the daratumumab-based era. We know that amongst different countries access to treatment varies. We know that there are a number of factors which determine your health-related outcomes. That's access to healthcare, speed of diagnosis, access to tertiary diagnostics, ability to biopsy, and then supportive care. And I think our staging system highlights the importance of organ dysfunction predominantly causing death early on. And I think that as treatments improve this should be refined. So the expectation I think is, as we have better anti-plasma cell directed therapies, and as we hopefully develop anti-fibril antibodies and anti-fibril clearance drugs, that we will need to revalidate new models to effectively prognosticate in this treatment era. And I also think that as we become a bit more sophisticated with our approaches, we know that this can be refined in the future looking at other prognostic factors with regards to healthcare outcomes. I would say one of the strengths, however, of this model is that it builds on the traditional model, and it's quite simple to use. You just have the NT-proBNP and the troponin, and then longitudinal strain, which is used quite frequently in amyloid centers, and an echocardiogram is used in essentially all patients for diagnosis. So I think it will certainly be quite practical. But certainly I think, as you say, as treatment approaches change over time, and as we have further options in the future, we will need to refine prognostication. Dr. Peter Li: For the listeners out there, let's say someone comes in our clinic and we diagnose them with stage lllC amyloidosis. Can you comment on what clinical trials are out there that potentially they can refer their patients to? You mentioned anti-fibril therapy, which I think would be the way of the future. Can you kind of comment what you know at this current stage and point listeners in the right direction? Dr. Jahanzaib Khwaja: This is the challenge in amyloidosis. We don't have specific trials that are looking at those with the highest risk. And at present, even the ISA International Guidelines talk about risk according to the old treatment approaches and discuss attenuating our current chemotherapy approaches. And I think that for clinicians out there who identify those at the highest risk, it is really important to have a multidisciplinary approach, to consider palliation and palliative services early, and really work with your fellow cardiologists and renal physicians and neurologists to enable the best supportive care you have in order to deliver this anti-plasma cell directed therapy. We know that actually you only need for most patients small amounts of doses of chemotherapy to get good clonal responses, and we have seen that even in the bortezomib era that actually they have good CR rates and more impressive CR rates with daratumumab. But because of the organ dysfunction, it can be really challenging to deliver these doses. And supportive care is going to be really important particularly for these challenging patients. The future will be designing clinical trials that are appropriate for these patients. At present, we currently don't have available options, but I think the more we gather this data, the more we work collaboratively as a community, we will be able to mobilize our resources and get the best outcomes for these patients.  Dr. Peter Li: First build the field of dreams and then hopefully more therapies will arrive in the future. Thank you so much, Dr. Khwaja, for speaking about the JCO article, "A New Validated Staging System for AL Amyloidosis With Stage lllC Defining Ultra-Poor Risk: AL International Staging System," and for all your valuable input today. Dr. Jahanzaib Khwaja: Thank you very much. Dr. Peter Li: Make sure to check out the presentation at this year's ASH Conference taking place from December 6 to December 9. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit 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.

In this special edition of the Best Science in Lung Cancer series, host Erin Gillaspie, MD, sits down with Brendon Stiles, MD, to discuss insights from ASCO, including perioperative immunotherapy, CheckMate 816, and expanding surgical boundaries.

Dr. Monty Pal and Dr. Jason Westin discuss the federal funding climate for cancer research and the persistent problem of drug shortages, two of the major concerns facing the oncology community in 2026. TRANSCRIPT Dr. Monty Pal: Hello and welcome to the ASCO Daily News Podcast. I am your host, Dr. Monty Pal. I am a medical oncologist and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles. There are always multiple challenges facing oncologists, and today, we discuss two of them that really stand out for 2026: threats to federal funding for cancer research and the persistent problem of drug shortages. I am thrilled to welcome Dr. Jason Westin, who believes that one way to meet these challenges is to get oncologists more involved in advocacy, and he will share some strategies to help us meet this moment in oncology. Dr. Westin is a professor in the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center, but he actually wears a lot of hats within ASCO. He is a member of the Board of Directors and has also previously served as chair of ASCO's Government Relations Committee. And he is also one of the inaugural members of ASCO's Political Action Committee, or PAC. He has testified before Congress about drug shortages and many other issues. Dr. Westin, I am really excited to have you on the podcast today and dive into some of these elements that will really impact our community in 2026. Thanks so much for joining us today. Dr. Jason Westin: Thank you for having me. Dr. Monty Pal: You've had such a range of experience. I already alluded to you testifying before Congress. You've actually run for office before. You wear so many different hats. I'm used to checking my PubMed every other day and seeing a new paper out from you and your group, and you publish in the New England Journal [of Medicine] on practice-setting standards and the diseases that you treat. But you've also done all this work in the domain of advocacy. I can't imagine that balancing that is easy. What has sort of motivated you on the advocacy front? Dr. Jason Westin: Advocacy to me is another way to apply our skills and help more people than just those that you're sitting across from at the time. Clinical research, of course, is a tool to try and take what we know and apply it more broadly to people that you'll never meet. And advocacy, I think, can do the same thing, where you can have a conversation with a lawmaker, you can advocate for a position, and that hopefully will help thousands or maybe even more people down the road who you'd never get to directly interact with. And so, I think it's a force multiplier in the same way that research can be. And so, I think advocacy is a wonderful part of how doctors care for our patients. And it's something that is often difficult to know where to start, but once people get into advocacy, they can see that the power, the rewarding nature of it is attractive, and most people, once they get going, continue with that through the rest of their career. Dr. Monty Pal: So, I'll ask you to expand on that a little bit. We have a lot of our younger ASCO members listening to this podcast, folks that are just starting out their careers in clinical practice or academia. Where does that journey begin? How do you get to the point that you're testifying in front of Congress and taking on these bigger sort of stances for the oncology community? Dr. Jason Westin: Yeah, with anything in medicine and in our careers, you have to start somewhere. And often you start with baby steps before you get in front of a panel of senators or other high-profile engagement opportunities. But often the first setting for junior colleagues to be engaged is doing things – we call them "Hill Days" – but basically being involved in kind of low-stakes meetings where you're with a group of peers, some of whom have done this multiple times before, and can get engaged talking to members of representatives' offices, and doing so in a way where it's a natural conversation that you're telling a story about a patient in your clinic, or that you're telling a personal experience from a policy that impacted your ability to deliver optimal care. It sounds stressful, but once you're doing it, it's not stressful. It's actually kind of fun. And it's a way that you can get comfort and skill with a group of peers who are there and able to help you. And ASCO has a number of ways to do that, both at the federal level, there's the Hill Day where we each April have several hundred ASCO members travel to Capitol Hill. There's also state engagement that can be done, so-called visiting at home, when representatives from the U.S. Congress or from state legislators are back in district. You can meet with your own representatives on behalf of yourself, on behalf of your organization, and advocate for policies in a way that can be beneficial to your patients. But those initial meetings that are in the office often they're low stakes because you could be meeting not with the representative but with their staff. And that staff sometimes is as young or even younger than our junior colleagues. These sometimes can be people in their 20s, but they're often extremely knowledgeable, extremely approachable, and are used to dealing with people who are new to advocacy. But they actually help make decisions within the office. So it's not a waste of time. It's actually a super useful way to engage. So, it's that first step of anything in life. The activation energy is always high to do something new. But I'd encourage people who are listening to this podcast already having some level of interest about it to explore ways that they could engage more. Dr. Monty Pal: You know, I have to tell you, I'm going to riff on what you just said for a second. ASCO couldn't make it any easier, I think, for folks to participate and get involved. So, if you're listening to this and scratching your head and thinking, "Well, where do I begin? How do I actually sign on for that meeting with a local representative?" Go to the ASCO ACT Network website. And I'll actually talk to our producer, Geraldine, to make sure we've got a link to that somewhere associated with this podcast after it's published, Jason, but I actually keep that on my browser and it's super easy. I check in there every now and then and see if there's any new policy or legislation that ASCO, you know, is sort of taking a stance on, and it gives me some fodder for conversation with my local representatives too. I mean, it's just an awesome, awesome vehicle. I'm going to segue right from there right to the issues. So, you and I are both at academic centers. You know, I think this is something that really pervades academia and enters into implications for general clinical practice. There's been this, you know, massive sort of proposal for decreased funding to the NCI and to the NIH and so forth. Tell us what ASCO is doing in that regard, and tell us perhaps how our community can help. Dr. Jason Westin: We live in interesting times, and I think that may be an understatement x 100. But obviously investments in research are things that when you're at an academic center, you see and feel that as part of your daily life. Members of Congress need to be reminded of that because there's a lot of other competing interests out there besides investing in the future through research. And being an elected representative is a hard job. That is something where you have to make difficult choices to support this, and that may mean not supporting that. And there's lots of good things where our tax dollars could be spent. And so, I'm sympathetic to the idea that there's not unlimited resources. However, ASCO has done an excellent job, and ASCO members have led the charge on this, of stating what research does, what is the benefit of research, and therefore why should this matter to elected representatives, to their staff, and to those people that they're elected to serve. And ASCO has led with a targeted campaign to basically have that message be conveyed at every opportunity to elected representatives. And each year on Hill Day, one of the asks that we have is to continue to support research: the NCI, NIH, ARPA-H, these are things that are always in the asks to make sure that there's appropriate funding. But effectively playing offense by saying, "It's not just a number on a sheet of paper, this is what it means to patients. This is what it means to potentially your loved ones in the future if you are in the opposite situation where you're not on the legislative side, but you're in the office receiving a diagnosis or receiving a difficult piece of news." We only have the tools we have now because of research, and each breakthrough has been years in the making and countless hours spent funded through the engine of innovation: clinical research and translational research. And so ASCO continues to beat that drum. You mentioned earlier the ACT Network. Just to bring that back again is a very useful, very easy tool to communicate to your elected representatives. When you sign up on the ASCO ACT website, you get emails periodically, not too much, but periodically get emails of, "This is a way you can engage with your lawmakers to speak up for this." And as you said, Monty, they make it as easy as possible. You click the button, you type in your address so that it figures out who your elected representatives are, and then it will send a letter on your behalf after like five clicks to say, "I want you to support research. I want you to vote for this particular thing which is of interest to ASCO and by definition to members of ASCO." And so the ACT Network is a way that people listening can engage without having to spend hours and significant time, but just a few clicks can send that letter to a representative in Congress. And the question could be: does that matter? Does contacting your senator or your elected representative do anything? If all they're hearing is somebody else making a different argument and they're hearing over and over again from people that want investments in AI or investments in something else besides cancer research, whatever it is, they may think that there's a ground shift that people want dollars to be spent over here as opposed to at the NIH or NCI or in federally funded research. It is important to continue to express the need for federal funding for our research. And so, it really is important for folks to engage. Dr. Monty Pal: 100%. One of the things that I think is not often obvious to a lot of our listeners is where the support for clinical trials comes from. You know, you've obviously run the whole gamut of studies as have I. You know, we have our pharmaceutical company-sponsored studies, which are in a particular bucket. But I would say that there's a very important and critical subset of studies that are actually government funded, right? NCI-funded clinical trials. If you don't mind, just explain to our audience the critical nature of the work that's being done in those types of studies and if you can, maybe compare and contrast the studies that are done in that bucket versus perhaps the pharmaceutical bucket. Dr. Jason Westin: Both are critical, and we're privileged that we have pharma studies that are sponsored and federally funded clinical research. And I think that part of a healthy ecosystem for us to develop new breakthroughs has a need for both. The pharma sponsored studies are done through the lens of trying to get an approval for an agent that's of interest so that the pharma company can then turn around and use that outside of a clinical trial after an FDA approval. And so those studies are often done through the lens of getting over the finish line by showing some superiority over an existing treatment or in a new patient population. But they're done through that lens of kind of the broadest population and sometimes relatively narrow endpoints, but to get the approval so that then the drug can be widely utilized. Clinical trials done through cooperative groups are sometimes done to try and optimize that or to try and look at comparative things that may not be as attractive to pharma studies, not necessarily going for that initial approval, but the fine tuning or the looking at health outcomes or looking at ensuring that we do studies in representative populations that may not be as well identified on the pharma sponsored trials, but basically filling out the gaps in the knowledge that we didn't gain from the initial phase 3 trial that led to the approval. And so both are critical. But if we only do pharma sponsored trials, if we don't fund federally supported research and that dries up, the fear I have, and many others have, is that we're going to be lacking a lot of knowledge about the best ways to use these great new therapies, these new immune therapies, or in my team, we do a lot of clinical trials on CAR T-cell therapies. If we don't have federally funded research to do the important clinical studies, we'll be in the dark about the best ways to use these drugs, and that's going to be a terrible shame. And so we really do need to continue to support federal research. Dr. Monty Pal: Yeah, there are no softball questions on this podcast, but I think everybody would be hard pressed to think that you and I would come on here and say, "Well, no, we don't need as much money for clinical trials and NCI funding" and so forth. But I think a really challenging issue to tackle, and this is something we thought to ask you ahead of the podcast, is what to do about the general climate of, you know, whether it's academic research or clinical practice here that seems to be getting some of our colleagues thinking about moving elsewhere. I've actually talked to a couple of folks who are picking up and moving to Europe for a variety of considerations, other continents, frankly. The U.S. has always been a leader when it comes to oncology research and, one might argue, research in general. Some have the mindset these days that we're losing that footing a little bit. What's your perspective? Are you concerned about some of the trends that you're seeing? What does your crystal ball tell you? Dr. Jason Westin: I am highly concerned about this. I think as you said, the U.S. has been a leader for a long time, but it wasn't always. This is not something that's preordained that the world-leading clinical research and translational research will always be done in the United States. That is something that has been developed as an ecosystem, as an engine for innovation and for job development, new technology development, since World War II. That's something that through intentional investments in research was developed that the best and brightest around the world, if they could choose to go anywhere, you wanted them to come to work at universities and academic places within the United States. And I think, as you said, that's at risk if you begin to dry up the investment in research or if you begin to have less focus on being engaged in research in a way that is forward thinking, not just kind of maintaining what we do now or only looking at having private, for profit sponsored research. But if you don't have the investment in the basic science research and the translational research and the forward-thinking part of it, the fear is that we lose the advantage and that other countries will say, "Thank you very much," and be happy to invest in ways to their advantage. And I think as you mentioned, there are people that are beginning to look elsewhere. I don't think that it's likely that a significant population of researchers in the U.S. who are established and have careers and families – I don't think that we're going to see a mass exodus of folks. I think the real risk to me is that the younger, up-and-coming people in undergraduate or in graduate school or in medical school and are the future superstars, that they could either choose to go into a different field, so they decide not to go into what could be the latest breakthroughs for cancer patients but could be doing something in AI or something in a different field that could be attractive to them because of less uncertainty about funding streams, or they could take that job offer if it's in a different country. And I think that's the concern is it may not be a 2026 problem, but it could be a 2036 or a 2046 problem that we reap what we sow if we don't invest in the future. Dr. Monty Pal: Indeed, indeed. You know, I've had the pleasure of reviewing abstracts for some of our big international meetings, as I'm sure you've done in the past too. I see this trend where, as before, we would see the preponderance of large phase 3 clinical trials and practice setting studies being done here in the U.S., I'm seeing this emergence of China, of other countries outside of the U.S. really taking lead on these things. And it certainly concerns me. If I had to sort of gauge this particular issue, it's at the top of my list in terms of what I'm concerned about. But I also wanted to ask you, Jason, in terms of the issues that are looming over oncology from an advocacy perspective, what else really sort of keeps you up at night? Dr. Jason Westin: I'm quite concerned about the drug shortages. I think that's something that is a surprisingly evergreen problem. This is something that is on its face illogical that we're talking about the greatest engine for research in the world being the United States and the investment that we've made in drug development and the breakthroughs that have happened for patients all around the world, many of them happen in the United States, and yet we don't necessarily have access to drugs from the 1970s or 1980s that are cheap, generic, sterile, injectable drugs. This is the cisplatins and the vincristines and the fludarabine type medications which are not the sexy ones that you see the ads in the magazine or on TV at night. These are the backbone drugs for many of our curative intent regimens for pediatrics and for heme malignancies and many solid tumors. And the fact that that's continuing to be an issue is, in my opinion, a failure to address the root causes, and those are going to require legislative solutions. The root causes here are basically a race to the bottom where the economics to invest in quality manufacturing really haven't been prioritized. And so it's a race to the cheapest price, which often means you undercut your competitor, and when you don't have the money to invest in good manufacturing processes, the factory breaks down, there's no alternative, you go into shortage. And this has been going on for a couple of decades, and I don't think there's an end in sight until we get a serious solution proposed by our elected officials. That is something that bothers me in the ways where we know what we should be doing for our patients, but if we don't have the drugs, we're left to be creative in ways we shouldn't have to do to figure out a plan B when we've got curative intent therapies. And I think that's a real shame.  There's obviously a lot of other things that are concerning related to oncology, but something that I have personally had experience with when I wanted to give a patient a CAR T-cell, and we don't have a supply of fludarabine, which is a trivial drug from decades ago in terms of the technology investments in genetically modified T-cells, to not then have access to a drug that should be pennies on the dollar and available at any time you want it is almost like the Air Force investing in building the latest stealth bomber, but then forgetting to get the jet fuel in a way that they can't use it because they don't have the tools that they need. And so I think that's something that we do need to have comprehensive solutions from our elected officials. Dr. Monty Pal: Brilliantly stated. I like that analogy a lot. Let's get into the weeds for a second. What would that proposal to Congress look like? What are we trying to put in front of them to help alleviate the drug shortages? Dr. Jason Westin: We could spend a couple hours, and I know podcasts usually are not set up to do that. And so I won't go through every part. I will direct you that there have been a couple of recent publications from ASCO specifically detailing solutions, and there was a recent white paper from the Senate Finance Committee that went through some legislative solutions being explored. So Dr. Gralow, ASCO CMO, and I recently had a publication in JCO OP detailing some solutions, more in that white paper from the Senate Finance. And then there's a working group actually going through ASCO's Health Policy Committee putting together a more detailed proposal that will be published probably around the end of 2026. Very briefly, what needs to happen is for government contracts for purchasing these drugs, there needs to be an outlay for quality, meaning that if you have a manufacturing facility that is able to deliver product on time, reliably, you get a bonus in terms of your contract. And that changes the model to prioritize the quality component of manufacturing. Without that, there's no reason to invest in maintaining your machine or upgrading the technology you have in your manufacturing plant. And so you have bottlenecks emerge because these drugs are cheap, and there's not a profit margin. So you get one factory that makes this key drug, and if that factory hasn't had an upgrade in their machines in 20 years, and that machine conks out and it takes 6 months to repair or replacement, that is an opportunity for that drug to go into shortage and causes a mad dash for big hospitals to purchase the drug that's available, leaving disparities to get amplified. It's a nightmare when those things happen, and they happen all the time. There are usually dozens, if not hundreds, of drugs in shortage at any given time. And this has been going on for decades. This is something that we do need large, system-wide fixes and that investment in quality, I think, will be a key part. Dr. Monty Pal: Yeah, brilliantly said. And I'll make sure that we actually include those articles on the tagline for this podcast as well. I'll talk to our producer about that as well.  I'm really glad you mentioned the time in your last comment there because I felt like we just started, but in fact, I think we're right at our close here, Jason, unfortunately. So, I could have gone on for a couple more hours with you. I really want to thank you for these absolutely terrific insights and thank you for all your advocacy on behalf of ASCO and oncologists at large. Dr. Jason Westin: Thank you so much for having me. I have enjoyed it. Dr. Monty Pal: Thanks a lot. And many thanks to our listeners too. You can find more information about ASCO's advocacy agenda and activities at asco.org. Finally, if you value the insights that you heard today on the ASCO Daily News Podcast, please rate, review, and subscribe wherever you get your podcasts. Thanks so much. ASCO Advocacy Resources: Get involved in ASCO's Advocacy efforts: ASCO Advocacy Toolkit Crisis of Cancer Drug Shortages: Understanding the Causes and Proposing Sustainable Solutions, JCO Oncology Practice 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. Monty Pal   @montypal   Dr. Jason Westin @DrJasonWestin   Follow ASCO on social media:      @ASCO on X     ASCO on Bluesky    ASCO on Facebook      ASCO on LinkedIn      Disclosures:     Dr. Monty Pal:    Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview   Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical   Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis   Dr. Jason Westin: Consulting or Advisory Role: Novartis, Kite/Gilead, Janssen Scientific Affairs, ADC Therapeutics, Bristol-Myers Squibb/Celgene/Juno, AstraZeneca, Genentech/Roche, Abbvie, MorphoSys/Incyte, Seattle Genetics, Abbvie, Chugai Pharma, Regeneron, Nurix, Genmab, Allogene Therapeutics, Lyell Immunopharma Research Funding: Janssen, Novartis, Bristol-Myers Squibb, AstraZeneca, MorphoSys/Incyte, Genentech/Roche, Allogene Therapeutics

In this JCO Precision Oncology Article Insights episode, Natalie DelRocco summarizes "Genomic Risk Classifiers in Localized Prostate Cancer: Precise but Not Standardized" by Góes et al. published on September 10, 2025. TRANSCRIPT Natalie DelRocco: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host, Natalie DelRocco, and today we will be discussing the editorial "Genomic Risk Classifiers in Localized Prostate Cancer: Precise but Not Standardized." This editorial by Góes, Li, and Chehrazi-Raffle, and Janopaul-Naylor et al. describes genomic risk classifiers, or GRCs, for patients with localized prostate cancer. Like any risk prediction model, GRCs are intended to help identify groups of patients that may benefit from less intense or more intense anticancer therapy. Risk prediction tools can be difficult to bring into clinical practice; they require a lot of validation. And as the authors describe, GRCs in localized prostate cancer are no exception. The authors of this editorial contextualize an article by Janopaul-Naylor et al., which attempts to retrospectively explore the clinical use of three available GRCs for localized prostate cancer: Decipher, Oncotype DX, and Prolaris. Each of these three GRCs is being used in clinical practice currently. In the original article, all three GRCs were associated with less intense therapy being prescribed in practice. However, the editorial authors note that this is likely selection bias due to the observational nature of the study design. It is conceivable that GRCs were more likely ordered to make decisions for patients who were already thought to be good candidates for less intensive therapy. Another weakness of the retrospective study design is that patient level covariates known to be associated with clinical prognosis in localized prostate cancer, such as staging, Gleason score, prostate specific antigen, were unavailable. The authors note that sampling bias may also be an issue. Uninsured patients are not included in the original article, and therefore may impede the ability to make conclusions about the association of GRC use with income level. The editorial authors highlight important study findings as well as these limitations, such as the heterogeneity of interventions following GRC result return. The Prolaris GRC was found to be associated with more surgical interventions, while the Decipher GRC was associated with more androgen deprivation therapy plus radiation. Additionally, patients with active surveillance were more likely to have a GRC in general ordered. While these conclusions are very interesting, the editorial authors note that further exploration and validation, given the retrospective study design and limitations outlined, are needed to fully understand the impact of GRCs in the practice of treating localized prostate cancer. Thank you for listening to JCO Precision Oncology Article Insights. Don't forget to give us a rating or a review and be sure to subscribe so that you never miss an episode. You can find all ASCO shows atasco.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.

