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Dr. Lakshmi Rajdev and Dr. Manish Shah join the podcast to discuss the updated guideline on immunotherapy and targeted therapy in unresectable locally advanced, advanced, or metastatic gastroesophageal cancer. They share first-line and subsequent-line recommendations for both gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma based on actionable biomarkers including PD-L1 expression, MMR and/or MSI, CLDN18.2 expression, and HER2 status. They note the importance of the algorithms and tables in the guidelines that provide visual illustrations and quick reference guides of the evidence-based recommendations. They also comment on ongoing and recently presented trials that may impact future guidelines in this space. Read the full guideline, "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update" at www.asco.org/gastrointestinal-cancer-guidelines" TRANSCRIPT This guideline, clinical tools and resources are available at www.asco.org/gastrointestinal-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-25-02958      Timestamps ·       00:00 – 02:15 Introduction and Overview ·       02:16 - 08:20 First-line treatment for patients with pMMR/MSS, HER2-negative gastroesophageal adenocarcinoma ·       08:21 –10:29 First-line treatment for patients with pMMR/MSS, HER2-positive gastroesophageal adenocarcinoma ·       10:30 – 14:39 First-line treatment for patients with dMMR/MSI-H, gastroesophageal adenocarcinoma ·       14:40 – 18:03 First-line treatment for ESCC ·       18:04 – 22:04 Second- and third-line therapy for gastroesophageal adenocarcinoma and ESCC ·       22:05 – 24:38 Importance of guideline ·       24:39 – 27:45 Outstanding questions and future research   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. Lakshmi Rajdev from the Icahn School of Medicine at Mount Sinai and Dr. Manish Shah from Weill Cornell Medicine, co-chairs on "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update." Thank you for being here today, Dr. Rajdev and Dr. Shah. Dr. Lakshmi Rajdev: Thank you. Dr. Manish Shah: Thank you for having us. It is wonderful. 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. Rajdev and Dr. Shah, 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. Shah, I would like to start first with what prompted the update to this guideline, which was previously published in 2023, and what is the scope of this updated guideline? Dr. Manish Shah: Yes, terrific. So even in the last few years, the pace of drug development in gastroesophageal cancers has just been astounding. So, what prompted this guideline is actually the practice-changing results for a new biomarker, CLDN18.2 hat was based on the GLOW and SPOTLIGHT studies, as well as a practice-changing study in HER2-positive disease where we added pembrolizumab to trastuzumab and chemotherapy for tumors that are HER2-positive and PD-L1 CPS 1 or greater. And then there were also new studies and new approvals in esophageal squamous cell cancer that you will hear about as well. So there were several studies, overall more than 5,000 patients were reported on, and that led to several new therapies, new indications, and it really necessitated this guideline. Brittany Harvey: Excellent. It is great to hear about all of these exciting updates in this space. So then to next review the key recommendations of this guideline by clinical question that the expert panel addressed. So, Dr. Rajdev, what is the recommended first-line treatment for patients with proficient mismatch repair, microsatellite stable, HER2-negative gastroesophageal adenocarcinoma? Dr. Lakshmi Rajdev: Thank you for that question. So historically, we have sort of used fluoropyrimidine and platinum doublets, which yielded a survival of about one year. More recently, immunotherapy and targeted therapy options have improved outcomes in patients with advanced esophageal and gastric adenocarcinoma, as well as squamous cell carcinoma. Patients with gastric and GE junction adenocarcinoma have a high rate of actionable alterations, so it is imperative that physicians test the following biomarkers upfront so that it can help guide therapy. The markers recommended by the ASCO panel are HER2, MMR or MSI, CLDN18.2, and PD-L1. And also, it was recommended to use NGS if feasible in this patient population. HER2, as we know, is expressed in about 15% to 25% of patients; PD-L1 expression occurs in about 80% of patients; MSI-high, deficient MMR is present in about 5% to 8% of patients; and CLDN18.2 expression is present in about 40% of patients. There is, of course, biomarker overlap. About 13% to 22% of CLDN18.2 patients are also PD-L1 positive. For patients with pMMR or microsatellite stable HER2-negative disease with PD-L1 expression greater than 1 and absence of CLDN18.2, the panel recommended a first-line therapy with fluoropyrimidine and platinum-based therapy in combination with immunotherapy. These recommendations stem from large phase 3 trials, and the agents approved in the United States are pembrolizumab, nivolumab, and tislelizumab. It has been shown that immunotherapy benefit is greater in patients with higher PD-L1 expression, and it is not possible to comment on the individual PD-L1 cutoff scores and sort of identify the optimal PD-L1 cutoff score that sort of balances benefits and harms. But what is recommended is that immunotherapy-based treatments can be offered in patients with a CPS score of greater than 1. With regard to the choice of immunotherapy agents, that is pembrolizumab, nivolumab, or tislelizumab, these agents are considered to have similar efficacy, and the selection of an agent could be based on dosing schedule, cost considerations, toxicity, and the method of