Listen to JCO's Art of Oncology article, "Are You Bereaved?" by Dr. Trisha Paul, who is an Assistant Professor in Pediatric Hematology/ Oncology and Palliative Care at University of Rochester Medical Center. The article is followed by an interview with Paul and host Dr. Mikkael Sekeres. Dr Paul reflects on a grieving father's question about her own bereavement. TRANSCRIPT Narrator: Are You Bereaved?, by Trisha Paul, MD, MFA  Dr. Mikkael Sekeres: Welcome back to JCO's Cancer Stories: The Art of Oncology. This ASCO podcast features intimate narratives and perspectives from authors exploring their experience in oncology. I'm your host, Mikkael Sekeres. I'm Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. Joining us today is Trisha Paul, an Assistant Professor in Pediatric Hematology Oncology and Palliative Care at University of Rochester Medical Center to discuss her Journal of Clinical Oncology article, "Are You Bereaved?" At the time of this recording, our guest has no disclosures. Trisha, thank you so much for contributing this terrific essay to the Journal of Clinical Oncology and for joining us to discuss your article. Dr. Trisha Paul: Thank you so much for having me today, Dr. Sekeres. Dr. Mikkael Sekeres: So we agreed for everyone listening to call each other by first names, and then Dr. Paul just called me Dr. Sekeres. Dr. Trisha Paul: Still adjusting to being an attending. Dr. Mikkael Sekeres: That is fantastic. Dr. Trisha Paul: Thank you so much for having me, Mikkael. Dr. Mikkael Sekeres: That was great. Well, you already gave us a little bit of a hint. Can we start off by my asking you if you can tell us about yourself - where are you from - and walk us through your career thus far? Dr. Trisha Paul: Sure. I'm originally from Ann Arbor, Michigan, born and raised there, and I completed my undergraduate medical school education at the University of Michigan. I proceeded to do a general pediatrics residency at the University of Minnesota and then went to St. Jude Children's Research Hospital for a combined fellowship in pediatric hematology oncology and hospice and palliative medicine. What brought me into this area of medicine was early experiences as a high school student volunteering at a children's hospital in my hometown. And that's where I found myself in a playroom, spending time with children with cancer and their families. And these experiences of being with patients and families and getting to know them outside of their illnesses was really what brought me to wanting to be not only a pediatric oncologist, but also a palliative care physician who could care for patients holistically. Dr. Mikkael Sekeres: Wow. So you were introduced to this field at a preternaturally young age. Dr. Trisha Paul: Yes, it's been more than a decade that I've been aspiring to be a pediatric oncologist and a palliative care physician, and I feel fortunate to be there now. Dr. Mikkael Sekeres: That's fantastic. And I should say, given your University of Michigan pedigree, 'Go Blue'. Dr. Trisha Paul: Thank you. Go Blue! Dr. Mikkael Sekeres: Although, at the time of this recording, Miami is undefeated in football, so, you know, go us. In your essay, I really love how you draw us as readers into your story. You signed up to volunteer at a writing workshop for bereaved parents of children who died from cancer. Can you set the scene for us? Where did this take place? How many people attended? And why did you sign up for the workshop in the first place? I can imagine this would be an incredibly moving experience. Dr. Trisha Paul: Yes. Day of Remembrance is an annual event hosted at St. Jude Children's Research Hospital. Many hospitals have similar events where we honor patients who have passed away and we invite their families back to campus to honor these patients. And I started my fellowship in 2021, and so we were still coming out of the pandemic. This workshop that I attended was the first time that I was having an opportunity to attend the annual Day of Remembrance. And at the time, I had completed my palliative care training, and I was wrapping up my pediatric oncology fellowship. The annual Day of Remembrance this year was hosted at a convention center on the banks of the Mississippi River, nearby and next to St. Jude Children's Research Hospital. And it was a large convention center that kind of spans the horizon. And it's one of those spaces where you go for medical conferences typically, and it was interesting to walk into this convention center space and all these conference rooms and instead see poster boards that are sharing the stories and the lives of all these children and adolescents who had died over the past several years. One reason I think the timing of this event occurred for me was that I realized that I also knew several patients and families who might be in attendance at this event. I was several years into my fellowship at the time. And so I think the other reason I chose to volunteer at this event was I had spent a lot of time with patients and families whose child was approaching the end of their life, and I had kind of gotten to be with parents and siblings in that period of time. But what often happens for me as a palliative care physician and as an oncologist is the relationship is different after the child dies. And so for many of the patients I cared for as a palliative care physician, or as an oncologist, I wouldn't necessarily see these parents after the death of a child. There are some times where I've been able to see them at a memorial service, but otherwise we spend all this time with families leading up to a child's death. And often there's kind of this black box around them and their lives afterwards. And so I found myself really wanting to better understand the experiences of families after a child's death, which is what led me to participate and volunteer in the annual Day of Remembrance event. I did not want to just attend, I wanted to be able to do something concrete and actionable with these families to learn more about their grief. And for me, as a writer, volunteering at the writing workshop with bereaved parents seemed like a perfect way for me to be able to spend time with them. Dr. Mikkael Sekeres: Many of us as oncologists place boundaries between our interactions with patients, confining them to the workplace, but many do not. That you attended this workshop tells me that you may fall into the latter category. Was this a deliberate decision or something that evolved over time? And do you ever worry that erosion of such boundaries could contribute to burnout, or is it actually the opposite, that it reminds us of why we do what we do? Dr. Trisha Paul: Yeah, I think this is a great question that I have been asking myself for years and that I anticipate spending the rest of my career wondering about and rediscovering for myself each time I have a patient and a family before me that I am exploring what I want those boundaries to look like or what I want those relationships to look like. I think that for me, my thinking about this has evolved even throughout the course of my training. And I think I've better understood that these are decisions that are made on a very personal level as well as decisions that have to be reassessed with each patient and with each family that we get to care for during this time. And so I think I'm always asking myself about, beyond being an oncologist and beyond being a person's palliative care physician, how do I want to care for them as another person? Dr. Mikkael Sekeres: Really nicely said. Did you recognize any of the parents at the writing workshop you attended or at the larger conference when you were there? Dr. Trisha Paul: I did. Dr. Mikkael Sekeres: And what was that like, seeing them out of context? Dr. Trisha Paul: In this specific situation, I think it was a little bit jarring in the sense that it was kind of this surprise, that especially these are patients I had cared for in the past several years, and so there was a little bit of a moment to recognize and place them in where we had seen each other before. And then there was this fleeting wonder about whether they also recognized me. Some of these are patients that I might have met while on service as a palliative care physician for a brief visit or an initial consultation. And so for some of those families that I knew, there was less longevity to the ways in which I had known them. And it was curious to wonder if they remembered me and then to wonder about that memory. Dr. Mikkael Sekeres: Did any of them? Did any of them come up to you and say, "Oh, Dr. Paul, it's good to see you again," or, "Do you remember me?" Dr. Trisha Paul: No, I did not have that happen. Dr. Mikkael Sekeres: I think jarring is a really interesting word to use. A lot of our interactions are so contextual, and I find it difficult when I run into a patient or a family member and I'm outside of work and have to remind myself of, not so much who they are, but where they are in their treatment course. And sometimes you forget because it's out of the context of our clinic rooms. Dr. Trisha Paul: Mm hmm. I think that's exactly right. Dr. Mikkael Sekeres: The author and grieving father who led the workshop in your essay writes in your copy of his book that he thanks you for your work. The way you describe that and isolate that phrase in your essay is to the reader, I will use your word again, jarring. Why was that so jarring to you? Dr. Trisha Paul: It definitely felt jarring when I read those words in my book. There is something about the word work and kind of the connotations of work that separate it from a humanity of caring. It feels a little bit like an obligation or a task or a livelihood. Dr. Mikkael Sekeres: You think of what we do as a calling? Dr. Trisha Paul: I don't think the phrase of it being a calling resonates with me personally that much. But it is more than just a thing I do. I think that's the problem with work. I think it's undermining why a lot of us choose to do this. Which I think for many people, kind of this idea of a calling is how they think of it. I think the calling implies there's a lot more choice than I actually feel. Ever since some of the first patients and families that I met within this space, I understood that these are the people I wanted to spend the rest of my life caring for. And I guess that kind of sounds like a calling. But... Dr. Mikkael Sekeres: I was not going to say it, but it sounds like a calling. You know that word, and I love how you reflect on semantics in this essay. The notion of a calling sounds so highfalutin and almost religious and as if we're being spoken to. But I don't know. I think you could define it as something that just feels right to you and something that you should be doing and that you fall into and you do not have as much deliberate choice in going into this field, but everything just feels right about it. Dr. Trisha Paul: I think that's exactly it. So I think it's just that you do not really question- for people who choose to do this work and to be with these patients and families, a lot of us from the time we arrive at the realization that this is what we want to do, we don't find ourselves really questioning it in a concrete sense because we understand it. It makes sense to us. Dr. Mikkael Sekeres: I think that's a great summary of that. It just makes sense to us. Dr. Trisha Paul: I think it's a mysterious idea to so many other people who don't do this work. And that's part of why it's interesting to a lot of people who just respond and say, "Oh, I can't imagine how you do this." Dr. Mikkael Sekeres: Well, it just feels as if we're contributing something so substantive to humanity by focusing on hematology, oncology, and particularly palliative care. I don't know about you, I do not know if you have children. I have certainly tried to impart to my children to do something meaningful, to do something that makes other people's lives better with whatever career they choose, because it's so meaningful not just to ourselves, but to other people. Dr. Trisha Paul: Mm hmm. Dr. Mikkael Sekeres: We are talking about semantics. In your essay, you reflect on the notion of bereavement. Should we, as medical caregivers, cop to being bereaved, or are we misappropriating a word that really wholly belongs to close family members and friends of a person with cancer? Dr. Trisha Paul: Yes. And I think that this essay was me kind of struggling to wrap my mind around what this question means and kind of what my own reactions to this idea of what it would look like and feel like to call ourselves bereaved. And I don't have an answer to this question. I think it's a question that everyone in this work should consider and think about and what it means for them as an individual. Dr. Mikkael Sekeres: Are there patients you have lost whom you think about even one, two, three years later on a regular basis? Dr. Trisha Paul: Yes, I would definitely say so. I am early in my career, but I anticipate that that is kind of an essential way in which I do this work. It's part of my own practice, and it's dependent on each patient, but I find ways that I keep their legacy alive in my life. Dr. Mikkael Sekeres: Yeah. I thought a lot about your essay since I first read it, and I think it's okay to say that we grieve the loss of our patients. I think that is a form of bereavement. Dr. Trisha Paul: I think so too. I think that it was interesting to realize my own hesitation about specifically calling ourselves bereaved when we do, as clinicians, talk about grief and secondary grief and something about using the language of grief and grieving feels more appropriate and within our purview as clinicians. But something about specifically identifying as bereaved felt like a different step. Dr. Mikkael Sekeres: It's closer, isn't it? I don't know, it feels like more of a personal relationship rather than a professional relationship to be bereaved. Dr. Trisha Paul: And I think that that's simultaneously terrifying and empowering as a way of acknowledging what the loss of a patient can do to us and also honoring the affection we have for people we care for. Dr. Mikkael Sekeres: I hope it's okay that we end on that phrase that you just said: It's both terrifying and empowering to admit to being bereaved and to feel that closeness to one of our patients. It has been such a pleasure to have Trisha Paul, who is an Assistant Professor in Pediatric Hematology, Oncology, and Palliative Care at the University of Rochester Medical Center to discuss her essay, "Are You Bereaved?" Trisha, thank you so much for submitting your article and for joining us today for this enlightening conversation. Dr. Trisha Paul: Thank you so much. Dr. Mikkael Sekeres: If you have enjoyed this episode, consider sharing it with a friend or colleague or leave us a review. Your feedback and support helps us continue to have these important conversations. If you are looking for more episodes and context, follow our show on Apple, Spotify, or wherever you listen, and explore more from ASCO at asco.org/podcasts. Until next time, this has been Mikkael Sekeres for Cancer Stories. 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. Show notes: Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio: Dr Trisha Paul is an Assistant Professor in Pediatric Hematology/ Oncology and Palliative Care at University of Rochester Medical Center.

In this episode of JCO Article Insights, host Dr. Ece Cali Daylan interviews author Dr. Jeffrey Bradley about the article, "Simultaneous Durvalumab and Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer" by Bradley, et al published October 13, 2025. TRANSCRIPT Dr. Ece Cali: Welcome to this episode of JCO Article Insights. This is Dr. Ece Cali, JCO Editorial Fellow. Today I'm joined by Dr. Jeffrey Bradley, Professor of Radiation Oncology at the University of Pennsylvania, to discuss the manuscript, "Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non-Small-Cell Lung Cancer: The Phase III PACIFIC-2 Study." The PACIFIC-2 study was a phase III, double-blind, randomized trial comparing the efficacy and safety of simultaneous durvalumab with concurrent chemoradiation followed by consolidation durvalumab to the concurrent chemoradiation followed by placebo in patients with unresectable stage III non-small cell lung cancer. The primary endpoint was progression-free survival by blinded independent central review. The secondary endpoints were overall response rate, overall survival, and safety. Three hundred twenty-eight patients were randomized 2:1 to durvalumab and placebo, respectively. Unfortunately, this trial did not meet its primary endpoint. There were no statistically significant differences in PFS or OS. The frequency of adverse events was similar between the two arms. Grade 3 or higher adverse events were observed in 53% of the patients in the durvalumab arm compared to 59% of the patients in the placebo arm. Of note, the frequency of pneumonitis was similar in the two arms. Approximately 28% of patients in each arm developed pneumonitis, and about 5% of the pneumonitis observed in each arm was grade 3 or higher in severity. Treatment discontinuation rates secondary to the adverse events were higher in the durvalumab arm, 25% compared to 12%. Adverse events leading to treatment discontinuation and death were more frequently seen in the durvalumab arm during the first four months of the treatment, which corresponds to the simultaneous administration of chemoradiation and durvalumab. Dr. Bradley, before we delve into the results, can you please explain the rationale for this study design and how this concept fits into the current treatment landscape? Dr. Jeffrey Bradley: Yeah, this trial came on the heels of PACIFIC after there was a progression-free survival benefit showed in PACIFIC that in the locally advanced unresectable population that consolidation immunotherapy, in this case durvalumab, had a progression-free survival benefit. A number of us in the clinical trial space thought to add concurrent immunotherapy in addition to consolidation immunotherapy that that would also improve outcomes for patients. So a number of trials were launched to follow up of PACIFIC. In this case, this is a phase III trial where the control arm was placebo. There was no overall survival results yet from PACIFIC, just a PFS benefit, and a number of countries across the world had not approved maintenance durvalumab in this space. So this trial looked at the experimental arm, which was concurrent immunotherapy, durvalumab, and chemoradiation followed by consolidation durvalumab versus placebo. Dr. Ece Cali: And if we were to focus on the safety profile first, an increased pneumonitis risk was a theoretical concern when immunotherapy is given concurrently with radiation. Do we see any major differences in the safety profile between the two arms in this trial? Dr. Jeffrey Bradley: No, and we were concerned about the addition of concurrent immunotherapy and chemoradiation, like you said, towards concern about increased pneumonitis rate, but we did not see increased pneumonitis in the experimental arm over placebo. And the grade 3 or higher, as you said, it was roughly 5%, more or less, in both arms, so we didn't see increase in pneumonitis toxicity with concurrent IO and chemoradiation. Dr. Ece Cali: But interestingly though, despite the lack of significantly increased toxicity with durvalumab, unfortunately, administering immunotherapy simultaneously with chemoradiation therapy did not improve survival. Lack of superiority of this treatment regimen, as you mentioned, is further confirmed across multiple similar negative trial readouts such as ECOG-ACRIN 5181 and CheckMate 73L. Dr. Bradley, in your view, what are some potential explanations for why this strategy did not pan out in clinical trials? Dr. Jeffrey Bradley: Regarding toxicity, let me go back and point out that we did see an increased number of immune-mediated adverse events. It was 34.7% in the concurrent immunotherapy arm versus 15.7% in the placebo arm. So that led to a higher number of discontinuations of immunotherapy which I think probably had an effect. So we didn't... there was an increased pneumonitis toxicity, but there were expected immune-mediated toxicities that caused people to stop giving immunotherapy. You can see that in the PFS curves. They were, you know, they crossed over after like a month, but initially there was lower PFS for the experimental arm, and then the experimental arm got better after we divided into four months, before four months and after four months. Dr. Ece Cali: For one reason or another, it looks like the simultaneous administration did not really improve outcomes. We now know that simultaneously giving them another concurrent radiation should really no longer be pursued in clinical trials for this patient population. Can you share with our audience what strategies are being studied in this setting and what trials to watch out for in the future? Dr. Jeffrey Bradley: Sure, I think when you add concurrent radiation to immunotherapy, there were more central tumors in this trial, I think you're killing lymphocytes and negating the effect of immunotherapy. So I think that's the smoking gun for this trial, for the ECOG trial, for the small cell trial that NRG reported, LU005, and other trials. So correct, I don't think there's any need to continue to pursue concurrent immunotherapy in this space of lung cancer. But that's not to say there aren't many other trials that are either ongoing, have accrued and awaiting results, or being planned for the next phase of clinical trials. We have a trial within NRG Oncology called NRG-LU008. It's a randomized phase III trial that is using an SBRT boost to a peripheral primary and chemoradiation to the nodes, because the primary tumor is the one that fails more often than the lymph nodes, and that's compared to PACIFIC in the control arm. PACIFIC-9 is another trial in the same line as the other PACIFIC trials. That one is using dual checkpoint inhibition versus the control arm being PACIFIC. So there are three arms in that trial, durva and oleclumab, durva and monalizumab versus the PACIFIC arm. And that trial is completed accrual, but we have no results from that study yet. Johnson & Johnson has a trial open looking at a nanoparticle. That's a radiosensitizer where bronchoscopy is used to inject the primary tumor and the lymph nodes with a radiosensitizer. That's a randomized phase ll trial that's ongoing. It's got three arms, two different doses of this radiosensitizing drug and then a control arm without injection at all. The control arm is again the PACIFIC arm. And then those of us within the NCI-based clinical trials evaluation program, CTEP, are proposing an intergroup trial that would compare induction chemo-immunotherapy followed by chemoradiation followed by maintenance immunotherapy versus PACIFIC in a phase III study. So I think there's other trials that are either completed, ongoing completed, or on the horizon to assess in this patient population. Dr. Ece Cali: Yeah, we definitely have an unmet need to improve survival outcomes for stage III patients, and it's great to hear that there are so many efforts looking at different strategies to improve outcomes for these patients.  Thank you so much, Dr. Bradley, for this informative discussion and for sharing your insights. Any last thoughts? Dr. Jeffrey Bradley: Yeah, we need something, you know. PACIFIC was first reported in 2017, and we really haven't made progress in terms of changing that standard of care control for the last eight years. So we need progress in this area. Dr. Ece Cali: Yep, definitely. Thank you so much for joining, Dr. Bradley.  And thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit 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. Bradley Honoria: Mevion Medical Systems, Inc. Consulting or Advisory Role: Varian, Inc, Genentech, Inc. Research Funding: Varian Medical Systems Dr. Cali Research Funding Company: BeiGene, Nuvalent, Inc., Astra Zeneca 

Dr. Linda Duska and Dr. Kathleen Moore discuss key studies in the evolving controversy over radical upfront surgery versus neoadjuvant chemotherapy in advanced ovarian cancer. TRANSCRIPT Dr. Linda Duska: Hello, and welcome to the ASCO Daily News Podcast. I am your guest host, Dr. Linda Duska. I am a professor of obstetrics and gynecology at the University of Virginia School of Medicine.  On today's episode, we will explore the management of advanced ovarian cancer, specifically with respect to a question that has really stirred some controversy over time, going all the way back more than 20 years: Should we be doing radical upfront surgery in advanced ovarian cancer, or should we be doing neoadjuvant chemotherapy? So, there was a lot of hype about the TRUST study, also called ENGOT ov33/AGO-OVAR OP7, a Phase 3 randomized study that compares upfront surgery with neoadjuvant chemotherapy followed by interval surgery. So, I want to talk about that study today. And joining me for the discussion is Dr. Kathleen Moore, a professor also of obstetrics and gynecology at the University of Oklahoma and the deputy director of the Stephenson Cancer Center, also at the University of Oklahoma Health Sciences.  Dr. Moore, it is so great to be speaking with you today. Thanks for doing this. Dr. Kathleen Moore: Yeah, it's fun to be here. This is going to be fun. Dr. Linda Duska: FYI for our listeners, both of our full disclosures are available in the transcript of this episode.  So let's just jump right in. We already alluded to the fact that the TRUST study addresses a question we have been grappling with in our field. Here's the thing, we have four prior randomized trials on this exact same topic. So, share with me why we needed another one and what maybe was different about this one? Dr. Kathleen Moore: That is, I think, the key question. So we have to level-set kind of our history. Let's start with, why is this even a question? Like, why are we even talking about this today? When we are taking care of a patient with newly diagnosed ovarian cancer, the aim of surgery in advanced ovarian cancer ideally is to prolong a patient's likelihood of disease-free survival, or if you want to use the term "remission," you can use the term "remission." And I think we can all agree that our objective is to improve overall survival in a way that also does not compromise her quality of life through surgical complications, which can have a big effect. The standard for many decades, certainly my entire career, which is now over 20 years, has been to pursue what we call primary cytoreductive surgery, meaning you get a diagnosis and we go right to the operating room with a goal of achieving what we call "no gross residual." That is very different – in the olden days, you would say "optimal" and get down to some predefined small amount of tumor. Now, the goal is you remove everything you can see.  The alternative strategy to that is neoadjuvant chemotherapy followed by interval cytoreductive surgery, and that has been the, quote-unquote, "safer" route because you chemically cytoreduce the cancer, and so, the resulting surgery, I will tell you, is not necessarily easy at all. It can still be very radical surgeries, but they tend to be less radical, less need for bowel resections, splenectomy, radical procedures, and in a short-term look, would be considered safer from a postoperative consideration. Dr. Linda Duska: Well, and also maybe more likely to be successful, right? Because there's less disease, maybe, theoretically. Dr. Kathleen Moore: More likely to be successful in getting to no gross residual. Dr. Linda Duska: Right. Yeah, exactly. Dr. Kathleen Moore: I agree with that. And so, so if the end game, regardless of timing, is you get to no gross residual and you help a patient and there's no difference in overall survival, then it's a no-brainer. We would not be having this conversation. But there remains a question around, while it may be more likely to get to no gross residual, it may be, and I think we can all agree, a less radical, safer surgery, do you lose survival in the long term by this approach? This has become an increasing concern because of the increase in rates of use of neoadjuvant, not only in this country, but abroad. And so, you mentioned the four prior studies. We will not be able to go through them completely. Dr. Linda Duska: Let's talk about the two modern ones, the two from 2020 because neither one of them showed a difference in overall survival, which I think we can agree is, at the end of the day, yes, PFS would be great, but OS is what we're looking for. Dr. Kathleen Moore: OS is definitely what we're looking for. I do think a marked improvement in PFS, like a real prolongation in disease-free survival, for me would be also enough. A modest improvement does not really cut it, but if you are really, really prolonging PFS, you should see that-  Dr. Linda Duska: -manifest in OS. Dr. Kathleen Moore: Yeah, yeah. Okay. So let's talk about the two modern ones. The older ones are EORTC and CHORUS, which I think we've talked about. The two more modern ones are SCORPION and JCOG0602. So, SCORPION was interesting. SCORPION was a very small study, though. So one could say it's underpowered. 170 patients. And they looked at only patients that were incredibly high risk. So, they had to have a Fagotti score, I believe, of over 9, but they were not looking at just low volume disease. Like, those patients were not enrolled in SCORPION. It was patients where you really were questioning, "Should I go to the OR or should I do neoadjuvant? Like, what's the better thing?" It is easy when it's low volume. You're like, "We're going." These were the patients who were like, "Hm, you know, what should I do?" High volume. Patients were young, about 55. The criticism of the older studies, there are many criticisms, but one of them is that, the criticism that is lobbied is that they did not really try. Whatever surgery you got, they did not really try with median operative times of 180 minutes for primary cytoreduction, 120 for neoadjuvant. Like, you and I both know, if you're in a big primary debulking, you're there all day. It's 6 hours. Dr. Linda Duska: Right, and there was no quality control for those studies, either. Dr. Kathleen Moore: No quality control. So, SCORPION, they went 451-minute median for surgery. Like, they really went for it versus four hours and then 253 for the interval, 4 hours. They really went for it on both arms. Complete gross resection was achieved in 50% of the primary cytoreduced. So even though they went for it with these very long surgeries, they only got to the goal half the time. It was almost 80% in the interval group. So they were more successful there. And there was absolutely no difference in PFS or OS. They were right about 15 months PFS, right about 40 months OS.  JCOG0602, of course, done in Japan, a big study, 300 patients, a little bit older population. Surprisingly more stage IV disease in this study than were in SCORPION. SCORPION did not have a lot of stage IV, despite being very bulky tumors. So a third of patients were stage IV. They also had relatively shorter operative times, I would say, 240 minutes for primary, 302 for interval. So still kind of short. Complete gross resection was not achieved very often. 30% of primary cytoreduction. That is not acceptable. Dr. Linda Duska: Well, so let's talk about TRUST. What was different about TRUST? Why was this an important study for us to see? Dr. Kathleen Moore: So the criticism of all of these, and I am not trying to throw shade at anyone, but the criticism of all of these is if you are putting surgery to the test, you are putting the surgeon to the test. And you are assuming that all surgeons are trained equally and are willing to do what it takes to get someone to no gross residual. Dr. Linda Duska: And are in a center that can support the post-op care for those patients. Dr. Kathleen Moore: Which can be ICU care, prolonged time. Absolutely. So when you just open these broadly, you're assuming everyone has the surgical skills and is comfortable doing that and has backup. Everybody has an ICU. Everyone has a blood bank, and you are willing to do that. And that assumption could be wrong. And so what TRUST said is, "Okay, we are only going to open this at centers that have shown they can achieve a certain level of primary cytoreduction to no gross residual disease." And so there was quality criteria. It was based on – it was mostly a European study – so ESGO criteria were used to only allow certified centers to participate. They had to have a surgical volume of over 36 cytoreductive surgeries per year. So you could not be a low volume surgeon. Your complete resection rates that were reported had to be greater than 50% in the upfront setting. I told you on the JCOG, it was 30%. Dr. Linda Duska: Right. So these were the best of the best. This was the best possible surgical situation you could put these patients in, right? Dr. Kathleen Moore: Absolutely. And you support all the things so you could mitigate postoperative complications as well. Dr. Linda Duska: So we are asking the question now again in the ideal situation, right? Dr. Kathleen Moore: Right. Dr. Linda Duska: Which, we can talk about, may or may not be generalizable to real life, but that's a separate issue because we certainly don't have those conditions everywhere where people get cared for with ovarian cancer. But how would you interpret the results of this study? Did it show us anything different? Dr. Kathleen Moore: I am going to say how we should interpret it and then what I am thinking about. It is a negative study. It was designed to show improvement in overall survival in these ideal settings in patients with FIGO stage IIIB and C, they excluded A, these low volume tumors that should absolutely be getting surgery. So FIGO stage IIIB and C and IVA and B that were fit enough to undergo radical surgery randomized to primary cytoreduction or neoadjuvant with interval, and were all given the correct chemo. Dr. Linda Duska: And they were allowed bevacizumab and PARP, also. They could have bevacizumab and PARP. Dr. Kathleen Moore: They were allowed bevacizumab and PARP. Not many of them got PARP, but it was distributed equally, so that would not be a confounder. And so that was important. Overall survival is the endpoint. It was a big study. You know, it was almost 600 patients. So appropriately powered. So let's look at what they reported. When they looked at the patients who were enrolled, this is a large study, almost 600 patients, 345 in the primary cytoreductive arm and 343 in the neoadjuvant arm. Complete resection in these patients was 70% in the primary cytoreductive arm and 85% in the neoadjuvant arm. So in both arms, it was very high. So your selection of site and surgeon worked. You got people to their optimal outcome. So that is very different than any other study that has been reported to date. But what we saw when we looked at overall survival was no statistical difference. The median was, and I know we do not like to talk about medians, but the median in the primary cytoreductive arm was 54 months versus 48 months in the neoadjuvant arm with a hazard ratio of 0.89 and, of course, the confidence interval crossed one. So this is not statistically significant. And that was the primary endpoint. Dr. Linda Duska: I know you are getting to this. They did look at PFS, and that was statistically significant, but to your point about what are we looking for for a reasonable PFS difference? It was about two months difference. When I think about this study, and I know you are coming to this, what I thought was most interesting about this trial, besides the fact that the OS, the primary endpoint was negative, was the subgroup analyses that they did. And, of course, these are hypothesis-generating only. But if you look at, for example, specifically only the stage III group, that group did seem to potentially, again, hypothesis generating, but they did seem to benefit from upfront surgery.  And then one other thing that I want to touch on before we run out of time is, do we think it matters if the patient is BRCA germline positive? Do we think it matters if there is something in particular about that patient from a biomarker standpoint that is different? I am hopeful that more data will be coming out of this study that will help inform this. Of course, unpowered, hypothesis-generating only, but it's just really interesting. What do you think of their subset analysis? Dr. Kathleen Moore: Yeah, I think the subsets are what we are going to be talking about, but we have to emphasize that this was a negative trial as designed. Dr. Linda Duska: Absolutely. Yes. Dr. Kathleen Moore: So we cannot be apologists and be like, "But this or that." It was a negative trial as designed. Now, I am a human and a clinician, and I want what is best for my patients. So I am going to, like, go down the path of subset analyses. So if you look at the stage III tumors that got complete cytoreduction, which was 70% of the cases, your PFS was almost 28 months versus 21.8 months. Dr. Linda Duska: Yes, it becomes more significant. Dr. Kathleen Moore: Yeah, that hazard ratio is 0.69. Again, it is a subset. So even though the P value here is statistically significant, it actually should not have a P value because it is an exploratory analysis. So we have to be very careful. But the hazard ratio is 0.69. So the hypothesis is in this setting, if you're stage III and you go for it and you get someone to no gross residual versus an interval cytoreduction, you could potentially have a 31% reduction in the rate of progression for that patient who got primary cytoreduction. And you see a similar trend in the stage III patients, if you look at overall survival, although the post-progression survival is so long, it's a little bit narrow of a margin.  But I do think there are some nuggets here that, one of our colleagues who is really one of the experts in surgical studies, Dr. Mario Leitao, posted this on X, and I think it really resonated after this because we were all saying, "But what about the subsets?" He is like, "It's a negative study." But at the end of the day, you are going to sit with your patient. The patient should be seen by a GYN oncologist or surgical oncologist with specialty in cytoreduction and a medical oncologist, you know, if that person does not give chemo, and the decision should be made about what to do for that individual patient in that setting. Dr. Linda Duska: Agreed. And along those lines, if you look carefully at their data, the patients who had an upfront cytoreduction had almost twice the risk of having a stoma than the patients who had an interval cytoreduction. And they also had a higher risk of needing to have a bowel resection. The numbers were small, but still, when you look at the surgical complications, as you've already said, they're higher in the upfront group than they are in the interval group. That needs to be taken into account as well when counseling a patient, right? When you have a patient in front of you who says to you, "Dr. Moore, you can take out whatever you want, but whatever you do, don't make me a bag." As long as the patient understands what that means and what they're asking us to do, I think that we need to think about that. Dr. Kathleen Moore: I think that is a great point. And I have definitely seen in our practice, patients who say, "I absolutely would not want an ostomy. It's a nonstarter for me." And we do make different decisions. And you have to just say, "That's the decision we've made," and you kind of move on, and you can't look back and say, "Well, I wish I would have, could have, should have done something else." That is what the patient wants. Ultimately, that patient, her family, autonomous beings, they need to be fully counseled, and you need to counsel that patient as to the site that you are in, her volume of disease, and what you think you can achieve. In my opinion, a patient with stage III cancer who you have the site and the capabilities to get to no gross residual should go to the OR first. That is what I believe. I do not anymore think that for stage IV. I think that this is pretty convincing to me that that is probably a harmful thing. However, I want you to react to this. I think I am going to be a little unpopular in saying this, but for me, one of the biggest take-homes from TRUST was that whether or not, and we can talk about the subsets and the stage III looked better, and I think it did, but both groups did really well. Like, really well. And these were patients with large volume disease. This was not cherry-picked small volume stage IIIs that you could have done an optimal just by doing a hysterectomy. You know, these were patients that needed radical surgery. And both did well. And so what it speaks to me is that anytime you are going to operate on someone with ovary, whether it be frontline, whether it be a primary or interval, you need a high-volume surgeon. That is what I think this means to me. Like, I would want high volume surgeon at a center that could do these surgeries, getting that patient, my family member, me, to no gross residual. That is important. And you and I are both in training centers. I think we ought to take a really strong look at, are we preparing people to do the surgeries that are necessary to get someone to no gross residual 70% and 85% of the time? Dr. Linda Duska: We are going to run out of time, but I want to address that and ask you a provocative question. So, I completely agree with what you said, that surgery is important. But I also think one of the reasons these patients in this study did so well is because all of the incredible new therapies that we have for patients. Because OS is not just about surgery. It is about surgery, but it is also about all of the amazing new therapies we have that you and others have helped us to get through clinical research. And so, how much of that do you think, like, for example, if you look at the PFS and OS rates from CHORUS and EORTC, I get it that they're, that they're not the same. It's different patients, different populations, can't do cross-trial comparisons. But the OS, as you said, in this study was 54 months and 48 months, which is, compared to 2010, we're doing much, much better. It is not just the surgery, it is also all the amazing treatment options we have for these patients, including PARP, including MIRV, including lots of other new therapies. How do you fit that into thinking about all of this? Dr. Kathleen Moore: I do think we are seeing, and we know this just from epidemiologic data that the prevalence of ovarian cancer in many of the countries where the study was done is increasing, despite a decrease in incidence. And why is that? Because people are living longer. Dr. Linda Duska: People are living longer, yeah. Dr. Kathleen Moore: Which is phenomenal. That is what we want. And we do have, I think, better supportive care now. PARP inhibitors in the frontline, which not many of these patients had. Now some of them, this is mainly in Europe, will have gotten them in the first maintenance setting, and I do think that impacts outcome. We do not have that data yet, you know, to kind of see what, I would be really interested to see. We do not do this well because in ovarian cancer, post-progression survival can be so long, we do not do well of tracking what people get when they come off a clinical trial to see how that could impact – you know, how many of them got another surgery? How many of them got a PARP? I think this group probably missed the ADC wave for the most part, because this, mirvetuximab is just very recently available in Europe. Dr. Linda Duska: Unless they were on trial. Dr. Kathleen Moore: Unless they were on trial. But I mean, I think we will have to see. 600 patients, I would bet a lot of them missed the ADC wave. So, I do not know that we can say we know what drove these phenomenal – these are some of the best curves we've seen outside of BRCA. And then coming back to your point about the BRCA population here, that is a really critical question that I do not know that we're ever going to answer. There have been hypotheses around a tumor that is driven by BRCA, if you surgically cytoreduced it, and then chemically cytoreduced it with chemo, and so you're starting PARP with nothing visible and likely still homogeneous clones. Is that the group we cured? And then if you give chemo first before surgery, it allows more rapid development of heterogeneity and more clonal evolution that those are patients who are less likely to be cured, even if they do get cytoreduced to nothing at interval with use of PARP inhibitor in the front line. That is a question that many have brought up as something we would like to understand better. Like, if you are BRCA, should you always just go for it or not? I do not know that we're ever going to really get to that. We are trying to look at some of the other studies and just see if you got neoadjuvant and you had BRCA, was anyone cured? I think that is a question on SOLO1 I would like to know the answer to, and I don't yet, that may help us get to that. But that's sort of something we do think about. You should have a fair number of them in TRUST. It wasn't a stratification factor, as I remember. Dr. Linda Duska: No, it wasn't. They stratified by center, age, and ECOG status Dr. Kathleen Moore: So you would hope with randomization that you would have an equal number in each arm. And they may be able to pull that out and do a very exploratory look. But I would be interested to see just completely hypothesis-generating what this looks like for the patients with BRCA, and I hope that they will present that. I know they're busy at work. They have translational work. They have a lot pending with TRUST. It's an incredibly rich resource that I think is going to teach us a lot, and I am excited to see what they do next. Dr. Linda Duska: So, outside of TRUST, we are out of time. I just want to give you a moment if there were any other messages that you want to share with our listeners before we wrap up. Dr. Kathleen Moore: It's an exciting time to be in GYN oncology. For so long, it was just chemo, and then the PARP inhibitors nudged us along quite a bit. We did move more patients, I believe, to the cure fraction. When we ultimately see OS, I think we'll be able to say that definitively, and that is exciting. But, you know, that is the minority of our patients. And while HRD positive benefits tremendously from PARP, I am not as sure we've moved as many to the cure fraction. Time will tell. But 50% of our patients have these tumors that are less HRD. They have a worse prognosis. I think we can say that and recur more quickly. And so the advent of these antibody-drug conjugates, and we could name 20 of them in development in GYN right now, targeting tumor-associated antigens because we're not really driven by mutations other than BRCA. We do not have a lot of things to come after. We're not lung cancer. We are not breast cancer. But we do have a lot of proteins on the surface of our cancers, and we are finally able to leverage that with some very active regimens. And we're in the early phases, I would say, of really understanding how best to use those, how best to position them, and which one to select for whom in a setting where there is going to be obvious overlap of the targets. So we're going to be really working this problem. It is a good problem. A lot of drugs that work pretty well. How do you individualize for a patient, the patient in front of you with three different markers? How do you optimize it? Where do you put them to really prolong survival? And then we finally have cell surface. We saw at ASCO, CDK2 come into play here for the first time, we've got a cell cycle inhibitor. We've been working on WEE1 and ATR for a long time. CDK2s may hit. Response rates were respectable in a resistant population that was cyclin E overexpressing. We've been working on that biomarker for a long time with a toxicity profile that was surprisingly clean, which I like to see for our patients. So that is a different platform. I think we have got bispecifics on the rise. So there is a pipeline of things behind the ADCs, which is important because we need more than one thing, that makes me feel like in the future, I am probably not going to be using doxil ever for platinum-resistant disease. So, I am going to be excited to retire some of those things. We will say, "Remember when we used to use doxil for platinum-resistant disease?" Dr. Linda Duska: I will be retired by then, but thanks for that thought. Dr. Kathleen Moore: I will remind you. Dr. Linda Duska: You are right. It is such an incredibly exciting time to be taking care of ovarian cancer patients with all the opportunities.  And I want to thank you for sharing your valuable insights with us on this podcast today and for your great work to advance care for patients with GYN cancers. Dr. Kathleen Moore: Likewise. Thanks for having me. Dr. Linda Duska: And thank you to our listeners for your time today. You will find links to the TRUST study and other 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. 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. Linda Duska  @Lduska Dr. Kathleen Moore Follow ASCO on social media:     @ASCO on X (formerly Twitter) ASCO on Bluesky   ASCO on Facebook     ASCO on LinkedIn     Disclosures of Potential Conflicts of Interest:    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. Kathleen Moore: Leadership: GOG Partners, NRG Ovarian Committee Chair Honoraria: Astellas Medivation, Clearity Foundation, IDEOlogy Health, Medscape, Great Debates and Updates, OncLive/MJH Life Sciences, MD Outlook, Curio Science, Plexus, University of Florida, University of Arkansas for Medical Sciences, Congress Chanel, BIOPHARM, CEA/CCO, Physician Education Resource (PER), Research to Practice, Med Learning Group, Peerview, Peerview, PeerVoice, CME Outfitters, Virtual Incision Consulting/Advisory Role: Genentech/Roche, Immunogen, AstraZeneca, Merck, Eisai, Verastem/Pharmacyclics, AADi, Caris Life Sciences, Iovance Biotherapeutics, Janssen Oncology, Regeneron, zentalis, Daiichi Sankyo Europe GmbH, BioNTech SE, Immunocore, Seagen, Takeda Science Foundation, Zymeworks, Profound Bio, ADC Therapeutics, Third Arc, Loxo/Lilly, Bristol Myers Squibb Foundation, Tango Therapeutics, Abbvie, T Knife, F Hoffman La Roche, Tubulis GmbH, Clovis Oncology, Kivu, Genmab/Seagen, Kivu, Genmab/Seagen, Whitehawk, OnCusp Therapeutics, Natera, BeiGene, Karyopharm Therapeutics, Day One Biopharmaceuticals, Debiopharm Group, Foundation Medicine, Novocure Research Funding (Inst.): Mersana, GSK/Tesaro, Duality Biologics, Mersana, GSK/Tesaro, Duality Biologics, Merck, Regeneron, Verasatem, AstraZeneca, Immunogen, Daiichi Sankyo/Lilly, Immunocore, Torl Biotherapeutics, Allarity Therapeutics, IDEAYA Biosciences, Zymeworks, Schrodinger Other Relationship (Inst.): GOG Partners

Guest Dr. Rusha Bhandari and host Dr. Davide Soldato discuss JCO article "Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study, " with a particular focus on mortality data, development of secondary malignancies and the importance of education for both patients and healthcare providers regarding long-term follow-up and care. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Davide Soldato: Hello, and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale Policlinico San Martino in Genoa, Italy. Today, we are joined by JCO author, Dr. Rusha Bhandari, a Pediatric Hematologist-Oncologist and Assistant Professor in the Department of Pediatrics and Population Science at City of Hope, California. Today, we will be discussing the article titled "Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study." So, thank you for speaking with us, Dr. Bhandari. Dr. Rusha Bhandari: Thanks so much for having me. Dr. Davide Soldato: So, I just want to go straight ahead in the paper and start from the title. So, we heard that you included in this study childhood survivors of pediatric cancer that were aged 50 years or higher. So, this is a very critical life stage when we know that there are a lot of aging-related comorbidities that can happen, also in the general population but potentially specifically in childhood cancer survivors. So, first of all, I wanted to ask you, why this specific study in this very specific population? Because I think that we had already some data in younger survivors, but now we are focusing specifically on patients aged 50 or more. Dr. Rusha Bhandari: Absolutely. So, to answer that question, I'll take a little bit of a step back in terms of where we are now and where we came from in terms of treatment for childhood cancers. So, thankfully, we now have great curative therapies and survival rates for many childhood cancers, including the most common ones. But this was not necessarily the case 50 or more years ago. So, we essentially are now seeing the first generation of older survivors who are 30, 40, or more years from completion of their cancer treatment. As you pointed out, we know from younger survivors that they have a markedly higher risk of malignancies and health conditions than the general population. You don't typically expect to see things like heart disease or diabetes, for example, in a young adult. But the question that remained was what the health status and risk of these conditions are in survivors who are entering this critical age, as you mentioned, 50 or older, when you do start to see these aging-related changes in the general population. And the question is whether we're still observing increased risks related to cancer treatment that was delivered 30 or more years ago in these survivors who are now entering ages 50 and beyond. Dr. Davide Soldato: Thanks so much. You used the data from a study that is called the Childhood Cancer Survivor Study. So, just a little bit of explanation for our listeners. How is the study conducted? What type of data are you collecting? And specifically for the interest of the study that was reported in this manuscript, which outcomes were really important for you and were so evaluated in the manuscript? Dr. Rusha Bhandari: Yes. So, the Childhood Cancer Survivor Study is a really excellent resource that combines information from children who were treated across North America at various different centers and sites. So it gives us a really good understanding of how different survivors are doing as they do progress through their survivorship journey. The Childhood Cancer Survivor Study includes a baseline questionnaire when participants are first eligible or first enter the study, and then includes a series of follow-up questionnaires to really understand how they're doing, like I mentioned, as they progress throughout their survivorship journey. And so for this study, we really wanted to take a global look at how these patients were doing as they entered that older age range. And so we wanted to look at outcomes ranging from mortality through the health conditions that we've seen from other survivorship studies, including subsequent malignant neoplasms, other health conditions, I mentioned earlier heart disease and other comorbidities we know survivors can be at increased risk for, and also things like frailty, which we know is, you know, the most widely recognized phenotype of aging. And we see that earlier on in our younger survivors. We want to see how this translated to these older survivors and then also other health outcomes like their health status. What is their self-report of their physical health, their mental health? Things like that. So we wanted a very comprehensive understanding of their health. Dr. Davide Soldato: This is a very comprehensive study. Right now it includes more than 30,000 patients that have been treated for childhood cancer, but specifically looking at the question of survivors aged 50 years or higher, you included more than 7,000 patients inside of this study. So, looking at the first outcome that you mentioned, which I think it's also one of the most important, you look specifically at mortality, and in this specific population, you saw a striking three-fold increase in mortality when comparing these survivors with the general population. I just wanted to dive in this result and ask you: What do you see as the main driver for this excess mortality in this population of survivors? And as you were mentioning, the study also collects information about the treatment received. So, was there any association with a specific kind of treatment that was received for curing these childhood cancers? Dr. Rusha Bhandari: I agree. I would say it's striking to see that mortality risk among the survivors relative to the general population. And we do know, again from prior studies, that survivors of childhood cancer do have an increased risk of mortality compared to the general population, but I think looking at those curves of the cumulative mortality risk was really quite striking as they diverge, and that's, you know, just so long past their initial diagnosis and treatment. We know that subsequent malignant neoplasms or secondary cancers are a really an important contributor to mortality among survivors. And I think it was important to note that even in these older survivors, it's still such an important contributor to mortality, and I think this really highlights the need for us to better understand what is driving specific secondary cancers and what are the differences in the biology and treatment approaches for some of these cancers? And how might that then be contributing to the mortality risk? Dr. Davide Soldato: Related to the treatment mortalities - because I think that one of the main forces of the study, as it is conducted, is that it contains a lot of information regarding radiotherapy, allogeneic transplant, surgery, type of chemotherapy received by these survivors - so, are we able right now with the data that we have to pinpoint which of these treatments can potentially lead to such increased risk of mortality? Dr. Rusha Bhandari: So, we weren't able to look at the comprehensive treatment exposures and mortality risk for this paper. So that might be one of the questions I would put on the side. We were able to look at that in relation to subsequent malignant neoplasms and health conditions though, as you mentioned. Dr. Davide Soldato: Another thing that I think is very important is that you were able to look at specific causes for mortality. So for example, you mentioned the increased rate of neoplasm in this population and specifically, more or less 7.6% of the patients that were included in the study developed another neoplasm after the ones they were cured for in the childhood period. So, you saw a wide range of cancer, for example, bone and soft tissue sarcomas, breast cancer, genitourinary cancer. And as you were mentioning, there were some associations for treatment modalities that were associated with a higher risk of developing this type of cancer. Can you expand a little bit on this? Dr. Rusha Bhandari: Absolutely. And so the key part here was that we really looked at any of these outcomes that occurred beyond age 50. What we found was there is still an increased risk of secondary cancers beyond that initial childhood cancer diagnosis, but when we really looked at that data, it was specifically among survivors who had a history of receiving radiation. And we did not necessarily see an association between different chemotherapy exposures and secondary cancers. And I think this speaks to what we're now learning in terms of the very long-term effects of radiation and how that impacts ongoing health risk even in patients who are 30 or more years out from their treatment. And I think it really highlights the importance of these- the efforts that have been made in the more recent decades to really try and reduce or eliminate radiation where possible, you know, as we've come to understand more about these long-term effects from it. Dr. Davide Soldato: A clear association with radiation therapy but no association when we look at specific types of chemotherapy that were used for curing this childhood cancer. Another thing that I think it's very interesting and you briefly mentioned before is that potentially when we look at these secondary malignant neoplasm that develop in this situation, we might also see some outcomes that are not comparable to the one of the general population, meaning that we managed to cure less this type of cancer when they develop in these childhood survivors. So, I just wanted to understand if you could provide us with a little bit of perspective also from a clinical standpoint being a pediatric hematologist-oncologist as to why this might be happening and how can we potentially increase the cure rate also in this population of childhood cancer survivors? Dr. Rusha Bhandari: Absolutely. While that was not the focus of this study, it was something that we were certainly interested in is understanding how even once a childhood cancer survivor, for example, develops a health condition or a secondary cancer further into survivorship, how does that outcome then differ from someone in the general population? And there's a lot of interest in ongoing studies actually evaluating that and understanding what are the differences from the initial presentation, biology, the characteristics of that cancer, through how they're treated. So I don't know if we have all of the answers for that quite yet, but you can imagine if someone hypothetically had a history of receiving a lot of anthracycline chemotherapy or already having received a lot of radiation, that might impact what treatment they might receive for that secondary cancer or if they already have other existing comorbidities that need to be taken into consideration. Dr. Davide Soldato: Speaking about comorbidities, you were mentioning in the beginning that one of the focuses of this scientific work was really to try and see whether also this type of adverse health outcomes that can be potentially related to treatments were more frequent among these childhood cancer survivors. So I think that it's very interesting that for this comparison, you were able to use the data from the siblings of the patients who were included inside of the study. So, just a little bit of a comment on why you decided to use this specific methodology, which I think has a very nice touch to it when we look at these outcomes like, for example, diabetes or cardiovascular disease, and in general, do we see an increased number of chronic health conditions among survivors who were treated for childhood cancers? Dr. Rusha Bhandari: Yes, so this is a really excellent strength of the Childhood Cancer Survivor Study is that they have information, longitudinal information, on survivors as well as their siblings. So, you know, when we were discussing the design of the study, I mentioned that we have initial baseline questionnaires as well as multiple follow-up questionnaires, and that is for both the survivors and the siblings. And so we're able to really understand their health course over time. We chose to evaluate sibling data because then you're really able to look at people who have similar characteristics, right? Similar environmental exposures in theory, potentially similar genetic predispositions and makeups and things like that. And so you can really try and have as good of a comparison as possible. Dr. Davide Soldato: Did we see any increase in chronic health condition when looking at survivors compared to the siblings? Dr. Rusha Bhandari: We did. And while that's been reported before, again, I think it's important to demonstrate that in this older population when you would expect that these siblings would now also be starting to develop different health conditions. Dr. Davide Soldato: One thing that was very interesting is that when we look at the coexistence of multiple comorbid conditions and chronic condition in this population, we also see that for some of these survivors, they basically have the same rates of comorbidities as compared to siblings who are potentially 20 years older than them. So I think that there is really that striking point, as you were mentioning before, of accumulation of changes, also physiological changes that can potentially drive a higher frailty index, which was also higher when looking at these survivors compared to their siblings. One outcome that was really not that worse when we look at survivors of childhood cancer was actually mental health. And as I read the paper, it was something that really surprised me a little bit because you would imagine that going through such a harsh diagnosis, such very complex treatment, very early in their life could potentially lead to some worse health outcomes also in terms of mental health over time. But this was not seen. And just a comment on this, because I think it's a very surprising data. Dr. Rusha Bhandari: Yes, I appreciate that question. So, as you mentioned, mental health is such an important issue for patients, both those undergoing treatment as well as those in long-term survivorship. And in our study, we found that survivors were not more likely, as you mentioned, to report poor mental health compared to their siblings. And I think there's a few possible reasons for this. You know, again, this is self-reported data amongst siblings and survivors who survived to at least 50 years of age and completed a questionnaire. And so that is the group of individuals that we were able to evaluate this in, so we have to keep that in mind. But I think our findings may also reflect the resilience of this particular cohort of aging survivors that we included. This finding has been reported in other studies of survivors as well, and so I think it very well may speak to the resilience of the cohort that we're looking at. Dr. Davide Soldato: Going back just a little bit, you mentioned that the majority potentially of these survivors who were included in the current analysis were treated between 1970s and 1980s. So, as you were mentioning before, radiotherapy was seen as a significant contributor to second neoplasm and also to the increase of this chronic health condition. So, do you believe that there is still a role for these survivorship studies as we are approaching treatment modalities where radiotherapy is administered less frequently or with lower doses or omitted at all in the treatment course of these survivors? Dr. Rusha Bhandari: Absolutely. I think you mentioned a very important point, which is these findings are most applicable to the patients who were included in this cohort or similar cohorts, those who were treated in the 1970s and 80s who now are 50 years or older at this point in time. And as you know, treatment modalities have really changed. You know, as you mentioned, we'll use less radiation in many cases whenever possible, but there are so many new modalities, so many different chemotherapeutic agents, immunotherapy. There's so much more we need to learn about the long-term effects of some of these newer treatment modalities. And also, we've been able to really intensify our treatment regimens with improvements in both treatment approaches and supportive care. And so I think we have a lot to learn about those late effects, and ongoing studies are certainly needed as we continue to have this growing population of older survivors. Dr. Davide Soldato: And now a more general question which builds on the results of the study but goes a little bit beyond what was the scope of the research. So we have just discussed that there is an excess mortality in general, there is a higher risk for secondary malignancies in this population, we see higher accumulation of chronic comorbid conditions that need to be treated. So building on these results, in your opinion, what would be the best framework to follow up these patients over time? Because I imagine that for some of these patients who have been treated 30, 40 years before the moment where we see this type of events, they can be potentially also discharged from more specialistic medical care. So what is the best course of action? Should we keep all of these patients under observation in a very specialistic environment under the care of the oncologist or the pediatric oncologist? Should we create a stronger bond with general practitioners so they know that there is this problem? Dr. Rusha Bhandari: Yes, I mean, I think you're reading my mind. We thankfully do have evidence-based guidelines. We utilize the Children's Oncology Group Long-Term Follow-Up Guidelines, which include screening recommendations for secondary cancers, chronic health conditions, everything based on the underlying diagnosis and treatment that these patients received. But we recognize that a large proportion of these survivors do not continue to have lifelong follow-up at a survivorship center, but really do need that specialized screening based on their treatment that they received. And I think for that reason, it's so important that we continue to build relationships with their primary care providers and really make sure that both patients and their providers have this information at hand regarding what their treatment is and what the screening is that they need and that we be able to have this community whereby we are able to help inform the screening in our own survivorship clinics, but also help guide some of the primary care providers who are going to be seeing these patients in the long run. Dr. Davide Soldato: Do we have any data showing what is the adherence rate of these patients to this type of continuous screening and monitoring over time? Because I imagine that that might also be a point for improvement in terms of quality of care. Can we retain as much childhood cancer survivors as we want as we are learning that there are all these potential negative health outcomes over time? Dr. Rusha Bhandari: We definitely within the survivorship community do want to help make sure as many survivors as possible are being engaged, again, whether it's at their specific cancer center or whether it's in the community, recognizing that for many reasons, it's not feasible to always return to that cancer center for your regular survivorship care. I think there's a lot we can do. Going a little bit outside the scope of your question, but I think there's a lot that we can do nowadays in terms of telehealth and being able to communicate with patients and their providers even if they're geographically not located right near us. But we do have data that shows that the further out many patients get from their initial diagnosis and treatment, the less often they might follow up with a survivorship provider. Some of this varies by different treatment. Dr. Davide Soldato: So, basically the final question is that we need more education and potentially more resources for survivorship clinics and in general to better inform patients and providers about these potential long-term outcomes. Dr. Rusha Bhandari: That's certainly a focus of our survivorship program, for example, is to make sure that we're able to educate patients, inform them of their risks, and why certain screening tests are recommended at certain times in their survivorship journey. And then I think again, thankfully nowadays with all of the electronic medical records and different methods for us to communicate, there's a lot of opportunity for us to continue building these relationships with those primary care providers and making sure they have the information at their fingertips as well as to be able to work in conjunction with these patients to continue to formulate their plans and carry out these screenings and then again, like I was saying, have an easy open line of communication with the oncology centers if they do have any questions. Dr. Davide Soldato: Thanks so much. This brings us to the end of this episode. I would like to thank again Dr. Bhandari for joining us today. Dr. Rusha Bhandari: Thank you so much. It's been a real pleasure speaking with you. Dr. Davide Soldato: And we appreciate you sharing more on your JCO article titled "Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study." If you enjoy our show, please leave us a rating and review and be sure to come back for another 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.  