administration. Typically, clinicians should avoid withholding the start of chemotherapy while awaiting biomarker testing, depending on the clinical scenario. Now, for patients with pMMR microsatellite stable disease that is HER2-negative with PD-L1 expression less than 1 and positive CLDN18.2 expression, zolbetuximab-based treatments or in combination with chemotherapy is recommended, and this is based on two global phase III randomized controlled trials, the GLOW and the SPOTLIGHT. And across both studies, the hazard ratio for the overall survival was 0.78, and similarly, there was also an improvement in progression-free survival favoring the zolbetuximab group compared to the chemotherapy group alone. An important note is that nausea, vomiting is commonly associated with zolbetuximab-based treatments, and the panel recommended prophylactic antiemetics, adjusting zolbetuximab infusion rates, pausing infusion temporarily, using non-prophylactic antiemetics, and hydration intravenously prior to discontinuation of zolbetuximab-based chemotherapy. So effective handling of the GI-related symptoms with zolbetuximab is recommended prior to discontinuation of therapy. Now, for patients with pMMR microsatellite stable HER2-negative gastric, GE junction adenocarcinoma with PD-L1 expression greater than 1 and CLDN18.2 positivity, the ones with the dual expression with CLDN18.2 as well as PD-L1 chemotherapy, the choice of therapy can be based on the degree of PD-L1 expression, the toxicity profile, the burden of symptoms, and the anticipated improvement in symptoms associated with response to treatment, the patient comorbidities, the prior medical and treatment history. So this decision needs to be made on a case-by-case basis, and these are some of the factors that we suggested that could potentially influence the choice of therapy. For patients with pMMR microsatellite stable disease that is HER2-negative and a PD-L1 expression less than 1 and an absence of CLDN18.2 expression, first-line therapy with fluoropyrimidine and platinum-based chemotherapy is recommended. So you can see we have segmented out patients based on PD-L1 expression, pMMR and microsatellite stable disease expression, and also based on CLDN expression. Brittany Harvey: Absolutely. And that first point you noted, I think is really important, that biomarker testing is really critical for treatment decision-making in this space. So then the next subgroup of patients that the panel looked at, Dr. Shah, what first-line therapy is recommended for patients with proficient mismatch repair, microsatellite stable, HER2-positive gastroesophageal adenocarcinoma? Dr. Manish Shah: So this was an update from a few years ago. So we have known for 15 years now that if you are HER2-positive, you should get trastuzumab plus chemotherapy. That was based on the ToGA trial. And the update now is based on a trial called KEYNOTE-811, where it examined the addition of pembrolizumab to trastuzumab and chemotherapy versus trastuzumab and chemotherapy, and there was a progression-free and overall survival benefit. And again, here, the biomarkers are important. If your CPS PD-L1 is less than 1, we would not recommend Pembrolizumab in that setting, so you would still get trastuzumab and chemotherapy. But if it is 1 or greater, the PD-L1 CPS score, then we do recommend pembrolizumab unless there is a contraindication to immunotherapy. The take-home message really is from the onset of diagnosis, please check your biomarkers. And I will just, it is worth repeating, it is important to check your PD-L1 status, HER2 status, mismatch repair status, and CLDN18.2 status. And then the optimal therapy, and it is outlined in the publication, is really biomarker-driven. We know that if we are able to hit the target that is overexpressed, we are going to have a better outcome. And Dr. Rajdev did mention where there is overlap, there can be a lack of data, and that is where we are with both PD-L1 positive and CLDN positive. Here we do have data in HER2-positive cases where if you are both HER2-positive and PD-L1 positive, you would combine trastuzumab and pembrolizumab for the best outcomes. Brittany Harvey: Understood. I really appreciate you detailing what is most important for each individual biomarker combination that patients may have. So then following that, Dr. Rajdev, what does the expert panel recommend for first-line treatment for patients with esophageal squamous cell carcinoma that is not amenable to definitive chemoradiation? Dr. Lakshmi Rajdev: There are three phase III randomized clinical trials that have influenced practice in patients with esophageal squamous cell carcinoma examining the benefit of immunotherapy in this patient population. The RATIONALE-306 was a randomized trial of tislelizumab plus chemotherapy with platinum and fluoropyrimidine or paclitaxel versus placebo with chemotherapy. And then you have the KEYNOTE-590, which compared pembrolizumab plus chemotherapy versus chemotherapy alone. And then you have CheckMate-648, which included comparisons of nivolumab plus chemotherapy versus nivolumab plus ipilimumab or chemotherapy. And the primary endpoints for these studies were overall survival, and they did look at subgroups with PD-L1 expression. They used TPS score greater than 1% in CheckMate-648 and PD-L1 CPS greater than 10 in KEYNOTE-590. The bottom line is that the overall hazard ratio for overall survival across this patient population was 0.72. So clearly, there is benefit in patients that express PD-L1 CPS greater than 1 for benefit for the addition of immunotherapy. Now, the benefit again in patients with a PD-L1 expression less than 1 remains limited, and so the panel has made a recommendation for using immunotherapy in combination