Authors Drs. Jessica Ross and Alissa Cooper share insights into their JCO PO article, "Clinical and Pathologic Landscapes of Delta-Like Ligand 3 and Seizure-Related Homolog Protein 6 Expression in Neuroendocrine Carcinomas"  Host Dr. Rafeh Naqash and Drs. Ross and Cooper discuss the landscape of Delta-like ligand 3 (DLL3) and seizure-related homolog protein 6 (SEZ6) across NECs from eight different primary sites. 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 PO and an Associate Professor at the OU Health Stephenson Cancer Center. Today, I'm excited to be joined by Dr. Jessica Ross, third-year medical oncology fellow at the Memorial Sloan Kettering Cancer Center, as well as Dr. Alissa Cooper, thoracic medical oncologist at the Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School. Both are first and last authors of the JCO Precision Oncology article entitled "Clinical and Pathologic Landscapes of Delta-like Ligand 3 and Seizure-Related Homolog Protein 6 or SEZ6 Protein Expression in Neuroendocrine Carcinomas." At the time of this recording, our guest disclosures will be linked in the transcript. Jessica and Alissa, welcome to our podcast, and thank you for joining us today. Dr. Jessica Ross: Thanks very much for having us. Dr. Alissa Cooper: Thank you. Excited to be here. Dr. Rafeh Naqash: It's interesting, a couple of days before I decided to choose this article, one of my GI oncology colleagues actually asked me two questions. He said, "Rafeh, do you know how you define DLL3 positivity? And what is the status of DLL3 positivity in GI cancers, GI neuroendocrine carcinomas?" The first thing I looked up was this JCO article from Martin Wermke. You might have seen it as well, on obrixtamig, a phase 1 study, a DLL3 bi-specific T-cell engager. And they had some definitions there, and then this article came along, and I was really excited that it kind of fell right in place of trying to understand the IHC landscape of two very interesting targets. Since we have a very broad and diverse audience, especially community oncologists, trainees, and of course academic clinicians and some people who are very interested in genomics, we'll try to make things easy to understand. So my first question for you, Jessica, is: what is DLL3 and SEZ6 and why are they important in neuroendocrine carcinomas? Dr. Jessica Ross: Yeah, good question. So, DLL3, or delta-like ligand 3, is a protein that is expressed preferentially on the tumor cell surface of neuroendocrine carcinomas as opposed to normal tissue. It is a downstream target of ASCL1, and it's involved in neuroendocrine differentiation, and it's an appealing drug target because it is preferentially expressed on tumor cell surfaces. And so, it's a protein, and there are several drugs in development targeting this protein, and then Tarlatamab is an approved bi-specific T-cell engager for the treatment of extensive-stage small cell lung cancer in the second line. SEZ6, or seizure-like homolog protein 6, is a protein also expressed on neuroendocrine carcinoma cell surface. Interestingly, so it's expressed on neuronal cells, but its exact role in neuroendocrine carcinomas and oncogenesis is actually pretty poorly understood, but it was identified as an appealing drug target because, similarly to DLL3, it's preferentially expressed on the tumor cell surface. And so this has also emerged as an appealing drug target, and there are drugs in development, including antibody-drug conjugates, targeting this protein for that reason. Dr. Alissa Cooper: Over the last 10 to 15 years or so, there's been an increasing focus on precision oncology, finding specific targets that actually drive the cancer to grow, not just within lung cancer but in multiple other primary cancers. But specifically, at least speaking from a thoracic oncology perspective, the field of non-small cell lung cancer has completely exploded over the past 15 years with the discovery of driver oncogenes and then matched targeted therapies. Within the field of neuroendocrine carcinomas, including small cell lung cancer but also other high-grade neuroendocrine carcinomas, there has not been the same sort of progress in terms of identifying targets with matched therapies. And up until recently, we've sort of been treating these neuroendocrine malignancies kind of as a monolithic disease process. And so recently, there's been sort of an explosion of research across the country and multiple laboratories, multiple people converging on the same open questions about why might patients with specific tumor biologies have different kind of responses to different therapies. And so first this came from, you know, why some patients might have a good response to chemo and immunotherapy, which is the first-line approved therapy for small cell lung cancer, and we also sort of extrapolate that to other high-grade neuroendocrine carcinomas. What's the characteristic of that tumor biology? And at the same time, what are other targets that might be identifiable? Just as Jesse was saying, they're expressed on the cell surface, they're not necessarily expressed in normal tissue. Might this be a strategy to sort of move forward and create smarter therapies for our patients and therefore move really into a personalized era for treatment for each patient? And that's really driving, I think, a lot of the synthesis of this work of not only the development of multiple new therapies, but really understanding which tumor might be the best fit for which therapy. Dr. Rafeh Naqash: Thank you for that explanation, Alissa. And as you mentioned, these are emerging targets, some more further along in the process with approved drugs, especially Tarlatamab. And obviously, DLL3 was something identified several years back, but drug development does take time, and readout for clinical trials takes time. Could you, for the sake of our audience, try to talk briefly about the excitement around Tarlatamab in small cell lung cancer, especially data that has led to the FDA approval in the last year, year and a half? Dr. Alissa Cooper: Sure. Yeah, it's really been an explosion of excitement over, as you're saying, the last couple of years, and work really led by our mentor, Charlie Rudin, had identified DLL3 as an exciting target for small cell lung cancer specifically but also potentially other high-grade neuroendocrine malignancies. Tarlatamab is a DLL3-targeting bi-specific T-cell engager, which targets DLL3 on the small cell lung cancer cells as well as CD3 on T cells. And the idea is to sort of introduce the cancer to the immune system, circumventing the need for MHC class antigen presentation, which that machinery is typically not functional in small cell lung cancer, and so really allowing for an immunomodulatory response, which had not really been possible for most patients with small cell lung cancer prior to this. Tarlatamab was tested in a phase 2 registrational trial of about 100 patients and demonstrated a response rate of 40%, which was very exciting, especially compared with other standard therapies which were available for small cell lung cancer, which are typically cytotoxic therapies. But most excitingly, more than even the response rate, I think, in our minds was the durability of response. So patients whose disease did have a response to Tarlatamab could potentially have a durable response lasting a number of months or even over a year, which had previously not ever been seen in this in the relapsed/refractory setting for these patients. I think the challenge with small cell lung cancer and other high-grade neuroendocrine malignancies is that a response to therapy might be a bit easier to achieve, but it's that durability. The patient's tumors really come roaring back quite aggressively pretty quickly. And so this was sort of the most exciting prospect is that durability of response, that long potential overall survival tail of the curve really being lifted up. And then most recently at ASCO this year, Dr. Rudin presented the phase 3 randomized controlled trial which compared Tarlatamab to physician's choice of chemotherapy in a global study. And the choice of chemotherapy did vary depending on the part of the world that the patients were enrolled in, but in general, it was a really markedly positive study for response rate, for progression-free survival, and for overall survival. Really exciting results which really cemented Tarlatamab's place as the standard second-line therapy for patients with small cell lung cancer whose disease has progressed on first-line chemo-immunotherapy. So that has been very exciting. This drug was FDA approved in May of 2024, and so has been used extensively since then. I think the adoption has been pretty widespread, at least in the US, but now in this global trial that was just presented, and there was a corresponding New England Journal paper, I think really confirms that this is something we really hopefully can offer to most of our patients. And I think, as we all know, that this therapy or other therapies like it are also being tested potentially in the first-line setting. So there was data presented with Tarlatamab incorporated into the maintenance setting, which also showed exciting results, albeit in a phase 1 trial, but longer overall survival than we're used to seeing in this patient population. And we await results of the study that is incorporating Tarlatamab into the induction phase with chemotherapy as well. So all of this is extraordinarily exciting for our patients to sort of move the needle of how many patients we can keep alive, feeling functional, feeling well, for as long as possible. Dr. Rafeh Naqash: Very exciting session at ASCO. I was luckily one of the co-chairs for the session that Dr. Rudin presented it, and I remember somebody mentioning there was more progress seen in that session for small cell lung cancer than the last 30, 35 years for small cell, very exciting space and time to be in as far as small cell lung cancer. Now going to this project, Jessica, since you're the first author and Alissa's the last, I'm assuming there was a background conversation that you had with Alissa before you embarked on this project as an idea. So could you, again, for other trainees who are interested in doing research, and it's never easy to do research as a resident and a fellow when you have certain added responsibilities. Could you give us a little bit of a background on how this started and why you wanted to look at this question? Dr. Jessica Ross: Yeah, sure. So, as with many exciting research concepts, I think a lot of them are derived from the clinic. And so I think Alissa and I both see a good number of patients with small cell, large cell lung cancer, and then high-grade neuroendocrine carcinomas. And so I think this was really born out of a basic conversation of we have these drugs in development targeting these two proteins, DLL3 and SEZ6, but really what is the landscape of cancers that express these proteins and who are the patients that really might benefit from these exciting new therapies. And of course, there was some data out there, but sort of less than one would imagine in terms of, you know, neuroendocrine carcinomas can really come from anywhere in the body. And so when you're seeing a patient with small cell of the cervix, for example, like what are the chances that their cancer expresses DLL3 or expresses SEZ6? So it was really derived from this pragmatic, clinically oriented question that we had both found ourselves thinking about, and we were lucky enough at MSK, we had started systematically staining patients' tumors for DLL3, tumors that are high-grade neuroendocrine carcinomas, and then we had also more recently started staining for SEZ6 as well. And so we had this nice prospectively collected dataset with which to answer this question. Dr. Rafeh Naqash: Excellent. And Alissa, could you try to go into some of the details around which patients you chose, how many patients, what was the approach that you selected to collect the data for this project? Dr. Alissa Cooper: This is perhaps a strength but also maybe a limitation of this dataset is, as Jesse alluded to, our pathology colleagues are really the stars of this paper here because we were lucky enough at MSK that they were really forethinking. They are absolute experts in the field and really forward-thinking people in terms of what information might be needed in the future to drive treatment decision-making. And so, as Jesse had said, small cell lung cancer tumor samples reflexively are stained for DLL3 and SEZ6 at MSK if there's enough tumor tissue. The other high-grade neuroendocrine carcinomas, those stains are performed upon physician request. And so that is a bit of a mixed bag in terms of the tumor samples we were able to include in this dataset because, you know, upon physician request depends on a number of factors, but actually at MSK, a number of physicians were requesting these stains to be done on their patients with high-grade neuroendocrine cancers of of other histologies. So we looked at all tumor samples with a diagnosis of high-grade neuroendocrine carcinoma of any histology that were stained for these two stains of interest. You know, I can let Jesse talk a bit more about the methodology. She was really the driver of this project. Dr. Jessica Ross: Yeah, sure. So we had 124 tumor samples total. All of those were stained for DLL3, and then a little less than half, 53, were stained for SEZ6. As Alissa said, they were from any primary site. So about half of them were of lung origin, that was the most common primary site, but we included GI tract, head and neck, GU, GYN, even a few tumors of unknown origin. And again, that's because I think a lot of these trials are basket trials that are including different high-grade neuroendocrine carcinomas no matter the primary site. And so we really felt like it was important to be more comprehensive and inclusive in this study. And then, methodologically, we also defined positivity in terms of staining of these two proteins as anything greater than or equal to 1% staining. There's really not a defined consensus of positivity when it comes to these two novel targets and staining for these two proteins. But in the Tarlatamab trials, for some of the correlative work that's been done, they use that 1% cutoff, and we just felt like being consistent with that and also using a sort of more pragmatic yes/no cutoff would be more helpful for this analysis. Dr. Alissa Cooper: And that was a point of discussion, actually. We had contemplated multiple different schemas, actually, for how to define thresholds of positivity. And I know you brought up that question before, what does it mean to be DLL3 positive or DLL3 high? I think you were alluding to prior that there was a presentation of obrixtamig looking at extra-pulmonary neuroendocrine carcinomas, and they actually divvied up the results between DLL3 50% or greater versus DLL3 low under 50%. And they actually did demonstrate differential efficacy certainly, but also some differential safety as well, which is very provocative and that kind of analysis has not been presented for other novel therapies as far as I'm aware. I could be wrong, but as far as I'm aware, that was sort of the first time that we saw a systematic presentation of considering patients to be, quote unquote, "high" or "low" in these sort of novel targets. I think it is important because the label for Tarlatamab does not require any DLL3 expression at all, actually. So it's not hinging upon DLL3 expression. They depend on the fact that the vast majority of small cell lung cancer tumors do express DLL3, 85% to 90% is what's been demonstrated in a few studies. And so, there's not prerequisite testing needed in that regard, but maybe for these extra-pulmonary, other histology neuroendocrine carcinomas, maybe it does matter to some degree. Dr. Rafeh Naqash: Definitely agree that this evolving landscape of trying to understand whether an expression for something actually really does correlate with, whether it's an immune cell engager or an antibody-drug conjugate is a very evolving and dynamically moving space. And one of the questions that I was discussing with one of my friends was whether IHC positivity and the level of IHC positivity, as you've shown in one of those plots where you have double positive here on the right upper corner, you have the double negative towards the left lower, whether that somehow determines mRNA expression for DLL3. Obviously, that was not the question here that you were looking at, but it does kind of bring into question certain other aspects of correlations, expression versus IHC. Now going to the figures in this manuscript, very nicely done figures, very easy to understand because I've done the podcast for quite a bit now, and usually what I try to do first is go through the figures before I read the text, and and a lot of times it's hard to understand the figures without reading the text, but in your case, specifically the figures were very, very well done. Could you give us an overview, a quick overview of some of the important results, Jessica, as far as what you've highlighted in the manuscript? Dr. Jessica Ross: Sure. So I think the key takeaway is that, of the tumors in our cohort, the majority were positive for DLL3 and positive for SEZ6. So about 80% of them were positive for DLL3 and 80% were positive for SEZ6. About half of the tumors were stained for both proteins, and about 65% of those were positive as well. So I think if there's sort of one major takeaway, it's that when you're seeing a patient with a high-grade neuroendocrine carcinoma, the odds are that their tumor will express both of these proteins. And so that can sort of get your head thinking about what therapies they might be eligible for. And then we also did an analysis of some populations of interest. So for example, we know that non-neuroendocrine pathologies can transform into neuroendocrine tumors. And so we specifically looked at that subset of patients with transformed tumors, and those were also- the majority of them were positive, about three-quarters of them were positive for both of these two proteins. We looked at patients with brain met samples, again, about 70% were positive. And then I'd say the last sort of population of interest was we had a subset of 10 patients who had serial biopsies stained for either DLL3 or SEZ6 or both. In between the two samples, these patients were treated with chemotherapy. They were not treated with targeted therapy, but interestingly, in the majority of cases, the testing results were concordant, meaning if it was DLL3 positive to begin with, it tended to remain DLL3 positive after treatment. And so I think that's important as well as we think about, you know, a patient who maybe had DLL3 testing done before they received their induction chemo-IO, we can somewhat confidently say that they're probably still DLL3 positive after that treatment. And then finally, we did do a survival analysis among specifically the patients with lung neuroendocrine carcinomas. We looked at whether DLL3 expression affected progression-free survival on first-line platinum-etoposide, and then we looked at did it affect overall survival. And we found that it did not have an impact or the median progression-free survival was similar whether you were DLL3 positive or negative. But interestingly, with overall survival, we found that DLL3 positivity actually correlated with slightly improved overall survival. These were small numbers, and so, you know, I think we have to interpret this with caution, for sure, but it is interesting. I think there may be something to the fact that five of the patients who were DLL3 positive were treated with DLL3-targeting treatments. And so this made me think of, like in the breast cancer world, for example, if you have a patient with HER2-positive disease, it initially portended worse prognosis, more aggressive disease biology, but on the other hand, it opens the door for targeted treatments that actually now, at least with HER2-positive breast cancer, are associated with improved outcomes. And so I think that's one finding of interest as well. Dr. Rafeh Naqash: Definitely proof-of-concept findings here that you guys have in the manuscript. Alissa, if I may ask you, what is the next important step for a project like this in your mind? Dr. Alissa Cooper: Jesse has highlighted a couple of key findings that we hope to move forward with future investigative studies, not necessarily in a real-world setting, but maybe even in clinical trial settings or in collaboration with sponsors. Are these biomarkers predictive? Are they prognostic? You know, those are still- we have some nascent data, data has been brewing, but I think that we we still don't have the answers to those open questions, which I think are critically important for determining not only clinical treatment decision-making, but also our ability to understand sequencing of therapies, prioritization of therapies. I think a prospective, forward-looking project, piggybacking on that paired biopsy, you know, we had a very small subset of patients with paired biopsies, but a larger subset or cohort looking at paired biopsies where we can see is there evolution of these IHC expression, even mRNA expression, as you're saying, is there differential there? Are there selection pressures to targeted therapies? Is there upregulation or downregulation of targets in response not just to chemotherapy, but for example, for other sort of ADCs or bi-specific T-cell engagers? I think those are going to be critically important future studies which are going to be a bit challenging to do, but really important to figure out this key clinical question of sequencing, which we're all contemplating in our clinics day in and day out. If you have a patient, and these patients often can be sick quite quickly, they might have one shot of what's the next treatment that you're going to pick. We can't guarantee that every patient is going to get to see every therapy. How can you help to sort of answer the question of like what should you offer? So I think that's the key question sort of underlying any future work is how predictive or prognostic are these biomarkers? What translational or correlative studies can we do on the tissue to understand clinical treatment decision-making? I think those are the key things that will unfold in the next couple of years. Dr. Rafeh Naqash: The last question for you, Alissa, that I have is, you are fairly early in your career, and you've accomplished quite a lot. One of the most important things that comes out from this manuscript is your mentorship for somebody who is a fellow and who led this project. For other junior investigators, early-career investigators, how did you do this? How did you manage to do this, and how did you mentor Jessica on this project with some of the lessons that you learned along the way, the good and other things that would perhaps help other listeners as they try to mentor residents, trainees, which is one of the important things of what we do in our daily routine? Dr. Alissa Cooper: I appreciate you calling me accomplished. Um, I'm not sure how true that is, but I appreciate that. I didn't have to do a whole lot with this project because Jesse is an extraordinarily smart, driven, talented fellow who came up with a lot of the clinical questions and a lot of the research questions as well. And so this project was definitely a collaborative project on both of our ends. But I think what was helpful from both of our perspectives is from my perspective, I could kind of see that this was a gap in the literature that really, I think, from my work leading clinical trials and from treating patients with these kinds of cancers that I really hoped to answer. And so when I came to Jessica with this idea as sort of a project to complete, she was very eager to take it and run with it and also make it her own. You know, in terms of early mentorship, I have to admit this was the first project that I mentored, so it was a great learning experience for me as well because as an early-career clinician and researcher, you're used to having someone else looking over your shoulder to tell you, "Yes, this is a good journal target, here's what we can anticipate reviewers are going to say, here are other key collaborators we should include." Those kind of things about a project that don't always occur to you as you're sort of first starting out. And so all of that experience for me to be identifying those more upper-level management sort of questions was a really good learning experience for me. And of course, I was fantastically lucky to have a partner in Jesse, who is just a rising star. Dr. Jessica Ross: Thank you. Dr. Rafeh Naqash: Well, excellent. It sounds like the first of many other mentorship opportunities to come for you, Alissa. And Jessica, congratulations on your next step of joining and being faculty, hopefully, where you're training. Thank you again, both of you. This was very insightful. I definitely learned a lot after I reviewed the manuscript and read the manuscript. Hopefully, our listeners will feel the same. Perhaps we'll have more of your work being published in JCO PO subsequently. Dr. Alissa Cooper: Hope so. Thank you very much for the opportunity to chat today. Dr. Jessica Ross: Yes, thank you. This was great. Dr. Rafeh Naqash: 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 as 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. Alissa Jamie Cooper Honoraria Company: MJH Life Scienes, Ideology Health, Intellisphere LLC, MedStar Health, Physician's Education Resource, LLC,  Gilead Sciences, Regeneron, Daiichi Sankyo/Astra Zeneca, Novartis,  Research Funding: Merck, Roche, Monte Rosa Therapeutics, Abbvie, Amgen, Daiichi Sankyo/Astra Zeneca Travel, Accommodations, Expenses: Gilead Sciences

Guest Dr. Sundar Jagannath and host Dr. Davide Soldato discuss JCO article "Long-Term (≥5-Year) Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma," and the efficacy of CAR-T cell therapy in patients with heavily pretreated RRMM (relapsed/refractory multiple myeloma). TRANSCRIPT Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by JCO author, Professor Sundar Jagannath, Professor of Medicine at the Icahn School of Medicine at Mount Sinai and the Tisch Cancer Institute. He also serves as Network Director for the Center of Excellence for Multiple Myeloma, and he is an internationally recognized expert in the field of multiple myeloma. Today, we will be discussing the article titled, "Long-Term Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma." Thank you for speaking with us, Professor Jagannath. Dr. Sundar Jagannath: Thank you for having me, Dr. Davide Soldato. It is a pleasure to be here. JCO is a highly recognized journal among the oncologists, so I am very happy and privileged to be here today. Dr. Davide Soldato: Thank you so much for being with us. So, I wanted to start a little bit with the rationale of the study and the population that was included in the study. So, the trial that we are discussing, CARTITUDE-1, was already published before, and we observed very good results with a single infusion of cilta-cel. So we had previously reported a median progression-free survival of 30 months, and median overall survival was not reached. So, I just wanted to ask you if you could guide us a little bit into the population that was included in the study and also explain a little bit to our listeners what is the drug that we are discussing, cilta-cel. Dr. Sundar Jagannath: It is a CAR T-cell. This is a patient's own lymphocytes, which goes through apheresis and is sent to the company, where they modify it and introduce the B cell receptor. In this case, you know, there is a heavy chain gene receptor for the BCMA, and in cilta-cel, there are actually two receptor sites on each molecule, or there are two binding domains on each receptor molecule. So, it is considered to be quite efficacious. As you reported, the earlier results that the patients who participated, 97% of the patient responded. Now, you asked about the patients who participated in the clinical trial. This clinical trial was conducted between July of 2018 and October of 2019. At that time, this was a phase 1b/phase 2 trial, and the whole idea was to take patients who had relapsed all the available treatment regimen so that these patients were considered to have, in the unmet medical need situation. So, what does that entail? That means the patient should have been exposed to a proteasome inhibitor, to an immunomodulatory molecule, and to an anti-CD38 monoclonal antibody and should have received at least three or more prior lines of therapy and should be actually progressing on their last line of therapy. So with that requirement, if you look at it, the median number of prior therapy on the patients who participated was actually six. So patients were heavily pretreated. They had exhausted all available treatment options. So, they can participate in this clinical trial. And if not, there have been real-world evidence, such as LocoMMotion, which had reported what is the outcome for such a patient if they were treated outside of this clinical trial, if they were treated with the then available regimen. Their median progression free survival would have been only 3 months, and most patients would have lost their life within a year. So, this was truly an unmet medical need with patients in a very difficult clinical situation. Let's put it that way. So, those were the patients who participated in this particular trial. Dr. Davide Soldato: Thank you very much. And as we mentioned before, the results that were obtained in this clinical trial were really very interesting. And now, in this issue of the Journal of Clinical Oncology, you are reporting data with a longer follow up. So we are actually at more than 5 years of follow up for the patients included in this trial. So, I just wanted a little bit of insight into why you decided to report these long-term outcomes and what type of information do you think you could provide with this study to the medical community? Dr. Sundar Jagannath: This is very important because this was a clinical trial that was done in patients who were, as I said, in unmet medical need. Most of the patients had prior stem cell transplantation, had gone through a proteasome inhibitor. Many of them have had both Velcade and carfilzomib treatment. Most of them had been exposed to lenalidomide and pomalidomide. And as required, all of the patients had to have had prior exposure to anti-CD38 monoclonal antibody or daratumumab. So, the patients were heavily pretreated. Typically, TIL CAR T-cells came into the field at this particular moment, until then, we were developing small molecules, and they usually would have a PFS of 3 months and median life expectancy of a year, the overall response rate of 30%, and that is how, if you look back, that is how carfilzomib was approved, that is how pomalidomide was approved. So, the drugs which were approved, including daratumumab, you know, the response rate was in the same ballpark. So you would see that most agents, single agents, would have had a response rate in the neighborhood of 30%, the progression-free survival would have been between 3 to 5 months or 6 months at the most, and the life expectancy was short. And here comes a drug, and when I was following the patients at Mount Sinai, I found that there were a subset of patients, they got one-time treatment and they were in complete remission, no trace of cancer with annual evaluation with PET CT and bone marrow evaluation for MRD. So, I said this is remarkable, and this needs to be reported. And I went to the Janssen and company, and they agreed to review the entire experience. This is remarkable that 32 of the 97 patients, or one third of the patients, were alive and progression-free. This is unheard of for any clinical trial until now, that the patient will be progression-free, one third of the patients on a clinical trial will be progression-free, in the late stage of their disease. So that is the most important impact. And that is why this 5-year follow-up results were presented. Dr. Davide Soldato: Thank you very much. That was very clear. And as you said, we are speaking about a population that was heavily pretreated, that had exhausted all type of treatment options outside of a clinical trial. And as you said, one third of the patients was alive and progression-free after 5 years from being included and infused inside of the study. So, considering this population that, as we said, had received all treatment options, I was wondering if you observed any kind of differences in terms of disease characteristics when looking at these patients that had exceptional response, so, alive and progression-free at 5 years, and the patients that sadly had developed a progression after the infusion in the study. Dr. Sundar Jagannath: This is very important because we wanted to see who are the patients who are having this exceptional outcome. And we looked at all the 97 patients. If we look at all the patients, we saw that there were initially, out of the 97, 17 patients died earlier in the disease course due to treatment related complications, etc. But there were about 46 patients who had progression of disease and 32 patients, or one third, were alive without progression of disease. Then we looked at the 46 patients who had progression of disease. Of them, we found that 30 had disease progression and its complication, and there were actually 13 patients who were still alive even after progression of disease. So we decided to compare these 46 patients who had progression of disease versus 32 patients who had no progression of disease to see what is the difference. To our surprise, the age was similar, male, female distribution was similar. High-risk cytogenetics, which we would have thought, you know, that is why we say high-risk disease, the term, high-risk cytogenetics was equally distributed. That was really a surprise. Number of lines of prior therapy, number of exposure to drugs, all of that was the same. So that was also interesting. But a theme did emerge. Patients, in general, tend to have lower burden of disease who had the exceptional outcome. But there is one which we considered as bad, the extramedullary disease. Multiple myeloma being a blood cancer, it is usually in the bone marrow. When it starts growing outside of the bone marrow, the extramedullary disease, usually it portends poor prognosis. But we were surprised that actually there were an equal number of extramedullary disease patients even in the long-term survivor as those who had progressed of disease. So the most important takeaway was patients who had lower burden of disease, they had less number of myeloma cells in their bone marrow, percentage wise, and the soluble BCMA level was lower. Soluble BCMA is an indirect measure of the amount of plasma cells in the patient's body. It is like a tumor burden. So they were low. So, this was an important finding because it has future ramification, as you can understand. If this treatment is made available earlier in the disease course of the patients, where we are able to control the disease better, then more patients are likely to have such wonderful outcomes as one third of the patient experience in the late stage of the disease. Dr. Davide Soldato: So, you already mentioned soluble BCMA as a marker of potentially better prognosis as being correlated to a lower volume of disease. I was wondering if you could give us some more information about the biomarkers that you evaluated in the study. For example, you evaluated a little bit the CAR T expansion kinetics and also some others that I think could be interesting and could point to some population that experienced such important benefit. Dr. Sundar Jagannath: That is a very important point because CAR T-cell, it is a live cell and its efficacy depends upon how well the CAR T-cell is going to function. And then, you know, the patient undergoes apheresis. This is a patient's own lymphocyte. So first and foremost is who would generate good CAR T-cell. Those who have plenty of lymphocytes at the time they are coming for apheresis. This is likely to happen earlier in the course of the disease than in patients who have gone through numerous lines of therapy and exhausted. So, in this particular trial, of course this was in late stage of the disease, and so we were able to show patients who had lower number of T cell in circulation, and the way to measure is if they had more neutrophils and less lymphocytes. So that is what is called as a higher T cell over neutrophil, they did better. If they have more neutrophil than T cells, then they did not do well. So, procurement. The second one is also whether the T cells are more naive, you know, not exhausted T cells. So more naive T cells, if you are able to procure from the patient, they did very well. Now, after the CAR T-cell manufacture, then the expansion, when you put it back into the patient, if the T cells expand very well, so that the effector, that is the CAR T-cells to the tumor ratio is good, so there are more effector cells, the CAR T was able to expand and the amount of tumor was less, then the efficacy was very, very good. As I said, the patients in this group, those who had a lower burden of disease, they did better, and that is because of the CAR T-cell expansion, so the effector to the target ratio was favorable. So that is another important. And then there are also the type of CAR T-cells, having CD4 T cells with central memory phenotype at the peak expansion also makes a difference. So all of that matters. But this is important because the efficacy of the CAR T-cell, it is persistent, long persistent and keeping the cancer down. Its ability to get rid of the cancer completely at the first go around because usually we are not able to detect the CAR T-cells beyond 6 months in the majority of patients and very rarely after a year or two. So it is very uncommon to find the CAR T-cells in circulation or even in the regular bone marrow evaluation. So, efficacy, the expansion, having naive T cells, having good effector to target ratio and more central memory kind of T cell, because if it is all effector T cell, they will get quickly utilized and get exhausted, whereas the central memory cells can expand more and give more effective CAR T-cells. Dr. Davide Soldato: Thank you very much. I was wondering if you could guide us a little bit into what is your opinion regarding the positioning of CAR T-cells given all of these logistics that is necessary compared, for example, with bispecific antibodies against BCMA, which have the same target, but they do not have all of these logistics before being administered to the patient. Dr. Sundar Jagannath: That is a very important question, how to sequence these treatments now that we have two BCMA-directed CAR T-cells available. We have three BCMA-directed bispecific and one GPRC5D-directed bispecific antibodies are available. And so the question comes in for at least the currently approved CAR T-cell therapy, there is an obligatory time. You have to go through apheresis and you have to ship to the company, and there is a manufacturing time, roughly about 2 months before they can receive it. During that time, you want to make sure the patient's disease is under control. So that is a given. There are several ways to look at it when we evaluate the patient and talk to the patient. One good thing is now the two CAR T-cells which are approved, one is cilta-cel we talked about, and the other one is ide-cel. Ide-cel is approved in earlier line of therapy, two or more prior lines of therapy, and cilta-cel is approved in patients who have failed one line of therapy and who are lenalidomide refractory. So, the treatment of CAR T-cell is available earlier. And as I said, when you administer CAR T-cell earlier, you are able to keep the disease burden down, and it is a one and done deal. There is a better quality of life for the patient, and you are able to produce long, durable remission and potentially a cure. Now coming to the bispecific, they are currently available in later lines of therapy. So if you look at it from a patient's perspective, you can use the CAR T-cell earlier and then go through the bispecific therapy. But if the patient comes with relapsed refractory myeloma and has not used the CAR T-cell therapy and has not used the bispecific therapy, then the physicians have to decide which one they want to use. If somebody's disease is rapidly progressing and they need immediate tumor reduction and they have already exhausted all available therapy, then going through BCMA bispecific therapy is quite appropriate. And secondly, CAR T-cell therapy is generally given to somewhat physically more fit patients, whereas bispecific therapy, because you are giving antibody at step-wise dosing in this patient, and you have the ability to stop at any particular dose and then come back and redose, whereas CAR T is, you just give it to them one time, you have a lot more control. So intermediate frail or even frail patients can go through bispecific therapy, whereas it would not be in the best interest of the patient to go through a CAR T-cell therapy when they are frail. So that is another important point. But from the information available, when the patient goes on a BCMA bispecific therapy and they start progressing on treatment, usually it is their T cells are exhausted or the BCMA is no longer expressed on the tumor cells. So coming with CAR T-cell later on is usually not effective, whereas giving CAR T-cell earlier, if the patient relapses later, they have good T-cell function and most of the time the BCMA is still expressed. So you are able to give the BCMA to the maximum benefit by using the CAR T first and BCMA later. So if somebody asked me how to sequence this, just off the bat, you will say CAR T first, BCMA bispecific second. But as I said, there are unique situations. Then there is another potential that is happening. You can change the target. You can use a BCMA against GPRC5D to reduce the tumor, and then go ahead and consolidate it with a CAR T-cell therapy. That is also possible. You are changing the target from GPRC5D to BCMA, the tumor is already down, so the patient is likely to benefit. So these are all newer treatment options which have become available to the physician. So they will have to look at individual patients and decide what is the best course of action for that patient. Dr. Davide Soldato: So, I just wanted to close a little bit with your opinion about how these results translate into clinical practice. So considering this outstanding 5-year data that we have seen, one third of the patients who are alive and progression-free after a single infusion of cilta-cel, do you think that we could start to think about functional cure even in patients who have a diagnosis of relapsed refractory multiple myeloma? Dr. Sundar Jagannath: My feeling is this is important because in this particular study which is published, 12 patients who were followed at Mount Sinai out of the 32 patients who are alive and progression-free, 12 were followed at Mount Sinai. And they were evaluated every year with bone marrow MRD testing by clonoSEQ in 11 of the 12 patients, and one was by multiparametric flow cytometry. So most of them were 10 to the minus 6, not even one in a million cancer cells, and all of them had functional imaging, which is called PET CT every year. So these were patients who had no evidence of disease that we could detect with the technology available today, serologically, in the bone marrow, or anywhere else in the body with a PET CT. They were found to be disease free after a single infusion of cilta-cel. So, that would be almost to the definition of a cure because if you look at cure as a definition for any cancer, cure is defined as a state of complete remission with no trace of cancer that persists over a period of 5 years or longer without maintenance. And that will be applicable for breast cancer, lymphoma, leukemia. So it is a general statement. And if we use that in myeloma too, then I could say that these 12 patients from my center, we proved that they are cured of their myeloma. They are not functionally cured. You've got to remember, there is only cure. That was the definition across all diseases. So there is nothing like a functional cure. They are cured of myeloma. So is myeloma curable? This is the first time we are looking at that. We do know, every physician treating myeloma that there are patients out there, 10 year and beyond, without evidence of disease. This has been published by University of Arkansas, Bart Barlogie's group, who has been saying that myeloma is a curable disease for a long time. And many others have shown long-term follow up. But this one in a late stage disease, we were able to show that they were one treatment with no maintenance. All other studies have been in newly diagnosed myeloma patients. Nobody has shown in late relapse patients on a clinical trial a third of the patient will be progression-free. And 12 of them who were studied were actually disease free. So they were cured of the disease. So if we accept that, then the next question is, first step towards cure is achieving complete remission. They should have no monoclonal protein by any technology you want to use, no measurable residual disease using next gen sequencing or clonoSEQ, and functional imaging whole body PET CT or whole body MRI. So that is important, definition of the complete remission. And then it has to be sustained. That is something the IMWG and IMS, International Myeloma Society, they will have to come together for a consensus. How many years should they be followed and should be in this kind of status with no trace of cancer? Is it, 3 years are enough? 4 years enough? 5 years is enough? For me, I said in this paper, 5 years is a good definition for achieving a potential cure. Then you use the term 'functionally cured'. I have a problem with functionally cured and operationally cured or whatever. Functionally cured was originally put out by Paiva from Spain. There were 8% of newly diagnosed myeloma patients who have, after they go get treated, they will have an MGUS like phenomenon, a small amount of paraprotein detectable, and they are only 8%. And he said that these patients could be off treatment and the disease does not progress. But the problem is when you are giving treatment like maintenance therapy continuously until progression, you do not know exactly who is in the MGUS situation. So you have to have done sophisticated flow cytometry like Paiva did, and it is not quite clinically applicable. So functionally cured applies only for 8% of the people, so it should go out of the vocabulary. Then you can say 'operationally cured'. These are the patients traditionally Bart Barlogie and others showed that they have a large number of patients who have been followed for 10 years with no recurrence of disease, not on treatment. But in those days, they did not have MRD PET CT and all of them done systematically. So that is why they had to come up with a situation where they said they were operationally cured. So yes, myeloma patients have been cured since auto transplant was introduced. I completely agree. It is not new to the CAR T-cell therapy. But the beauty of the CAR T-cell therapy was it was in relapsed refractory myeloma, unmet medical need, number one. Number two, they were studied systematically. It was a clinical trial adjudicated by FDA and EMA for drug approval, cilta-cel was approved. So these patients were carefully followed, and it was a multi-center study. And in that group of patients, we were able to show patients- So, I think this would indicate cure is a reality in myeloma, and as these kind of treatments, immunologic treatment, either it is a CAR T-cell therapy or BCMA bispecific or whatever, there is a chance more patients are likely to be cured, and these treatments have to move forward and so that we are looking towards a cure. That is the beauty of it, and I just thank you for asking and also throwing in this so-called functionally cured, which people like to use casually, and I say it is time to talk more cure and not stuck with functionally cured because that does not allow the field to progress. Dr. Davide Soldato: Thank you very much. That was very interesting. Dr. Sundar Jagannath: And provocative. Dr. Davide Soldato: A little bit, but I think that we needed to close the podcast with this kind of reflection coming from someone who is an expert in the field, as you are. So, I really wanted to thank you for joining us today and for sharing more on your article, which is titled, "Long-Term Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma." If you enjoy our show, please leave us a rating and a review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts. Dr. Sundar Jagannath: 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.      

Listen to JCO's Art of Oncology article, "The Man at the Bow" by Dr. Alexis Drutchas, who is a palliative care physician at Dana Farber Cancer Institute. The article is followed by an interview with Drutchas and host Dr. Mikkael Sekeres. Dr. Drutchas shares the deep connection she had with a patient, a former barge captain, who often sailed the same route that her family's shipping container did when they moved overseas many times while she was growing up. She reflects on the nature of loss and dignity, and how oncologists might hold patients' humanity with more tenderness and care, especially at the end of life. TRANSCRIPT Narrator: The Man at the Bow, by Alexis Drutchas, MD  It was the kind of day that almost seemed made up—a clear, cerulean sky with sunlight bouncing off the gold dome of the State House. The contrast between this view and the drab hospital walls as I walked into my patient's room was jarring. My patient, whom I will call Suresh, sat in a recliner by the window. His lymphoma had relapsed, and palliative care was consulted to help with symptom management. The first thing I remember is that despite the havoc cancer had wreaked—sunken temples and a hospital gown slipping off his chest—Suresh had a warm, peaceful quality about him. Our conversation began with a discussion about his pain. Suresh told me how his bones ached and how his fatigue left him feeling hollow—a fraction of his former self. The way this drastic change in his physicality affected his sense of identity was palpable. There was loss, even if it was unspoken. After establishing a plan to help with his symptoms, I pivoted and asked Suresh how he used to spend his days. His face immediately lit up. He had been a barge captain—a dangerous and thrilling profession that took him across international waters to transport goods. Suresh's eyes glistened as he described his joy at sea. I was completely enraptured. He shared stories about mornings when he stood alone on the bow, feeling the salted breeze as the barge moved through Atlantic waves. He spoke of calm nights on the deck, looking at the stars through stunning darkness. He traveled all over the globe and witnessed Earth's topography from a perspective most of us will never see. The freedom Suresh exuded was profound. He loved these voyages so much that one summer, despite the hazards, he brought his wife and son to experience the journey with him. Having spent many years of my childhood living in Japan and Hong Kong, my family's entire home—every bed, sheet, towel, and kitchen utensil—was packed up and crossed the Atlantic on cargo ships four times. Maybe Suresh had captained one, I thought. Every winter, we hosted US Navy sailors docked in Hong Kong for the holidays. I have such fond memories of everyone going around the table and sharing stories of their adventures—who saw or ate what and where. I loved those times: the wild abandon of travel, the freedom of being somewhere new, and the way identity can shift and expand as experiences grow. When Suresh shared stories of the ocean, I was back there too, holding the multitude of my identity alongside him. I asked Suresh to tell me more about his voyages: what was it like to be out in severe weather, to ride over enormous swells? Did he ever get seasick, and did his crew always get along? But Suresh did not want to swim into these perilous stories with me. Although he worked a difficult and physically taxing job, this is not what he wanted to focus on. Instead, he always came back to the beauty and vitality he felt at sea—what it was like to stare out at the vastness of the open ocean. He often closed his eyes and motioned with his hands as he spoke as if he was not confined to these hospital walls. Instead, he was swaying on the water feeling the lightness of physical freedom, and the way a body can move with such ease that it is barely perceptible, like water flowing over sand. The resonances of Suresh's stories contained both the power and challenges laden in this work. Although I sat at his bedside, healthy, my body too contained memories of freedom that in all likelihood will one day dissipate with age or illness. The question of how I will be seen, compared to how I hoped to be seen, lingered in my mind. Years ago, before going to medical school, I moved to Vail, Colorado. I worked four different jobs just to make ends meet, but making it work meant that on my days off, I was only a chairlift ride away from Vail's backcountry. I have a picture of this vigor in my mind—my snowboard carving into fresh powder, the utter silence of the wilderness at that altitude, and the way it felt to graze the powdery snow against my glove. My face was windburned, and my body was sore, but my heart had never felt so buoyant. While talking with Suresh, I could so vividly picture him as the robust man he once was, standing tall on the bow of his ship. I could feel the freedom and joy he described—it echoed in my own body. In that moment, the full weight of what Suresh had lost hit me as forcefully as a cresting wave—not just the physical decline, but the profound shift in his identity. What is more, we all live, myself included, so precariously at this threshold. In this work, it is impossible not to wonder: what will it be like when it is me? Will I be seen as someone who has lived a full life, who explored and adventured, or will my personhood be whittled down to my illness? How can I hold these questions and not be swallowed by them? "I know who you are now is not the person you've been," I said to Suresh. With that, he reached out for my hand and started to cry. We looked at each other with a new understanding. I saw Suresh—not just as a frail patient but as someone who lived a full life. As someone strong enough to cross the Atlantic for decades. In that moment, I was reminded of the Polish poet, Wislawa Szymborska's words, "As far as you've come, can't be undone." This, I believe, is what it means to honor the dignity of our patients, to reflect back the person they are despite or alongside their illness…all of their parts that can't be undone. Sometimes, this occurs because we see our own personhood reflected in theirs and theirs in ours. Sometimes, to protect ourselves, we shield ourselves from this echo. Other times, this resonance becomes the most beautiful and meaningful part of our work. It has been years now since I took care of Suresh. When the weather is nice, my wife and I like to take our young son to the harbor in South Boston to watch the planes take off and the barges leave the shore, loaded with colorful metal containers. We usually pack a picnic and sit in the trunk as enormous planes fly overhead and tugboats work to bring large ships out to the open water. Once, as a container ship was leaving the port, we waved so furiously at those working on board that they all started to wave back, and the captain honked the ships booming horn. Every single time we are there, I think of Suresh, and I picture him sailing out on thewaves—as free as he will ever be. Mikkael Sekeres: Welcome back to JCO's Cancer Stories: The Art of Oncology. This ASCO podcast features intimate narratives and perspectives from authors exploring their experiences in oncology. I'm your host, Mikkael Sekeres. I'm Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. What a treat we have today. We're joined by Dr. Alexis Drutchas, a Palliative Care Physician and the Director of the Core Communication Program at the Dana-Farber Cancer Institute, and Assistant Professor of Medicine at Harvard Medical School to discuss her article, "The Man at the Bow." Alexis, thank you so much for contributing to Journal of Clinical Oncology and for joining us to discuss your article. Dr. Alexis Drutchas: Thank you. I'm thrilled and excited to be here. Mikkael Sekeres: I wonder if we can start by asking you about yourself. Where are you from, and can you walk us a bit through your career? Dr. Alexis Drutchas: The easiest way to say it would be that I'm from the Detroit area. My dad worked in automotive car parts and so we moved around a lot when I was growing up. I was born in Michigan, then we moved to Japan, then back to Michigan, then to Hong Kong, then back to Michigan. Then I spent my undergrad years in Wisconsin and moved out to Colorado to teach snowboarding before medical school, and then ended up back in Michigan for that, and then on the east coast at Brown for my family medicine training, and then in Boston for work and training. So, I definitely have a more global experience in my background, but also very Midwestern at heart as well. In terms of my professional career trajectory, I trained in family medicine because I really loved taking care of the whole person. I love taking care of kids and adults, and I loved OB, and at the time I felt like it was impossible to choose which one I wanted to pursue the most, and so family medicine was a great fit. And at the core of that, there's just so much advocacy and social justice work, especially in the community health centers where many family medicine residents train. During that time, I got very interested in LGBTQ healthcare and founded the Rhode Island Trans Health Conference, which led me to work as a PCP at Fenway Health in Boston after that. And so I worked there for many years. And then through a course of being a hospitalist at BI during that work, I worked with many patients with serious illness, making decisions about discontinuing dialysis, about pursuing hospice care in the setting of ILD. I also had a significant amount of family illness and started to recognize this underlying interest I had always had in palliative care, but I think was a bit scared to pursue. But those really kind of tipped me over to say I really wanted to access a different level of communication skills and be able to really go into depth with patients in a way I just didn't feel like I had the language for. And so I applied to the Harvard Palliative Care Fellowship and luckily and with so much gratitude got in years ago, and so trained in palliative care and stayed at MGH after that. So my Dana-Farber position is newer for me and I'm very excited about it. Mikkael Sekeres: Sounds like you've had an amazing career already and you're just getting started on it. I grew up in tiny little Rhode Island and, you know, we would joke you have to pack an overnight bag if you travel more than 45 minutes. So, our boundaries were much tighter than yours. What was it like growing up where you're going from the Midwest to Asia, back to the Midwest, you wind up settling on the east coast? You must have an incredible worldly view on how people live and how they view their health. Dr. Alexis Drutchas: I think you just named much of the sides of it. I think I realize now, in looking back, that in many ways it was living two lives, because at the time it was rare from where we lived in the Detroit area in terms of the other kids around us to move overseas. And so it really did feel like that part of me and my family that during the summers we would have home leave tickets and my parents would often turn them in to just travel since we didn't really have a home base to come back to. And so it did give me an incredible global perspective and a sense of all the ways in which people develop community, access healthcare, and live. And then coming back to the Midwest, not to say that it's not cosmopolitan or diverse in its own way, but it was very different, especially in the 80s and 90s to come back to the Midwest. So it did feel like I carried these two lenses in the world, and it's been incredibly meaningful over time to meet other friends and adults and patients who have lived these other lives as well. I think for me those are some of my most connecting friendships and experiences with patients for people who have had a similar experience in living with sort of a duality in their everyday lives with that. Mikkael Sekeres: You know, you write about the main character of your essay, Suresh, who's a barge captain, and you mention in the essay that your family crossed the Atlantic on cargo ships four times when you were growing up. What was that experience like? How much of it do you remember? Dr. Alexis Drutchas: Our house, like our things, crossed the Atlantic four times on barge ships such as his. We didn't, I mean we crossed on airplanes. Mikkael Sekeres: Oh, okay, okay. Dr. Alexis Drutchas: We flew over many times, but every single thing we owned got packed up into containers on large trucks in our house and were brought over to ports to be sent over. So, I'm not sure how they do it now, but at the time that's sort of how we moved, and we would often go live in a hotel or a furnished apartment for the month's wait of all of our house to get there, which felt also like a surreal experience in that, you know, you're in a totally different country and then have these creature comforts of your bedroom back in Metro Detroit. And I remember thinking a lot about who was crossing over with all of that stuff and where was it going, and who else was moving, and that was pretty incredible. And when I met Suresh, just thinking about the fact that at some point our home could have been on his ship was a really fun connection in my mind to make, just given where he always traveled in his work. Mikkael Sekeres: It's really neat. I remember when we moved from the east coast also to the Midwest, I was in Cleveland for 18 years. The very first thing we did was mark which of the boxes had the kids' toys in it, because that of course was the first one we let them close it up and then we let them open it as soon as we arrived. Did your family do something like that as well so that you can, you know, immediately feel an attachment to your stuff when they arrived? Dr. Alexis Drutchas: Yeah, I remember what felt most important to our mom was our bedrooms. I don't remember the toys. I remember sort of our comforters and our pillowcases and things like that, yeah, being opened and it feeling really settling to think, "Okay, you know, we're in a completely different place and country away from most everything we know, but our bedroom is the same." That always felt like a really important point that she made to make home feel like home again in a new place. Mikkael Sekeres: Yeah, yeah. One of the sentences you wrote in your essay really caught my eye. You wrote about when you were younger and say, "I loved those times, the wild abandon of travel, the freedom of being somewhere new, the way identity can shift and expand as experiences grow." It's a lovely sentiment. Do you think those are emotions that we experience only as children, or can they continue through adulthood? And if they can, how do we make that happen, that sense of excitement and experience? Dr. Alexis Drutchas: I think that's such a good question and one I honestly think about a lot. I think that we can access those all the time. There's something about the newness of travel and moving, you know, I have a 3-year-old right now, and so I think many parents would connect to that sense that there is wonderment around being with someone experiencing something for the first time. Even watching my son, Oliver, see a plane take off for the first time felt joyous in a completely new way, that even makes me smile a lot now. But I think what is such a great connection here is when something is new, our eyes are so open to it. You know, we're constantly witnessing and observing and are excited about that. And I think the connection that I've realized is important for me in my work and also in just life in general to hold on to that wonderment is that idea of sort of witnessing or having a writer's eye, many would call it, in that you're keeping your eye open for the small beautiful things. Often with travel, you might be eating ramen. It might not be the first time you're eating it, but you're eating it for the first time in Tokyo, and it's the first time you've had this particular ingredient on it, and then you remember that. But there's something that we're attuned to in those moments, like the difference or the taste, that makes it special and we hold on to it. And I think about that a lot as a writer, but also in patient care and having my son with my wife, it's what are the special small moments to hold on to and allowing them to be new and beautiful, even if they're not as large as moving across the country or flying to Rome or whichever. I think there are ways that that excitement can still be alive if we attune ourselves to some of the more beautiful small moments around us. Mikkael Sekeres: And how do we do that as doctors? We're trained to go into a room and there's almost a formula for how we approach patients. But how do you open your mind in that way to that sense of wonderment and discovery with the person you're sitting across from, and it doesn't necessarily have to be medical? One of the true treats of what we do is we get to meet people from all backgrounds and all walks of life, and we have the opportunity to explore their lives as part of our interaction. Dr. Alexis Drutchas: Yeah, I think that is such a great question. And I would love to hear your thoughts on this too. I think for me in that sentence that you mentioned, sitting at that table with sort of people in the Navy from all over the world, I was that person to them in the room, too. There was some identity there that I brought to the table that was different than just being a kid in school or something like that. To answer your question, I wonder if so much of the challenge is actually allowing ourselves to bring ourselves into the room, because so much of the formula is, you know, we have these white coats on, we have learners, we want to do it right, we want to give excellent care. There's there's so many sort of guards I think that we put up to make sure that we're asking the right questions, we don't want to miss anything, we don't want to say the wrong thing, and all of that is true. And at the same time, I find that when I actually allow myself into the room, that is when it is the most special. And that doesn't mean that there's complete countertransference or it's so permeable that it's not in service of the patient. It just means that I think when we allow bits of our own selves to come in, it really does allow for new connections to form, and then we are able to learn about our patients more, too. With every patient, I think often we're called in for goals of care or symptom management, and of course I prioritize that, but when I can, I usually just try to ask a more open-ended question, like, "Tell me about life before you came to the hospital or before you were diagnosed. What do you love to do? What did you do for work?" Or if it's someone's family member who is ill, I'll ask the kids or family in the room, "Like, what kind of mom was she? You know, what special memory you had?" Just, I get really curious when there's time to really understand the person. And I know that that's not at all new language. Of course, we're always trying to understand the person, but I just often think understanding them is couched within their illness. And I'm often very curious about how we can just get to know them as people, and how humanizing ourselves to them helps humanize them to us, and that back and forth I think is like really lovely and wonderful and allows things to come up that were totally unexpected, and those are usually the special moments that you come home with and want to tell your family about or want to process and think about. What about you? How do you think about that question? Mikkael Sekeres: Well, it's interesting you ask. I like to do projects around the house. I hate to say this out loud because of course one day I'll do something terrible and everyone will remember this podcast, but I fancy myself an amateur electrician and plumber and carpenter and do these sorts of projects. So I go into interactions with patients wanting to learn about their lives and how they live their lives to see what I can pick up on as well, how I can take something out of that interaction and actually use it practically. My father-in-law has this phrase he always says to me when a worker comes to your house, he goes, he says to me, "Remember to steal with your eyes." Right? Watch what they do, learn how they fix something so you can fix it yourself and you don't have to call them next time. So, for me it's kind of fun to hear how people have lived their lives both within their professions, and when I practiced medicine in Cleveland, there were a lot of farmers and factory workers I saw. So I learned a lot about how things are made. But also about how they interact with their families, and I've learned a lot from people I've seen who were just terrific dads and terrific moms or siblings or spouses. And I've tried to take those nuggets away from those interactions. But I think you can only do it if you open yourself up and also allow yourself to see that person's humanity. And I wonder if I can quote you to you again from your essay. There's another part that I just loved, and it's about how you write about how a person's identity changes when they become a patient. You write, "And in that moment the full weight of what he had lost hit me as forcefully as a cresting wave. Not just the physical decline, but the profound shift in identity. What is more, we all live, me included, so precariously at this threshold. In this work, it's impossible not to wonder, what will it be like when it's me? Will I be seen as someone who's lived many lives, or whittled down only to someone who's sick?" Can you talk a little bit more about that? Have you been a patient whose identity has changed without asking you to reveal too much? Or what about your identity as a doctor? Is that something we have to undo a little bit when we walk in the room with the stethoscope or wearing a white coat? Dr. Alexis Drutchas: That was really powerful to hear you read that back to me. So, thank you. Yeah, I think my answer here can't be separated from the illness I faced with my family. And I think this unanimously filters into the way in which I see every patient because I really do think about the patient's dignity and the way medicine generally, not always, really does strip them of that and makes them the patient. Even the way we write about "the patient said this," "the patient said that," "the patient refused." So I generally very much try to have a one-liner like, "Suresh is a X-year-old man who's a barge captain from X, Y, and Z and is a loving father with a," you know, "period. He comes to the hospital with X, Y, and Z." So I always try to do that and humanize patients. I always try to write their name rather than just "patient." I can't separate that out from my experience with my family. My sister six years ago now went into sudden heart failure after having a spontaneous coronary artery dissection, and so immediately within minutes she was in the cath lab at 35 years old, coding three times and came out sort of with an Impella and intubated, and very much, you know, all of a sudden went from my sister who had just been traveling in Mexico to a patient in the CCU. And I remember desperately wanting her team to see who she was, like see the person that we loved, that was fighting for her life, see how much her life meant to us. And that's not to say that they weren't giving her great care, but there was something so important to me in wanting them to see how much we wanted her to live, you know, and who she was. It felt like there's some important core to me there. We brought pictures in, we talked about what she was living for. It felt really important. And I can't separate that out from the way in which I see patients now or I feel in my own way in a certain way what it is to lose yourself, to lose the ability to be a Captain of the ship, to lose the ability to do electric work around the house. So much of our identity is wrapped up in our professions and our craft. And I think for me that has really become forefront in the work of palliative care and in and in the teaching I do and in the writing I do is how to really bring them forefront and not feel like in doing that we're losing our ability to remain objective or solid in our own professional identities as clinicians and physicians. Mikkael Sekeres: Well, I think that's a beautiful place to end here. I can only imagine what an outstanding physician and caregiver you are also based on your writing and how you speak about it. You just genuinely come across as caring about your patients and your family and the people you have interactions with and getting to know them as people. It has been again such a treat to have Dr. Alexis Drutchas here. She is Director of the Core Communication Program at Dana-Farber Cancer Institute and Assistant Professor of Medicine at Harvard Medical School to discuss her article, "The Man at the Bow." Alexis, thank you so much for joining us. Dr. Alexis Drutchas: Thank you. This has been a real joy. Mikkael Sekeres: If you've enjoyed this episode, consider sharing it with a friend or colleague, or leave us a review. Your feedback and support helps us continue to save these important conversations. If you're looking for more episodes and context, follow our show on Apple, Spotify, or wherever you listen, and explore more from ASCO at ASCO.org/podcasts. Until next time, this has been Mikkael Sekeres for the ASCO podcast Cancer Stories: The Art of Oncology. 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. Show notes: Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio: Dr. Alexis Drutchas is a palliative care physician at Dana Farber Cancer Institute.

Dr. Pedro Barata and Dr. Aditya Bagrodia discuss the evolving landscape of testicular cancer survivorship, the impact of treatment-related complications, and management strategies to optimize long-term outcomes and quality of life. TRANSCRIPT:  Dr. Pedro Barata: Hello and welcome to By the Book, a podcast series from ASCO that features engaging conversations between editors and authors of the ASCO Educational Book. I'm Dr. Pedro Barata. I'm a medical oncologist at University Hospitals Seidman Cancer Center and associate professor of medicine at Case Western Reserve University in Cleveland, Ohio. I'm also an associate editor of the ASCO Educational Book. We all know that testicular cancer is a rare but highly curable malignancy that mainly affects young men. Multimodal advances in therapy have resulted in excellent cancer specific survival, but testicular cancer survivors face significant long term treatment related toxicities which affect their quality of life and require surveillance and management. With that, I'm very happy today to be joined by Dr. Aditya Bagrodia, a urologic oncologist, professor, and the GU Disease Team lead at UC San Diego[KI1]  Health, and also the lead author of the recently published paper in the ASCO Educational Book titled, "Key Updates in Testicular Cancer: Optimizing Survivorship and Survival." And he's also the host of the world-renowned BackTable Urology Podcast. Dr. Bagrodia, I'm so happy that you're joining us today. Welcome. Dr. Aditya Bagrodia: Thanks, Pedro. Absolutely a pleasure to be here. Really appreciate the opportunity. Dr. Pedro Barata: Absolutely.  So, just to say that our full disclosures are available in the transcript of this episode.  Let's get things started. I'm really excited to talk about this. I'm biased, I do treat testicular cancer among other GU malignancies and so it's a really, really important topic that we face every day, right? Fortunately, for most of these patients, we're able to cure them. But it always comes up the question, "What now? You know, scans, management, cardio oncology, what survivorship programs we have in place? Are we addressing the different survivorship piece, psychology, fertility, et cetera?" So, we'll try to capture all of that today. Aditya, congrats again, you did a fantastic job putting together the insights and thoughts and what we know today about this important topic. And so, let's get focused specifically about what happens when patients get cured. So, many of us, in many centers, were fortunate enough to have these survivorship programs together, but I find that sometimes from talking to colleagues, they're not exactly the same thing and they don't mean the same thing to different people, to different institutions, right? So, first things first. What do you tell a patient perhaps when they ask you, "What can happen to me now that I'm done with treatment for testicular cancer?" Whether it's chemotherapy or just surgery or even radiation therapy? "So, what about the long term? What should I expect, Doctor, that might happen to me in the long run?" Dr. Aditya Bagrodia: Totally. I mean, I think that question's really front and center, Pedro, and really appreciate you all highlighting this topic. It was an absolute honor to work with true thought leaders and the survivorship bit of it is front and center, in my opinion. It's really the focus, you know, we, generally speaking should be able to cure these young men, but it's the 10, 15, 20 years down the way that they're going to largely contend with. The conversation really begins at diagnosis, pre-education. Fortunately, the bulk of patients that present are those with stage one disease, and even very basic things like before orchiectomy, talking about a prosthetic; we know that that can impact body image and self esteem, whether or not they decide to receive it or not. Actually, just being offered a prosthetic is important and this is something, you know, for any urologist, it's kind of critical. To discussing fertility elements to this, taking your time to examine the contralateral testicle, ask about fertility problems, issues, concerns, offer sperm banking, even in the context of a completely normal contralateral testicle, I think these things are quite important.  So if it's somebody with stage one disease, you know, without going too far down discussing adjuvant therapy and so forth, I will start the conversation with, "You know, the testes do largely two things. They make testosterone and they make sperm." By and large, patients are going to be able to have acceptable levels of testosterone, adequate sperm parameters to maintain kind of a normal gonadal state and to naturally conceive, should that be something they're interested in. However, there's still going to be, depending on what resource you look at, somewhere in the order of 10-30% that are going to have issues. Where I think for the stage one patients, it's really incumbent upon us is actually to not wait for them to discuss their concerns, particularly with testosterone, which many times can be a little bit vague, but to proactively ask about it every time. Libido, erectile quality, muscle mass maintenance, energy, fatigue. All of these are kind of associated symptoms of hypogonadism. But for a lot of kids 18-20 years old, it's going to be something insidious that they don't think about. So, for the stage one patients, it absolutely starts with gonadal function. If they are stage two getting surgery, I think the counseling really needs to center around a possibility for ejaculatory dysfunction. Now, for a chemotherapy-naive, nerve-sparing RPLND, generally these days we should be able to preserve ejaculatory function at high volume centers, but you still want to bring that up and again kind of touch base on thinking about sperm banking and so forth before the operation, scars, those are things I think worth talking about, small risk of ascites. Then, I think the intensity of potential long term adverse effects really ramps up when we're talking about systemic therapy, chemotherapy. And then there's of course some radiation therapy specific elements that come up. So, for the chemotherapy bits of it, I really think this is going to be something that can be a complete multi-system affected intervention. So, anxiety, depression, our group has actually shown using some population resources that even suicidality can be increased among patients that have been treated for germ cell tumor. You know, really from the top down, tinnitus, hearing changes, those are things that we need to ask about at every appointment. Neuropathy, sexual health, that we kind of talked about, including ED (erectile dysfunction), vertigo, dizziness, Raynaud's phenomenon, these are kind of more the symptoms that I think we need to inquire about every time. And what we do here and I think at a lot of survivorship programs is use kind of a battery of validated instruments, germ cell tumor specific, platinum treated patient specific. So we use a combination of EORTC questions and PROMIS questions, which actually serves as like a review of systems for the patient, also as a research element. We review that and then depending on what might be going on, we can dig into that further, get them over to colleagues in audiology or psychology, et cetera.  And then of course, screening for the hypertension, hyperlipidemia, metabolic syndrome with basically you or myself or somebody kind of like us serving, many times it's the role of the PCP, just making sure we're checking out, you know, CBC, CMP, et cetera, lipid parameters to screen for those kind of cardiac associated issues along with secondary malignancies. Dr. Pedro Barata: So that's super comprehensive and thorough. Thank you so much. Actually, I love how you break it down in a simple way. Two functions of the testes, produce testosterone and then, you know, the problem related to that is the hypogonadism, and then the second, as you mentioned, produce sperm and of course related to the fertility issues with that.  So, let's start with the first one that you mentioned. So, you do cite that in your paper, around 5-10% of men end up getting, developing hypogonadism, maybe clinical when they present with symptoms, maybe subclinical. So, I'm wondering, for our audience, what kind of recommendations we would give for addressing that or kind of thinking of that? How often are you ordering those tests? And then, when you're thinking about testosterone replacement therapy, is that something you do immediately or are there any guidelines into context that? How do you approach that? Dr. Aditya Bagrodia: So, just a bit more on digging into it even in terms of the questions to ask, you know, "Do you have any decrease in sexual drive? Any erectile dysfunction? Are your morning erections still taking place? Has the ejaculate volume changed? Physically, muscle mass, strength? Have you been putting on weight? Have you noticed increase in body fat?" And sometimes this is complicated because there's some anxiety that comes along with a cancer diagnosis when you're 20, 30 years old, multifactorial, hair loss, hot flashes, irritability. Sometimes they'll, you know, literally they'll say, "You know, my significant other or partners noticed that I'm really just a little bit labile." So I think, you know, there's the symptoms and then checking, usually kind of a gonadal panel, FSH, LH, free and total testosterone, sex hormone binding globulin, that's going to be typically pretty comprehensive. So if you've got symptoms plus some laboratory work, and ideally that pre-orchiectomy testosterone gives you some delta. If they started out at an 800, 900, now they're 400, that might be a big change for them. And then, when you talk about TRT (Testosterone Replacement Therapy) recommendations, you know, Pedro, yourself, myself, we're kind of lucky to be at academic centers and we've got men's health colleagues that are ultra experts, but at a high level, I would say that a lot of the TRT options center around fertility goals. Exogenous testosterone treats the low T, but it does suppress gonadal function, including spermatogenesis. So if that's not a priority, they can just get TRT. It should be done under the care of a urologist, a men's health, an endocrinologist, where we're checking liver chemistries and CBCs and a PSA and so forth. If they're interested in fertility preservation, then I would say engaging an endocrinologist, men's health expert is important. There's medications even like hCG, Clomid, which works centrally and stimulate the gonadal access. Niche scenarios where they might want standard TRT now, and then down the way, 5, 7 years, they're thinking about coming off of that for fertility purposes, I think that's really where you want to have an expert involved because there's quite a bit of nuance there in recovery of actual spermatogenesis and so forth.  To kind of summarize, you got to ask about it. Checking it is, is not overly complicated. We do a baseline pre-orchiectomy and at least once annually, you can tag it in with the tumor markers, so it's not an extra blood draw. And if they have symptoms of course, kind of developed, then we'll move that up in the evaluation. Dr. Pedro Barata: Got it. And you also touch base on the fertility angle, which is truly important. And I'm just curious, you know, a lot of times many of us might see one, two patients a year, right, and we forget these protocols and what we've got to do about that.  And so I'm interested to hear your thoughts about when you think about fertility, and how proactive you get. In other words, who do you refer for the fertility clinic, for a fertility preservation program? You know, do all cases despite getting through orchiectomy or just the cases that you're going to, you know you're going to seek chemotherapy at some point? What kind of selection or it depends on the chemo, like how do you do that assessment about the referral for preservation program that you might have available at UCSD? Dr. Aditya Bagrodia: Yeah, I mean I feel really fortunate to sit on the NCCN Testis Cancer Guidelines. It's in there that fertility counseling should be discussed prior to orchiectomy. So 100% bring it up. If there are risk factors, undescended testicles, previous history of fertility concerns, atrophic contralateral testicle, anything on the ultrasound like microlithiasis in the contralateral testicle, you kind of wanna get it there. And then again, there's kind of niche scenarios where you're really worried, maybe get a semen analysis and it doesn't look that good, arrange for the time of orchiectomy to have onco-testicular sperm extraction from the, quote unquote, "normal" testis parenchyma. You know, I think you have to be kind of prepared to go that route and really make sure you're doing this completely comprehensively.  So pre-orchiectomy all patients. Don't really push for it too hard if they've got a contralateral testicle, if they've had no issues having children. There's some cost associated with this, sperm banking still isn't kind of covered even in the context of men with cancer. If they've got risk factors, absolutely pre-orchiectomy. Pre-RPLND, even though the rates of ejaculatory dysfunction at a high-volume center should be low single digits, I'll still offer it. That'd be a real catastrophe if they were in that small proportion of patients and now they're going to be reliant on things like intrauterine insemination, where it becomes quite expensive.  Pre-chemo, everybody. That's basically a standard these days where it should be discussed and it's kind of amazing currently, even if you don't have an accessible men's health fertility clinic, there are actually companies, I have no vested interest, Fellow is one such company where you can actually create an account, receive a FedEx semen analysis and cryopreservation kit, send it back in, and all CLIA certified, it's based out of California. The gentleman that runs it, is a urologist and very, very bright guy who's done a lot of great stuff for testis cancer. So, even for patients that are kind of in extremis at the hospital that kind of need to get going like yesterday, we still discuss it. We've got some mechanisms in place to either have them take a semen analysis over to our Men's Health clinic or send it off to Fellow, which I think is pretty cool and that even extends to some of our younger adolescent patients where going to a clinic and providing a sample might be tricky.  So, I think bringing it up every stage, anytime there's an intervention that might be offered, orchiectomy, chemo, surgery, radiation, it's kind of incumbent on us to discuss it. Dr. Pedro Barata: Gotcha. That's super helpful. And you also touch base on another angle, which is the psychosocial angle around this. You mentioned suicidal rates, you mentioned anxiety, perhaps depression in some cases as well as chronic fatigue, not necessarily just because of the low testosterone that you can get, but also from a psychological perspective. I'm curious, what do the recommendations look like for that? Do these patients need to see a social worker or a psychologist, or do they need to answer a screening test every time they come to see us and then based on that, we kind of escalate, take the next steps according to that? Do they see a psychologist perhaps every so often? How should that be managed and addressed? Dr. Aditya Bagrodia: It's an excellent question and again, these can be rather insidious symptoms where if you don't really dig in and inquire, they can be glossed over. I mean, how easy to say, "Your markers look okay, your scans look okay. See you in six months," and keep it kind of brief. First off, I think bringing it up proactively and normalizing it, that, "This may be something that you experience. Many people do, you're not alone, there's nothing kind of wrong with you." I also think that this is an area where support groups can be incredibly useful. We host the Testicular Cancer Awareness Foundation support group here. They'll talk about chemo brain or just like a little bit of an adjustment disorder after their diagnosis. Support groups, I think are critical. As I mentioned, we have a survivorship program that's led by a combination of our med oncs, myself on the uro-onc side, as well as APPs, where we are systematically asking about essentially the whole litany of issues that may arise, including psychosocial, anxiety, depression, suicidality. And we've got a nice kind of fast path into our cancer center support services for these young men to meet with a psychologist. If that isn't going to be sufficient, they can actually see a psychiatrist to discuss medications and so forth. I do think that we've got to screen for these because, as anticipated from diagnosis, those first 2 years, we see a rise. But even 10, 15 years out, we note, compared to controls, that there is an increased level of anxiety, depression, suicidality that might not just take place at that initial acute period of diagnosis and treatment. Dr. Pedro Barata: Really well said. Super important.  So I guess if I were to put all these together, with these really amazing advances in technology, we all know AI, some of us might be more or less aware of biomarkers coming up, including microRNA for example, and others, like as I think of all these potential long term complications for these patients, look at the future, I guess, can we use this as a way to deescalate treatment where it's not really necessary, as a way to actually prevent some of these complications? Like, how do we see where we're heading? As we manage testicular cancer, let's say, within the next 5 or 10 years, do you think there's something coming up that's going to be different from what we're doing things today? Dr. Aditya Bagrodia: Totally. I mean, I think it's as exciting as a time as there's ever been, you know, maybe notwithstanding circa 1970s when platinum was discovered. So microRNAs, which you mentioned, you know, there's a new candidate biomarker, microRNA-371. We are super excited here at UCSD. We actually have it CLIA-certified available in our lab and are ordering these tests for patients kind of in their acute stage, you know, stage one and surveillance, stage two, post-RPLND, receiving chemotherapy. And essentially this is a universal germ cell tumor specific biomarker, except for teratoma, suffice it to say 90% sensitive and specific. And I think it's going to change the way that we diagnose and manage patients. You know, pre-orchiectomy, that's pretty straightforward. Post-orchiectomy, maybe we can really decrease the number of CT scans that are done. Maybe we can identify those patients that basically have occult disease where we can intervene early, either with RPLND or single cycle chemo. Post-RPLND, identify the patients who are at higher risk of relapse that may benefit from some adjuvant therapy. In the advanced setting, look at marker decline for patients in addition to standard tumor markers. Can we modulate their systemic therapy?  So, the international interest is largely on modifying things. There's really cool clinical trials that we have for stage one patients, that treatment would be prescribed based on a post-orchiectomy microRNA. I think the microRNAs are really exciting. Teratoma remains an outstanding question. I think this is where maybe ctDNA, perhaps some radiomics and advanced imaging processing and incorporating AI may allow us to safely avoid a lot of these post-chemo RPLNDs. And then identification using SNPs and so forth of who might be most susceptible to some of the cardiac toxicity, autotoxicity and personalizing things in that way as well. Dr. Pedro Barata: Super exciting, right, what's about to come? And I agree with you, I think it's going to change dramatically how we manage this disease.  This has been a pleasure sitting down with you. I guess before letting you go, anything else you'd like to add before we wrap it up? Dr. Aditya Bagrodia: Yeah, first off, again, just want to thank you and ASCO for the opportunity. And it's easy enough to, I think, approach a patient with the testicular germ cell tumor as, "This is an easy case. We're just going to do whatever we've done. Go to the guidelines that says do X, Y, or Z." But there's so much more nuance to it than that. Getting it done perfectly, I think, is mandatory. Whatever we do is an impact on them for the next 50, 60, 70 years of their life. And I found the germ cell tumor community, people are really passionate about it. If you're ever uncertain, there's experts throughout the country and internationally. Ask somebody before you do something that you can't undo. I think we owe it to them to get it perfect so that we can really maximize the survivorship and the survival like we've been talking about. Dr. Pedro Barata: Aditya, thanks for sharing your fantastic insights with us on this podcast. Dr. Aditya Bagrodia: All right, Pedro. Fantastic. Appreciate the opportunity. Dr. Pedro Barata: And also, thank you to our listeners for your time today. I actually encourage you to check out Dr. Bagrodia's article in the 2025 ASCO Educational Book. We'll post a link to the paper in the show notes. Remember, it's free access online, and you can actually download it as well as a PDF. You can also find on the website a wealth of other great papers from the ASCO Educational Book on key advances and novel approaches that are shaping modern oncology.  So with that, thank you everyone. Thank you, Aditya, one more time, for joining us. Thank you, have a good 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. Pedro Barata  @PBarataMD   Dr. Aditya Bagrodia @AdityaBagrodia Follow ASCO on social media:         @ASCO on X (formerly Twitter)         ASCO on Bluesky        ASCO on Facebook         ASCO on LinkedIn         Disclosures:      Dr. Pedro Barata:  Stock and Other Ownership Interests: Luminate Medical  Honoraria: UroToday  Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Merck, Ipson, Astellas Medivation, Novartis, Dendreon  Speakers' Bureau: AstraZeneca, Merck, Caris Life Sciences, Bayer, Pfizer/Astellas  Research Funding (Inst.): Exelixis, Blue Earth, AVEO, Pfizer, Merck   Dr. Aditya Bagrodia: Consulting or Advisory Role: Veracyte, Ferring  

Featuring an interview with Dr Aaron Lisberg, including the following topics: Prevention and Management of Adverse Events of Special Interest with Datopotamab Deruxtecan (Dato-DXd) (0:00) Rugo H et al. US expert Delphi consensus on the prevention and management of stomatitis in patients treated with datopotamab deruxtecan. Support Care Cancer 2025;33(9):756. Abstract Lisberg A et al. Datopotamab deruxtecan-associated select adverse events: Clinical practices and institutional protocols on prophylaxis, monitoring, and management. Oncologist 2025;[Online ahead of print]. Abstract Meric-Bernstam F et al. Prophylaxis, clinical management, and monitoring of datopotamab deruxtecan-associated oral mucositis/stomatitis. Oncologist 2025;30(3). Abstract Novel Strategies Combining Dato-DXd with Osimertinib (10:44) Lu S et al. TROPION-Lung14: A phase 3 study of osimertinib ± datopotamab deruxtecan (Dato-DXd) as first-line (1L) treatment for patients with EGFR-mutated locally advanced or metastatic (LA/M) non-small cell lung cancer (NSCLC). ASCO 2025;Abstract TPS8647. Nadal E et al. TROPION-Lung15: A phase III study of datopotamab deruxtecan (Dato-DXd) ± osimertinib vs platinum doublet chemotherapy in patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) and disease progression on prior osimertinib. ELCC 2025;Abstract 124TiP. Intracranial Activity Observed with TROP2-Targeting Antibody-Drug Conjugates (15:14) Felip E et al. Brain metastases and actionable genetic alterations with sacituzumab govitecan versus docetaxel in metastatic non-small cell lung cancer: Subgroups of the phase III EVOKE-01 trial. ELCC 2025;Abstract 13P. Lisberg A et al. Intracranial efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously treated advanced/metastatic non-small cell lung cancer (a/m NSCLC) with actionable genomic alterations (AGA): Results from TROPION-Lung05. ASCO 2024;Abstract 8593. Pons-Tostivint E et al. Intracranial efficacy of datopotamab deruxtecan (Dato- DXd) in patients with advanced/metastatic NSCLC in TROPION-Lung01. WCLC 2025;Abstract OA10.01. CME information and select publications

Curious about what life and real estate really look like in Mexico's Rocky Point?  In this episode of Live by Design - Mexico Edition, host Taniel Chemsian sits down with Joseph Toland, a seasoned real estate expert with over two decades of experience in Puerto Peñasco (Rocky Point), Sonora.   Joseph shares how Americans and Canadians are successfully investing, retiring, and building new lives in this coastal gem - just a few hours from the U.S. border. From navigating property purchases with licensed AMPI agents and setting up bank trusts to understanding market trends, rental income opportunities, and day-to-day living, this conversation is packed with firsthand insights and practical guidance.   If you've ever dreamed about owning property or starting a new life by the sea, this episode will show you why Puerto Peñasco continues to attract expats seeking affordable luxury, community, and a lifestyle that feels truly free.   Connect Joseph :  Website: https://www.rockypointbestrealestate.com/ Email: jtoland@rockypointbest.com Facebook: https://www.facebook.com/rockypointbest   Want to own a home in Mexico? Start your journey with confidence – download your FREE Taniel Chemsian Properties Buyer's Guide now for expert tips and clear steps to make it happen! Click here -  https://tanielchemsian.com/buyers-guide-podbean/   Contact Information: Email: info@tanielchemsian.com Website: www.tanielchemsian.com Mex Office: +52.322.688.7435 USA/CAN Office: +1.323.798.8893

Dr. Monty Pal and Dr. Pauline Funchain discuss the latest efforts to diagnose, prevent, and treat the series of immune-related adverse events that have emerged in the era of immunotherapy. TRANSCRIPT Dr. Monty Pal: Hello, and welcome to the ASCO Daily News Podcast. I am Monty Pal, a medical oncologist, professor and vice chair of medical oncology at the City of Hope Comprehensive Cancer Center in Los Angeles, California. Now, it is probably no surprise to this audience that immunotherapy has transformed the treatment landscape for multiple cancer types. It remains a pillar of modern oncology. Having said that, I think we have all been baffled by certain toxicities that we run into in the clinic. Today, I am delighted to be joined by Dr Pauline Funchain to discuss some of the checkpoint inhibitor toxicities that people struggle with most. And we will also touch on some side effects of immunotherapy beyond checkpoint inhibitors: CAR-T cells, bispecifics, so on and so forth. Dr Funchain is a dear friend, and she is an associate professor and associate director of cancer research training and education at the Stanford Cancer Institute. She is co-director of the Immunotherapy Toxicity Program and the Skin Cancer Genomics Program at Stanford, where she also serves as associate program director of hematology and oncology fellowship. Dr. Funchain is also the co-founder of ASPIRE, and we are going to talk about that a little bit today, the Alliance for the Support and Prevention of Immune-Related Events. FYI for listeners, if you are interested in our disclosures, they are available at the transcript of this episode. Pauline, thanks so much for joining us today. Dr. Pauline Funchain: Monty, thank you for this invitation. It is always great to talk. Dr. Monty Pal: So, for the audience, Pauline and I know each other from my days as a fellow at City of Hope. She was a resident at Harbor UCLA and a stellar resident at that. It has just been amazing to sort of see your career grow and blossom and to witness all the cool things that you are doing. ASPIRE, in particular, sort of caught my eye. So again, for listeners, this is the Alliance for the Support and Prevention of Immune-Related Events. Can you tell us a little bit briefly about the genesis of that, how that came about? Dr. Pauline Funchain: So, there was a bunch of us who were really struggling, I mean, all of us have struggled with these immune-related adverse events, these irAEs. You know, they are new disease states, and even though they look like autoimmune diseases, they tend to need a whole lot more steroid than autoimmune diseases do and they do not totally present in the same way. And in fact, you know, Triple-M, or Triple-M overlap syndrome, is a completely new irAE, a new immune state that we have never had before the advent of checkpoint inhibitor. And so a Triple-M, for those of you who are not as familiar, that is the constellation of myocarditis, myositis, and myasthenia gravis, something that never occurs as a natural autoimmune disease. So we were starting to realize that there were some major differences with these irAEs and autoimmune diseases. We could not treat them the right way. We really needed to learn more about them. And a bunch of us who had interest in this said, "Look, we really need to be all in one space to talk about what we are doing," because all of our treatments were our own little homegrown brews, and we needed to really get together and understand how to treat these things, how to diagnose them, and then learn more about them. So, Dr. Alexa Meara from Ohio State, Dr. Kerry Reynolds from Mass Gen, we put together this research consortium, brought together all of our irAE friends, got our best subspecialists together in a research consortium, which is now only about a year and a half old. And we made this research consortium, the Alliance for Support of Prevention of Immune-Related Events, and we reached out to ASCO, and ASCO was so kind to grant us a [Alliance for Support and Prevention of Immune-Related adverse Events (ASPIRE)] Community of Practice. So we met for the first time as a Community of Practice at the ASCO Annual Meeting just this past June and really got an ASCO community together to really think about how to again, diagnose, prevent, treat irAEs. Dr Monty Pal: This is interesting to me. The ASCO Community of Practice phenomenon is something that I was not super familiar with. Can you explain to our listenership what is the ASCO Community of Practice model? If you have particular interests, how do you sort of get one started? Dr Pauline Funchain: Yeah, so ASCO has an entire page on their Community of Practice. There are multiple Community of Practice groups or COPs. There are ones for Supportive Oncology and Survivorship. There is Women in Oncology. There is a group for International Medical Graduates. And there is about, I think 10 or 12 now that have a physical presence at ASCO but also a virtual presence on the ASCO Community of Practice site. So, if you were interested in any one of these, and you can see them on the ASCO Communities of Practice sites, you would ask to become a member. Once granted membership, then there is a whole webpage of postings and conversations that people can have. You can get email digests of conversations that happen on the website, and then you can anchor it with in-person participation at the Annual Meeting. Dr Monty Pal: That is awesome, and I can think of so many different foci within oncology that really sort of deserve a Community of Practice. This definitely being one of them. You know, it strikes me as being so interesting. I mean, the checkpoint inhibitors have been around for a while now. I think when you and I were in training, gosh, back then, these were just a little bit of a pipe dream, right? But having said that, I would probably say that more than half of my kidney cancer practice is either on checkpoint inhibitors, and the vast majority have been on one at some point in their past, right? With that in mind, you know, we have all treated a lot of patients with these drugs. Why is it that we still struggle to manage the toxicities? And just to take that one step further, what are some of the toxicities that, perhaps through ASPIRE or through your experience, people struggle with the most? Dr Pauline Funchain: So, I think we are still struggling with these because again, they are new disease states, right? This is what we all experienced with COVID, a brand-new virus and a brand-new syndrome. We now have 20-plus of these as irAEs. And what we have realized about them is the immune activation that happens with these is so much more than what we have seen with autoimmune diseases. So for instance, if you have a Crohn's or ulcerative colitis, you will top out at 40 to 60 milligrams of prednisone if a Crohn's flare or ulcerative colitis flare happens. But for our severe IR colitises, you know, it is at least 1 mg per kg, often goes up to 2 mg per kg. We, in some cases, have done 1 gram pulses if we are worried that somebody is going to perforate. So that was sort of like the first 5 years of treating irAE, and then now in the sort of second 5 years of treating irAE, we have realized that that is a lot of immunosuppression, and we might be able to get away with less with the newer biologics that are on board. So, we are struggling to try to get the data for some of these irAEs that we knew, we have known for a while, but to try to get newer treatments that may immunosuppress less so that you may still be able to retain that tumor response. And in fact, some of the preclinical studies suggest that some of these biologics may actually synergize with the immunotherapy and actually make the immunotherapy more effective from a tumor perspective and calm down the irAE as sort of the bystander effect. So we are still trying to optimize those. Getting up trials in the space has been very difficult. That is one of the reasons for the genesis of ASPIRE because we realized we needed to band together to have a bigger voice in that realm. Then there are other things that are brand new. So we talked about Triple-M. So Triple-M, again, with Triple-M or any myocarditis or myasthenia, I mean, there is about a 50% chance of death from irAE based on the literature. I think we are getting better at recognizing this, and so at Stanford we have some data to say that if you serially follow troponin, that maybe your outcomes are better. You can potentially lower the percentage of cases that are fatal because you can catch them early. I mean, this is all preliminary data, but again, these are all things that are evolving, and we do not all have the right answer. I mean, even the serial troponin thing, I think, is pretty controversial. And in fact, at one of our quarterly Zoom meetings that we are doing in ASPIRE in December is going to sort of flush out that controversy about serial troponin measuring and what is the best thing to use? Would you use something like abatacept or would you use ruxolitinib? Which one is better? I think there is a lot of controversy still about these things. Dr Monty Pal: You have really piqued my curiosity here because you think about the cons of treating irAEs, right? And I worry exactly about what you had mentioned, right, which is, "Gosh, what is going on with this tumor in terms of immunosuppression?" But you think about some of the newer agents, you mentioned ruxolitinib, I have heard of dasatinib, for instance, in this setting. Frankly speaking, a lot of these, as you point out, are really thought of as being also anticancer drugs. So you have really got me thinking about the potential synergy between perhaps suppressing an irAE and augmenting antitumor activity, which I think is very interesting. Am I on the right track with that? Dr Pauline Funchain: I think so, but you will find that a lot of people will not even go there because they are worried about how much immunosuppression you are going to cause. I am at heart a geneticist, but I think an immunologist will happily tell you that the immune system is very complex. There are multiple pathways, and these drugs do not all target the same immune pathways. So if we understand a little bit more about the pathways we are targeting and pick apart the pathways that are really, really tumor relevant and the other pathways that are not tumor relevant, you may be able to piece together a better marriage of tumor response and irAE control. Dr Monty Pal: Kind of on this topic, and again, leaning on your background in genetics, where are we in terms of predicting these irAEs? I mean, you would think the holy grail would be picking out a snip or something of this for it, right, that could potentially identify that patient who is going to get Triple-M or, you know, at the very least a significant high-grade irAE event. Are we anywhere closer to that in 2025? Dr Pauline Funchain: There have been data published. There have been some big GWAS studies. All of the effect sizes are pretty small. So there are some prediction algorithms, but none of them are clinically useful. And I think when you look at the odds ratios, they will increase risk by maybe 20%. I think one of the things that we found in a very small series and supported anecdotally is something as easy as family history of autoimmune disease is probably more predictive at this point than any of those types of markers. I think we will get there, but we are not anywhere near where we would like to be. Things like TMB also, actually, there is some good data about higher TMB, higher risk of irAE too. Dr Monty Pal: Interesting. I see all this data coming through, IL-8 polymorphisms, etc. And I just wondered if any of that was ready for prime time. But I mean, this is a good message for the practicing clinician. Sounds like we are not quite there yet. And I could probably keep you on for another entire podcast to talk about this topic, but let us see if we can at least skim the surface. I never thought I would see the day when BiTEs and CAR-Ts were entering into my kidney cancer practice, but in fact, it is really become central to a lot of our clinical trials in RCC these days. I would be lying if I did not say that I was not struggling with the toxicities and so forth associated with these drugs. Can you give us a quick primer, maybe just good resources that people can go to for managing toxicity with BiTEs and with CAR and with some of these novel therapeutic modalities that we are using in the oncology clinics? Dr Pauline Funchain: I know there is a recently published toxicity manual for BiTEs in hematologic malignancies, I think it was in Blood. CAR-T is covered in many irAE guidelines. So ASCO guidelines actually has a CAR-T [cell therapy guideline], and I would be remiss not to point out that actually ASCO has a, I am a little biased, but a wonderful guideline on irAE that is actually being updated as we speak. We are hoping for publication next year. I find the format of that, there are many guidelines out there, actually. There is ASCO, SITC, ESMO has a guideline for irAE, but I find the formatting of the ASCO guideline to be much easier to flip through during clinic, just because of the visual format of the tables. But that is going to be updated next year. And with CAR-T, there is now multiple publications also in terms of guidelines. But what I will say about bispecifics and CAR-T, so they have very similar toxicities in terms of the cytokine release and also with the ICANS, so the neurotoxicity. But what we have been finding that is really interesting with BiTEs and CAR-T, and actually even with TIL, cytokine release is very similar to some of the IL-2 toxicities but not identical that we see with TIL treatment. But now we are starting to see overlap. So patients who have been treated with immunotherapy and then go on to get a bispecific or then go on to get TIL, so I have seen some colitises that have occurred after the fact. Some of the newer CAR-Ts without checkpoint have been causing some really interesting, probably not in a good way, but interesting biologically, colitises that are really refractory. So we are starting to see some overlap, and again, I think this field is just evolving constantly. Dr Monty Pal: Yeah, no, I almost think I need to go back to that fellowship that you and I did together 20 years ago and, you know, and see if I could repeat some coursework on CAR-T management.  You know, Pauline, I could probably keep you on the horn for hours, but this has just been terrific. Thank you so much for sharing all of your insights with us today on the ASCO Daily News Podcast. Dr Pauline Funchain: Thank you for the invitation. It was wonderful to talk about this, and it was wonderful to catch up a little bit, Monty. Dr Monty Pal: Same here, same here. And thanks to our listeners too. If you value the insights you heard today on the ASCO Daily News Podcast, please 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. Monty Pal    @montypal   Dr. Pauline Funchain @FunchainMD Follow ASCO on social media:       @ASCO on Twitter      ASCO on Bluesky     ASCO on Facebook       ASCO on LinkedIn     Disclosures: Dr. Monty Pal:     Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview    Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical    Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis    Dr. Pauline Funchain: Consulting or Advisory Role: Merck, Replimune, Sanofi/Regeneron, Immunocore, Tempus Research Funding (Inst.): Pfizer, Bristol-Myers Squibb, IDEAYA Biosciences, Linnaeus Therapeutics Travel, Accommodations, Expenses: Merck

Listen to JCO's Art of Oncology article, "Reflection" by Dr. Jamie Riches, who is an Assistant Professor at Columbia University and Director of the Hematology Oncology Hospitalist Service. The article is followed by an interview with Riches and host Dr. Mikkael Sekeres. Dr Riches shares a deeply personal narrative, reflecting on the profound personal and professional impact of losing her young family member to cancer, illuminating the intimate intersection of grief, loss, and healing. TRANSCRIPT Narrator: Reflection, by Jaime C. Riches, DO If I stand this way, with my shoulders back, my chin lifted, if I hold my breath for a moment, my skin fits my bones just right. Each subtle motion is an effort to make my clavicle more prominent, to manifest my ribs. I feel so ignorant about beauty. I was at the side of her hospital bed as she uncovered herself and asked me to look away. Her eyes, glassy and hollow, met mine. "I'm so ugly right now." It's an interesting piece of practicing medicine, to be an observer of bodies, their look, their feel, and their function. Which lines are strength and which are fatigue…which ones are scars and how they have healed. My words were soft and aching, "You are beautiful" I said, knowing that her skin fits her bones too tight. They are almost all that's left. My 38-year-old cousin's oncologist is my colleague, my friend. When she was diagnosed, he reminded me that there were excellent treatments available. I reminded him that none of them would allow her to see her children start kindergarten. Redefining excellence, I thought, sounded like a cancer center's marketing strategy that just missed the mark. As I looked away, a piece of me splintered. It isn't the same when it's someone you know, when it's someone you love. Maybe I feel shame for underappreciating my own fertile marrow, my fat and muscle, and my own existence. Maybe it's guilt for dedicating my whole life to work that can't save her, for being the one to look her mother in the eye and say she can't be saved. Maybe, just sadness. This lonely world, that only exists right at the bedside, is like a magically devastating song and I am humming the rhythmic asynchrony of being a doctor, and just being. "From where do we yearn?," I wonder. It's from within these little spaces we look to fill the absence of something beautiful. The moments that we're longing to be a part of. We are all mothers—the seven of us now in her room, aunts and cousins united by a last name—by the successes and losses we previously thought unimaginable. We've known the brittle anticipation of a new life, the longing, the joy of spending time, and the sense of simply existing in these spaces. We are the daughters and sisters of firefighters. We are women who know the low bellow of the bagpipes, women who own "funeral clothes." We've tried to disinherit the same shades of blue, and all of our distance has brought us right here, where they're making her comfortable. She knows that her time has been spent. Her eyes are the color of her favorite flower, a yellow rose, and her once sterile room appears almost sunlight by the garden of bouquets. Her mother is sitting by her side, gently moving her fingers across what would be a hairline, the way you would touch a newborn in those moments when you're just realizing you didn't know you could love someone so much. There's a song running through my head, "Golden Slumbers" (The Beatles, Abbey Road, 1969). Even playing in my memory, it gives me chills, starting right beneath my jaw and circulating through my limbs. Once, there was a way To get back homeward Once, there was a way To get back home Sleep, pretty darling, do not cry And I will sing a lullaby Nothing illustrates the frailty of existence like a mother preparing for her inevitable goodbye. Once you see it, you can be certain that biology is imperfect. We're convinced that we're grieving throughout the whole of motherhood, as our babies become grown people of their own, as they live their lives. But it isn't grief. We're simply living a life that is singular, in a series of moments that are final. "Golden Slumbers" doesn't actually seem to end. It just subtly transforms into the next track as if they were one, and before the chills are fully absorbed, you're struck by something totally new…triumphant trumpets. When her breath stopped, it wasn't held. I don't think she realized the bravery it took to leave this world with such grace, to be unlonely. I've been witness to so many punctuated pulseless yawns, but not this one. I wish I knew by which of these wounds am I softened and by which I am hardened, but I don't. They heal, with secondary intention, naturally and slowly, from the inside out. Mikkael Sekeres: Welcome back to JCO's Cancer Stories: The Art of Oncology. This ASCO podcast features intimate narratives and perspectives from authors exploring their experiences in oncology. I'm your host, Mikkael Sekeres. I'm Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. Today, I am so thrilled to be joined by Jamie Riches, who is Assistant Professor at Columbia University and Director of the Hematology Oncology Hospitalist Service. We'll be discussing her absolutely gorgeous article, "Reflection." At the time of this recording, our guest has no disclosures. Jamie, I want to thank you so much for contributing your essay to the Journal of Clinical Oncology, and welcome you to discuss your article. Jamie Riches: Thank you so much for having me. Mikkael Sekeres: I have to say, I was so moved by this and just loved the writing. I don't drop the 'G word', gorgeous, very often when describing pieces, but this was truly moving and truly lovely. Jamie Riches: Thank you. Thank you so much. It was a really deeply personal story to me. Mikkael Sekeres: So I wonder if you can tell us a little bit about yourself. Where are you from, and walk us through your career? For example, where did you do your training? Jamie Riches: Well, I am from Brooklyn, New York, and I did my training at an osteopathic medical school in Harlem called Touro, and my residency training at what used to be called St. Luke's-Roosevelt, and now is Mount Sinai West after many of the New York City mergers. I did a chief resident year at Memorial Sloan Kettering and started my oncology hospitalist career there for many years and have been at Columbia now for three years. Mikkael Sekeres: Wonderful. Isn't it interesting how the institutions of our youth are no longer, and that seems to happen at a faster and faster pace? Jamie Riches: I know. I feel the need to reference the old name sometimes when I'm discussing it. Mikkael Sekeres: Can you tell us a little bit about your own story as a writer? How long have you been writing reflective or narrative pieces? Jamie Riches: I have probably always been a jotter. I think that's for as long as I can remember, and I've enjoyed that process. And I think once I was an undergrad, I studied chemistry, I majored in chemistry, but I really filled up a bunch of elective time with writing classes and learning what I could about the processes of writing. And I guess almost 10 years ago now, I enrolled in the graduate certificate program in Narrative Medicine at Columbia. And that program helped me explore a little bit in terms of form and function and in terms of really relating my writing to my own personal experience as a physician. Mikkael Sekeres: And if I'm not mistaken, the field of narrative medicine was really in part born at Columbia, wasn't it? Jamie Riches: It was. Yeah. Rita Charon was the founder of the practice as a field, yeah. Mikkael Sekeres: And what was it that that experience- what did the formal training teach you that you couldn't have figured out on your own by the iterative process of reading and writing? Jamie Riches: I think there's something to having a group of people critiquing you that really allows you to become better in any field, in any practice. And I think there's something to having a, you know, a relatively safe space to explore different ways of doing something. For example, writing poetry, which I really hadn't done much of before and have done a bit of since. I think having a space where there are both educated critics and experts being able to look at your work and say, "This is working and this isn't," was really helpful for me. Mikkael Sekeres: You know, I've heard with writing, the notion that your first critics should be people you trust and feel as if you're in a safe space with because you're so vulnerable with writing. Even exposing it to relative strangers in a formal course can be, I don't want to use the word damaging, but I guess damaging, or at least get you out of a safe space that you need for writing. Do you have an inner circle that you trust for your writing? Jamie Riches: I do. I do. Mikkael Sekeres: If you feel comfortable doing so, can you tell us what prompted you to write this piece? Jamie Riches: This piece just sort of came out. This piece is real, and it's a real experience, and the processing of this experience has happened on so many different planes for me, and writing is really one of them. And once I sat down and said, "Let me write some of this down," it just kind of poured out. Mikkael Sekeres: Sometimes we write to process. I once heard somebody say that writing is the only time in life when you get a free redo, right, or a do over. We say something or we post something on social, and it's out there in the universe. But with writing, it's very personal, and we can look at a paragraph or a sentence and say, "Gee, that just doesn't feel right," and rework it if it's not communicating exactly what I was hoping it would. The other aspect of writing, of course, is that it allows us to ruminate on something that's just occurred and to try to make sense of it. Do you think that was some basis for writing this? Jamie Riches: I think so. And I think maybe just relating one really specific experience into the greater realm of the work that we do every day, and how that experience both stood on its own, but also is woven into so many other patient encounters and encounters with families. And that's a form of processing, I think, for sure. Mikkael Sekeres: Can you tell us in your own words about the main character in this piece and what was going on? Because you write it in a lovely way that allows the reader to discover what's transpiring gradually, but if you could tell us in your own words, who is this person? Jamie Riches: Yeah. So the person that I'm talking to in some parts of the story and talking about in much of the story is my cousin, Patrice, who was diagnosed with bladder cancer at 38 years old and who has had interactions with the medical field as a patient but is not a physician, is not a medical professional, and so had a lot of questions and a lot of trust and reliance on those of us in the family who had some medical knowledge and experience. And so I wound up being pretty intimately involved in her care as a family member, and that was really a fine line in a lot of ways because my friends and colleagues were the care team, and I was the family member. And many of us have been in that position in many different ways, but it's always a fine line. And she was young, and she was very positive throughout really the course of her illness. She had twins who were two years old at the time of her diagnosis. And I think, I'm a little bit speechless now, as you can see, I think she just was so incredibly graceful, and I think I used this word in the story, throughout the entirety of her illness, which included multiple lengthy hospitalizations where she had spent time away from her children. And I still don't know how she did it with the patience and the thoughtfulness and the love for everyone else that she did. Mikkael Sekeres: You really honor her in this piece and paint such a beautiful portrait of her. In the essay, you write, "It's an interesting piece of practicing medicine to be an observer of bodies, their look, their feel, their function. Which lines are strength and which are fatigue, which ones are scars and how they've healed." It's a beautiful couple of sentences. In this case, you aren't really playing the role of doctor, are you? Can you talk a little bit more about when that line's blurred between being a family member and and the practice of medicine when people are relying on you to help out with their medical care? Jamie Riches: Yeah, I think most of us know this gray area fairly well, and the gravity of the situation really dictates how blurry the line is. And it's true, I wasn't the doctor in this situation, and I had as much information about the scans and the clinical picture and the day to day trajectory and the lab results and the toxicity profiles and the data from the studies that the regimens were approved based on. And that made it impossible to step out of the doctor role or mentality, and I also wasn't making the formal recommendations by any means, but I think it's hard to sort of exempt yourself from that space once you're in it. Mikkael Sekeres: Yeah. I think we also sometimes don't realize how even the smallest contribution we have in advising somebody about their medical care becomes very, very meaningful and how much those words can have an effect on somebody. I recall my uncle was diagnosed with acute leukemia, so that's right in my bailiwick, of course. And I remember talking with him about transplant and being as neutral as humanly possible about whether he should proceed with the transplant given the characteristics of his leukemia. And months later, after he had gone through the transplant, he said, "You know, I went through this even though you really advised me not to." So as neutral and trying not to sway someone and giving advice as we are, people hear us differently. Did you find that also with your cousin? Jamie Riches: I did. I phoned into one of her oncologist appointments, and her oncologist, who I have to say is wonderful and who I have the utmost respect and really love for, who took great care in taking care of her, went through in detail everything they could about her disease and about treatment options and really explained everything, and took a minute and said, "Okay, do you have any questions?" And my cousin said, "No, whatever Jamie thinks." So I said, "Okay, well, we'll chat a little bit later." But that made me realize, which I think I just hadn't before, how much having an opinion matters. Mikkael Sekeres: Yeah, and that it's a gift to people when they can cede some of that decision making or some of that knowledge to somebody else and feel as if they don't have to take it on themselves. Jamie Riches: Yeah. Mikkael Sekeres: I want to read one other quote from your piece. I could just reread the whole piece, I enjoyed it so much and keep quoting it. You write, "We've known the brittle anticipation of a new life, the longing, the joy of spending time, the sense of simply existing in these spaces. We are the daughters and sisters of firefighters. We are women who know the low bellow of the bagpipes. Women who own funeral clothes." There's a lot that swims beneath the surface, I think, in that quote, that family members get together at births and deaths, that these become the occasions for the family to get together, that we put on uniforms for them, and that they happen frequently enough that we actually own the uniform to be part of them. Is that what defines us as families? Is that what we've come to? Or how about us as physicians? We own uniforms as physicians also. Are the gatherings, the only gatherings we have with our colleagues at tumor boards when we discuss successes and failures of our patients? Jamie Riches: That's a great question and a great reading, and thank you for these questions. I think every family is different, obviously, and I won't speak for the masses here, but there is a bit of a structure to the events that you're expected to attend and that you're expected to not be absent for, to sort of show up for. And those events are sort- you're right, you know, births and funerals and weddings, and they have a bit of a code to them. And as physicians, it's interesting to think about things like tumor board as the gathering spaces, because although as colleagues we're not families, we are the closest thing to going through some of these moments together. And I think these moments at the bedside, and I use that term so often because I work in the hospital, and I am literally often sitting in a hospital bed holding someone's hand, talking to them. Those are the moments that we feel. We feel them in our bodies. I can feel it right here, and I'm touching my chest when I say that. I don't get that same visceral feeling from looking at most scans, looking at most lab reports, or even having academic conversations with people. And I think that you're right, things like tumor board or even other academic conferences really are the gathering spaces for physicians, but that makes me question if those are the spaces that matter most. Mikkael Sekeres: I think that's a great point also to end our time together. It has been such a true, true pleasure to have Jamie Riches on our JCO Cancer Stories podcast to talk about her gorgeous piece, "Reflection." Dr. Riches is Assistant Professor at Columbia University and Director of the Hematology Oncology Hospitalist Service. Thank you so much again for submitting your piece to us. Jamie Riches: Thank you so much. Mikkael Sekeres: And thank you to our listeners for choosing JCO Cancer Stories: The Art of Oncology. If you've enjoyed this episode, consider sharing it with a friend or colleague or leave us a review. Your feedback and support helps us continue to have these important conversations. If you're looking for more episodes and context, follow our show on Apple, Spotify, or wherever you listen and explore more from ASCO at asco.org/podcasts. Until next time, this has been Mikkael Sekeres. 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. Show notes: Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio: Dr Jamie Riches is an Assistant Professor at Columbia University and Director of the Hematology Oncology Hospitalist Service.

Featuring an interview with Dr Kevin Kalinsky, including the following topics: Prophylaxis, Monitoring and Management of Adverse Events of Special Interest with Datopotamab Deruxtecan (0:00) Lisberg A et al. Datopotamab deruxtecan-associated select adverse events: Clinical practices and institutional protocols on prophylaxis, monitoring, and management. Oncologist 2025;30(9). Abstract  Meric-Bernstam F et al. Prophylaxis, clinical management, and monitoring of datopotamab deruxtecan-associated oral mucositis/stomatitis. Oncologist 2025;30(3). Abstract   Clinical Data with Neoadjuvant Datopotamab Deruxtecan from the I-SPY 2.2 Phase II Trial (5:17) Khoury K et al. Datopotamab–deruxtecan in early-stage breast cancer: The sequential multiple assignment randomized I-SPY2.2 phase 2 trial. Nat Med 2024;30(12):3728-36. Abstract  Shatsky RA et al. Datopotamab-deruxtecan plus durvalumab in early-stage breast cancer: The sequential multiple assignment randomized I-SPY2.2 Phase II trial. Nat Med 2024;30(12):3737-47. Abstract  NeoSTAR: A Phase II Study of Response-Guided Neoadjuvant Sacituzumab Govitecan and Pembrolizumab for Localized Triple-Negative Breast Cancer (9:09) Abelman RO et al. A phase 2 study of response-guided neoadjuvant sacituzumab govitecan and pembrolizumab (SG/P) in patients with early-stage triple-negative breast cancer: Results from the NeoSTAR trial. ASCO 2025;Abstract 511.  OptimICE-RD: A Phase III Study Evaluating Sacituzumab Govitecan with Pembrolizumab versus Pembrolizumab with or without Capecitabine for Residual Triple-Negative Breast Cancer (12:56) Tolaney SM et al. OptimICE-RD: Sacituzumab govitecan + pembrolizumab vs pembrolizumab (± capecitabine) for residual triple-negative breast cancer. Future Oncol 2024;20(31):2343-55. Abstract  CME information and select publications

In this episode, Braheem Santos, US Segment Leader for Healthcare at Schneider Electric, and Andrew Carréno, Business Development Manager for Healthcare at ASCO, discusses how hospitals can retrofit existing facilities to enhance power resilience, reduce downtime, and improve patient care through collaboration and intelligent infrastructure. Learn more about how Schneider Electric is engineered for every moment of care for your health organization here: https://www.se.com/us/en/work/solutions/healthcare/?utm_source=beckershealthcare&utm_medium=affiliates&utm_campaign=2025_oct_us_de_ehealth_beckershealthcare_consideration_directmedia-contentbuy_local&utm_term=octpod&campaign_objective=consideration&mcl_name=ehealth

Featuring an interview with Dr Eunice S Wang, including the following topics: Hypomethylating agent/venetoclax combinations for the treatment of acute myeloid leukemia (AML); integration in community practice (0:00) All-oral regimen of decitabine/cedazuridine with venetoclax for patients with newly diagnosed AML not eligible for intensive induction chemotherapy (9:39) Efficacy of targeted therapy options for AML; potential role of MRD (minimal residual disease) assays in monitoring treatment response (13:07) Treatment approach for patients with FLT3-mutant AML; mutation profiles and predicting response to quizartinib (20:14) Targeting the differentiation of AML tumor cells with IDH and menin inhibitors; associated differentiation syndrome (29:24) Efficacy and tolerability of the IDH inhibitors ivosidenib and olutasidenib (36:54) Key clinical data with approved and investigational menin inhibitors for AML; current and potential integration of menin inhibitors in the AML treatment algorithm (42:30) CME information and select publications

Dr Eunice S Wang from Roswell Park Comprehensive Cancer Center in Buffalo, New York, discusses recent datasets and their implications for the current and future management of acute myeloid leukemia. CME information and select publications here.

Featuring a slide presentation and related discussion from Dr Eunice S Wang, including the following topics: All-oral regimen of decitabine/cedazuridine with venetoclax for patients with newly diagnosed acute myeloid leukemia (AML) not eligible for intensive induction chemotherapy (0:00) Quizartinib-based treatment approaches for FLT3-ITD-mutated and FLT3-ITD wild-type AML (5:21) First- and second-generation IDH inhibitors for AML (17:40) Updated results from the AUGMENT-101 Phase II study of the menin inhibitor revumenib for relapsed/refractory KMT2A-rearranged AML (22:59) Phase Ib/II KOMET-001 study of ziftomenib for relapsed/refractory NMP1-mutant AML (26:42) Novel combination approaches with menin inhibitors for AML (29:11) CME information and select publications

Featuring an interview with Dr Aaron Lisberg, including the following topics: Efficacy and Safety of Datopotamab Deruxtecan (Dato-DXd) for Patients with Previously Treated EGFR-Mutated Advanced Non-Small Cell Lung Cancer (NSCLC): A Pooled Analysis of the TROPION-Lung01 and TROPION-Lung05 Trials (0:00) Ahn M-J et al. Efficacy and safety of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously-treated EGFR-mutated advanced non-small cell lung cancer (NSCLC): A pooled analysis of TROPION-Lung01 and TROPION-Lung05. ESMO Asia 2024;Abstract LBA7 Ahn M-J et al. A pooled analysis of datopotamab deruxtecan in patients with EGFR-mutated NSCLC. J Thorac Oncol 2025;[Online ahead of print]. Abstract Sacituzumab Tirumotecan for Previously Treated Advanced EGFR-Mutated NSCLC: Results from the Randomized OptiTROP-Lung03 Study (7:08) Fang W et al. Sacituzumab tirumotecan versus docetaxel for previously treated EGFR-mutated advanced non-small cell lung cancer: Multicentre, open label, randomised controlled trial. BMJ 2025;389:e085680. Abstract Zhang L et al. Sacituzumab tirumotecan (sac-TMT) in patients (pts) with previously treated advanced EGFR-mutated non-small cell lung cancer (NSCLC): Results from the randomized OptiTROP-Lung03 study. ASCO 2025;Abstract 8507. Combination of Dato-DXd and Immunotherapy as First-Line Therapy for Patients with Advanced NSCLC (13:12) Cuppens K et al. First-line (1L) datopotamab deruxtecan (Dato-DXd) + durvalumab ± carboplatin in advanced or metastatic non-small cell lung cancer (a/mNSCLC): Results from TROPION-Lung04 (cohorts 2 and 4). ESMO Targeted Anticancer Therapies Congress 2025;Abstract 8O. Okamoto I et al. TROPION-Lung07: Phase III study of Dato-DXd + pembrolizumab ± platinum-based chemotherapy as 1L therapy for advanced non-small-cell lung cancer. Future Oncol 2024;20(37):2927-36. Abstract Levy BP et al. TROPION-Lung08: Phase III study of datopotamab deruxtecan plus pembrolizumab as first-line therapy for advanced NSCLC. Future Oncol 2023;19(21):1461-72. Abstract Aggarwal C et al. AVANZAR: Phase III study of datopotamab deruxtecan (Dato-DXd) + durvalumab + carboplatin as 1L treatment of advanced/mNSCLC. World Conference on Lung Cancer (WCLC) 2023;Abstract P2.04-02. TROP2-Targeting Antibody-Drug Conjugates as Neoadjuvant and/or Adjuvant Therapy for Patients with Resectable NSCLC (19:08) A phase III, randomised, open-label, global study of adjuvant datopotamab deruxtecan (Dato-DXd) in combination with rilvegostomig or rilvegostomig monotherapy versus standard of care, following complete tumour resection, in participants with Stage I adenocarcinoma non-small cell lung cancer who are ctDNA-positive or have high-risk pathological features (TROPION-Lung12). NCT06564844 Cascone T et al. Perioperative durvalumab plus chemotherapy plus new agents for resectable non-small-cell lung cancer: The platform phase 2 NeoCOAST-2 trial. Nat Med 2025;31(8):2788-96. Abstract CME information and select publications

Dr. Monty Pal and Dr. Fumiko Chino discuss several of the top abstracts presented at the 2025 ASCO Quality Care Symposium, including research on federally funded clinical trials and financial reimbursement for trial participation. TRANSCRIPT Dr. Monty Pal: Hello, and welcome to the ASCO Daily News Podcast. I am your host, Dr. Monty Pal. I am a medical oncologist, professor, and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles. Today, we are highlighting key abstracts that were presented at the 2025 ASCO Quality Care Symposium. I am delighted to be joined today by the chair of this year's meeting, Dr. Fumiko Chino. Dr. Chino is an associate professor in radiation oncology at MD Anderson Cancer Center with a research focus on access, affordability, and equity. She is also a consultant editor of JCO Oncology Practice and the host of the Put into Practice podcast. I have got to listen to that.  Dr. Chino, welcome, and thanks so much for being on the podcast today. Dr. Fumiko Chino: I am overjoyed to be here, and absolutely, you should take a listen. Dr. Monty Pal: Definitely. And FYI for listeners, our full disclosures are all available in the transcript of this episode, so do have a look if you are inclined. Now, we have really seen some fantastic advances in health services and quality and supportive care, digital health, and beyond. There are some great abstracts that were presented at this year's meeting. I have actually picked a couple that I am particularly interested in and that I believe you share my interest in as well.  So, the first is an abstract actually from my friends at SWOG (Abstract 94). So, this was a terrific abstract from Joe Unger and Michael LeBlanc and Dawn Hershman. And this, I think, really hits on a very, very key issue right now, which is the benefit of federally funded trials. Do you mind just kind of spelling out some of the observations from what I think is a really brilliant piece of work? Dr. Fumiko Chino: Absolutely, and I think Dr. Unger's work is really important for our current funding environment. I think that this research is really essential to do to show the role of federal sponsorship in the design and conduct of clinical trials. Because what they did was really look at a landscape analysis over the last 20 years looking at funding and were able to show quite clearly that federal funding really matters for advancing the science in cancer care. So what they showed was that the federal funding was more commonly essential for early-stage clinical trials, so those phase 1, phase 2 trials that really help advance the science. And that federal funding was really essential for multimodality drug combinations, combinations with drug and surgery, combinations with drug and radiation. Those trials were much more likely to be federal funded. And then the last thing is that they showed that the patients that are, I think, the largest at risk for gaps in care who really need the advancements in science that keep U.S. health care amazing and wonderful and world-leading, so the kids, the pediatric patients, the patients with rare cancers, and the patients actually that could benefit from de-escalation or right-sizing of treatment, they were also all more likely to have federal funding. So I think this research that was presented really shows that if, unfortunately, current status of restricted federal funding continues, that we are going to lose out in terms of the next generation of cancer cures, cancer de-escalations, and the type of combination treatments that make advancements in science. Dr. Monty Pal: Indeed. You know, I always point to Joe Unger's paper, and I think it is in JAMA Oncology, right, that showed life-years gained from NCI trials. It is such an important piece of work. I think this is a really nice complement to that, isn't it, to show the specific areas that otherwise would be, am I right in saying, kind of largely untouched? Dr. Fumiko Chino: I think you are right in that what we know from what industry will sponsor versus what the federal government will sponsor, that the federal government really helps make up the gap to really make those advancements that save lives, that lead to more birthdays, that advance our knowledge and our capacity for providing more cures and more successful futures for our patients. I always like pointing to the de-escalation research, which is, and this is not to dig pharma, but no pharmaceutical company is going to run a trial that says you can give less of their drug, right? It just does not make sense for the business end of the science. And so, thinking about how to right-size treatments, how to do more with less, that really is the purview of the federal government. Dr. Monty Pal: Absolutely. Absolutely.  I am going to shift gears here and bring up another abstract that I found to be quite intriguing, and this relates to reimbursement of expenses, et cetera, for clinical trials. This is an abstract from Courtney Williams and team. It brings to mind the importance, I think, of recognizing the hardships that patients take on by clinical trials, but I also would love for you to comment on that sort of fine line between reimbursement for expenses and then, you know, sort of undue enticement. It is a challenging balance there. But give me your reflections on this abstract. Dr. Fumiko Chino: Absolutely. You are speaking about Dr. Williams' Abstract 93 from the Alabama group, and Alabama actually has this incredible group of health services researchers which is, are doing really important work in this space. What this trial shows is that, you know, it is a small pilot study, it is 30-something patients that received some support primarily for their travel and additional expenses related to their clinical trial participation for breast cancer. It showed that the money helps, and I think what we all know is that it is expensive to participate in clinical trials. It requires additional visits. It often requires some significant travel burden for our patients, and I do not feel that money reimbursement for clinical trial expenses is an inducement. Nobody participates in a clinical trial to get the money for their gas, right? We know that our patients are making some pretty significant sacrifices in order to participate in clinical trials, and what this type of program does is just actually reimburse them for their outlaying of funds.  And I loved this trial because the patients were actually given $1,000 a month for the first 4 months of their trial participation, and what the study showed is that the patients were using it for things like travel-related food, for things like transportation, caregiver expenses, or even some of their out-of-pocket medical expenses like cost sharing or prescriptions. And that they said that overall, the reimbursement really made a difference in terms of their capacity for staying on the clinical trial. Because we know our clinical trials really are not able to enroll the full diversity of patients that often have a disease, and that the patients that are at biggest risk for a health care disparity or a gap in care are also the least likely to enroll in a clinical trial.  Programs like this are an essential part of showing how financial toxicity can be overcome with pretty straightforward assistance to patients to help reimburse them for the things that they are already taking out of their pocket, for parking costs, for that $10 soup that they buy at the cancer center, for those additional expenses that we are, unfortunately, putting on them. Dr. Monty Pal: Very well said. And you know, I have started to dabble in clinical trials looking at CAR T-cell therapies for kidney cancer, and I have to tell you, it is just insane the amount of cost that a patient would have to take on to comply with the stipulations for some of these novel therapies. We require that they stay within 30 minutes of the facility for 28 days, and unless we are compensating for some of that, I mean, how can one afford a hotel stay that is that long? I mean, it is just, it is unprecedented, and it would certainly provide a huge barrier to many patients who would otherwise enroll. Really well said. I also wanted to bring up another financially driven topic, and treating renal cell, again, I would say the vast majority, 90% plus of my patients in clinic are on oral drug therapies. And I cannot tell you how often a patient will show up in my practice and say, "Doc, I have got 15 days out of this 30-day prescription left. What do I do with it?" You know, or some come with pill bottles from a deceased loved one. And it is so frustrating to say, "Take it to the pharmacy and they will just get rid of it for you." But sounds like there is an abstract from Dr. Mackler, Abstract 102, that seems to address this topic quite well. Am I right? Dr. Fumiko Chino: Absolutely. This presentation, I was the most excited about seeing because this group, which helps run a cancer drug repository, theirs is called YesRx, presented their data from the last approximately two years of running this repository, and they were able to show incredible benefit for their patients in Michigan. And it is a really straightforward program. It is run by pharmacists. It has support from the legislation in Michigan. And what they were able to show is that they repurposed medications that would otherwise have been discarded. They delivered them directly to the oncologist, which then actually dispersed them to the patients. They helped 1,000 patients in less than two years. They saved them millions of dollars, over $15 million presented in the abstract. And it is just a win-win-win because I know that patients actually, and sometimes patient caregivers, they feel very sad to have spent a lot of money out of pocket for their medication, and then if they have a dose reduction or, obviously, you know, if the surviving spouse then has to get rid of their medication, just dispose of them, it is very disheartening. And this is a way of kind of reclaiming power for patients. So they were able to accept donations from all over the state of Michigan and then also help over 1,000 patients. And so, it is a phenomenal program. Dr. Monty Pal: Just wild when I came across the dollar amounts, right, that they were saving. It just, it seems like a place that, you know, we just have to look, as cancer centers, right, and really take this on. Just brilliant. On that same theme of cost savings and so forth, you know, I think there has been a lot of focus on what recent policies have done in the context of us having access to therapies and so forth. And one of the topics that has come up is the Inflation Reduction Act and how changes pertaining to the IRA have really played a role in one's ability to take on some of these expensive prescriptions. And I believe John Lin and colleagues tackled that issue in Abstract 97. Could you comment on that, Fumiko? Dr. Fumiko Chino: Absolutely. Dr. Lin is one of my colleagues here at MD Anderson, so I know him very well, and he has been doing really phenomenal work over the last several years with looking at drug affordability and access. And what his analysis shows is that for patients, after the Inflation Reduction Act's cap on out-of-pocket expenses, is that it really did show that out-of-pocket expenses decreased. So what the Inflation Reduction Act did is that it eliminated the 5% co-insurance and placed this $2,000 cap on out-of-pocket expenses. And what that led to for these patients that were not able to have the low-income subsidy is that there were lower costs, and that there was a lower rate of drug abandonment, meaning that the prescription was not refilled. There was also a lower rate of unfilled prescriptions as well. And I think that it shows that health policy really can improve access to care. I think the flip side of the fact that the IRA, this policy, really did seem to help people is that what his research showed is that actually, even with the benefits of this cap, is that actually it is still really high in terms of the rate of people who are not able to fill their prescriptions or that completely abandon them over time. And that unfortunately, even with this change, that over half of people without the low-income subsidy were potentially not getting the full benefit of their medications because they were not able to afford them. And so I think it really kind of highlights that we still need to do more work about making drugs affordable. Dr. Monty Pal: Indeed, indeed. And I mean, in a setting like this, I mean, I think it is important to recognize that $2,000 is a lot, it is a big chunk of change, right, for a lot of families in the U.S. What do you think of the prospect of, like, decreasing that cap? Is that something that from a policy standpoint you would be supportive of? Dr. Fumiko Chino: Well, so something that is a real option for patients on Medicare is there is something called the Medicare Prescription Payment Plan, and what it allows you to do is actually prorate the $2,000 over the whole year. And so instead of having to pay $2,000 as soon as you fill your prescription, because you are going to have, if you have an expensive medication, it is essentially you have to pay the $2,000 in January, right? It allows you to prorate it, so essentially $170 a month, and that comes to you as like a regular bill. And I think that as rolled out as part of the IRA is a really lovely way of thinking about how do we make these payments more stable over time, so it is not a huge hit sort of at the beginning of the year. And I think that alone actually can make a difference in terms of trying to help make sure that people can actually get their medications. Dr. Monty Pal: That is an excellent tip. Excellent tip.  We are going to shift gears entirely. We have been talking a lot about the dollars and cents of things and talk about an abstract from Sophia Smith and colleagues. So this is Abstract 550 at your meeting. And this hinged on a program of sorts to deal with post-traumatic stress disorder. We do not often think about PTSD in the vernacular for oncology patients, but indeed, I mean, it is something that they must face, especially in the context of long-term survivorship. Can you talk a little bit about Dr. Smith's abstract? Dr. Fumiko Chino: Absolutely. I love this work from Dr. Smith, who is at Duke. She worked with Dr. Applebaum, who was my old colleague at Memorial Sloan Kettering. And this group of researchers really is trying to figure out how to best support people into survivorship so that they can actually thrive. And their patient population for this work was actually people who received stem cell transplant, and they focused on people who had PTSD symptoms. And what they were able to show through this SMART design, which is essentially this serial, multiple randomized trial, so everyone got randomized upfront to either usual care or this app, so this digital app that actually helped coach people through cancer distress. And then for the people who were non-responders, they were then additionally randomized to either the app plus coaching or a therapist versus the cognitive behavioral therapy or CBT.  And what they were able to show is that, number one, anyone who had the app seemed like they did better than those who did not start the path with the app. But then the additional help of either the therapist or the coach or the CBT made additional benefit over time. And so, I think this shows a really nice stepped care, which is you can potentially have some right-sizing of treatments cost saving, if we sort of give everyone the app, which is, I think, overall pretty low cost. And that for the people who do not get the full benefit from the app, then you can think about these maybe more tailored approaches, the therapist, the coach, the CBT, but that some people actually just respond to the app. And I think it allows us to, again, right-size the care for our patients. And I think it is really innovative to think about how technology can help improve access to care in the setting of something like PTSD. Dr. Monty Pal: Brilliant summary. Brilliant summary.  Gosh, it looks like such an exciting meeting this year. Congratulations on a terrific program for the ASCO Quality Care Symposium. I know you played a huge role in developing it, and thanks for sharing your insights on the ASCO Daily News Podcast. Dr. Fumiko Chino: No, I really appreciate you having me. ASCO Quality is my favorite meeting of the year. You know, it is really a phenomenal meeting, and I am so excited for next year in Boston in 2026. Dr. Monty Pal: Awesome. And thanks to our listeners too. You are going to find links to all the abstracts that we discussed today in the transcript of this episode. Finally, if you value the insights that you heard today on the ASCO Daily News Podcast, please 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. Sumanta (Monty) Pal  @montypal Dr. Fumiko Chino @fumikochino Follow ASCO on social media: @ASCO on Twitter ASCO on Bluesky ASCO on Facebook ASCO on LinkedIn Disclosures of Potential Conflicts of Interest: Dr. Monty Pal:     Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis Dr. Fumiko Chino:  Consulting or Advisory Role: Institute for Value Based Medicine Research Funding: Merck

Send us a textIn our Season 11 opening episode, we're bringing you the latest updates from the 2025 ASCO Annual Meeting on metastatic breast cancer. Dr. Ashley Schreier, breast oncologist at Weill Cornell Medicine, breaks down key research and explains what it could mean for people living with MBC.Topics include:Research results for hormone therapy options like camizestrantThe role of ESR1 mutation testingResults from treatment combinations like Enhertu and Perjeta, and Trodelvy and KeytrudaHow to navigate clinical trial accessTips for staying hopeful while exploring treatment optionsWhether you're a patient, caregiver, or advocate, this episode is packed with insights to help you stay informed and empowered.

Featuring perspectives from Dr Sara A Hurvitz and Dr Sara M Tolaney, including the following topics: Introduction: View from Outer Space (0:00) Hormone Receptor-Positive Breast Cancer (6:23) HER2-Positive Breast Cancer (40:54) Triple-Negative Breast Cancer (52:48) CME information and select publications

In this episode of the Oncology Brothers podcast, we dive deep into the latest advancements in treating extensive stage small cell lung cancer (SCLC), focusing on the IMforte data and its clinical implications. We welcomed esteemed thoracic medical oncologists Drs. Isabel Preeshagul, Ticiana Leal, and Dr. Stephen Liu to discuss the findings presented at ASCO 2025 and World Lung 2025. Key topics included: • Overview of the IMforte study design and patient population • The role of lurbinectedin and atezolizumab as maintenance therapy • Significant improvements in progression-free survival (PFS) and overall survival (OS) • Management of side effects and the importance of prophylactic growth factors • Patient selection criteria for this new standard of care With a focus on bridging the gap between community and academia, this episode provides valuable insights for medical oncologists and patients alike. Tune in to learn how these advancements are changing the landscape of SCLC treatment and improving patient outcomes.  Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Don't forget to like, subscribe, and check out our other discussions on recent approvals, treatment algorithms, and challenging cases. We are the Oncology Brothers! #IMforte #SCLC #Lurbinectedin #MaintenanceTherapy #ASCO2025 #OncologyBrothers #ES-SCLC

Featuring case presentations and related discussion from Dr Sara A Hurvitz and Dr Sara M Tolaney, including the following topics: Case: A woman in her mid 50s with localized HR-negative, HER2-positive breast cancer — Dr Tolaney (0:00) Case: A woman in her mid 40s with localized HR-positive breast cancer with a germline BRCA2 mutation — Dr Tolaney (7:08) Case: A woman in her early 30s with HR-negative, HER2-positive metastatic breast cancer with one isolated liver metastasis — Dr Tolaney (11:30) Case: A woman in her early 50s with metastatic triple-negative breast cancer — Dr Tolaney (17:52) Case: A woman in her early 30s with localized HR-positive, HER2-negative breast cancer — Dr Hurvitz (31:49) Case: A woman in her early 60s with HR-positive, HER2-negative metastatic breast cancer with concurrent PIK3CA and ESR1 mutations — Dr Hurvitz (40:39) Case: A woman in her early 40s with recurrent HR-positive advanced breast cancer with a PIK3CA mutation — Dr Hurvitz (51:28) Case: A woman in her early 50s with HR-positive, HER2-negative breast cancer eligible for the SERENA-6 switching strategy — Angela DeMichele, MD, MSCE (58:41) CME information and select publications