with platinum-based chemotherapy in patients with a PD-L1 greater than 1. Again, we know that it is hard to make recommendations on what PD-L1 cutoffs are recommended in this patient population, meaning that should it be limited to patients with a PD-L1 of 1 to 4 or greater than 10? I think that the general consensus that has been gleaned from the data is that the higher the PD-L1 expression, the greater the benefit. I do want to comment on another option that is available in patients with squamous cell carcinoma compared to adenocarcinoma, and that is the combination of nivolumab and ipilimumab. Now, in CheckMate-648, nivolumab with ipilimumab was also recommended as a treatment option in patients that have a PD-L1 score of greater than 1. There was a survival benefit demonstrated with this combination compared to chemotherapy alone. And an important observation in this study is that, although there was a slightly increased rate in early death, but there was really no significant difference in PFS and OS compared to chemotherapy alone. Importantly, the treatment appeared to be pretty well tolerated by the study population. There was a notable difference in the objective response rate, which was 35% in the nivolumab plus ipilimumab group compared to patients receiving nivolumab and chemotherapy, where it was 53%. So superiority is, so the importance of chemotherapy in patients with esophageal squamous cell carcinoma is to be noted. However, there is no difference in overall survival and progression-free survival when using the combination of nivolumab and ipilimumab, and thus it affords a chemotherapy-free option for this patient population with esophageal squamous cell carcinoma and a CPS with a score of greater than 1. Brittany Harvey: Understood. I appreciate you reviewing the evidence underpinning those recommendations as well. So then the next patient population that the guideline panel addressed, what first-line therapy is recommended for patients with deficient mismatch repair, microsatellite instability-high, gastroesophageal adenocarcinoma or esophageal squamous cell carcinoma? Dr. Lakshmi Rajdev: The rate of MSI-high expression is about 3% to 7% across different studies. Now, the KEYNOTE-158 was a tumor-agnostic study in patients with non-colorectal cancers, and again, the problem with the MSI-high population, given that it is so rare, the numbers in the individual studies are fairly small. But consistent outcomes do emerge, indicating high response to immunotherapy. So in KEYNOTE-158, a response rate of about 46% was noted. The number of patients was small, it was about 24. In CheckMate-649, which is a study of chemotherapy plus or minus nivolumab in patients with advanced gastric adenocarcinoma, there was again a very small number of patients, and patients that were MSI-high or deficient MMR did experience substantial benefits with the addition of immunotherapy, with hazard ratios in the order of about 0.38. In KEYNOTE-062, again, it was a very small number of patients, again about 6% or so, and similar to CheckMate-649, a substantial benefit was noted in combination with chemotherapy, but also there were benefits noted with pembrolizumab alone. The RATIONALE-305 again was a study of tislelizumab in combination with chemotherapy and similarly showed benefits to the combination of chemotherapy plus immunotherapy in this patient population. I think that we are all aware of the dramatic benefits of immunotherapy in this particular subset of patients, deficient MMR MSI-high, and also we have seen in CheckMate-649 they did have a subset of patients that received nivolumab and ipilimumab. And in this patient population, they noted unstratified hazard ratio of 0.28. So I think that the overall consensus is that immunotherapy is a very important treatment modality in patients with deficient MMR MSI-high disease, given that a lot of the trials in gastroesophageal adenocarcinoma have utilized chemotherapy-based options, that is certainly a recommendation of the panel to use chemotherapy in combination with immunotherapy. However, on a case-by-case basis, the panel recommended immunotherapy alone as well, and given the high response rates noted in trials across different diseases as well as noted in this disease as well. Brittany Harvey: Certainly. And I appreciate you both for reviewing these first-line recommendations. So moving to later lines of therapy, Dr. Rajdev, what recommendations did the expert panel make for second or third-line therapy for gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma? Dr. Lakshmi Rajdev: So, I think that the RAINBOW trial that investigated the utility of the addition of ramucirumab as second-line therapy has been around since 2014, and those results have led to the addition of ramucirumab to taxane-based therapy in the second-line setting. Based on the utilization of oxaliplatin and platinum-based therapy in the front-line setting, there may be patients that have an underlying neuropathy, and so we wanted to really include treatment options for this patient population so that an agent that is less neurotoxic could also be recommended in combination with ramucirumab. The RAMIRIS trial is one such trial where ramucirumab was combined with FOLFIRI, and it demonstrated benefit in combination with ramucirumab. So we have listed that as a potential treatment option for patients in the second-line setting who may have an underlying neuropathy or even for whatever reason that based on the toxicity profile, that needs to be the preferred option by a physician, that recommendation is new from the older guidelines that we have. With regard to the utility of PD-1 inhibitors, there really has been no benefit noted in the second-line setting with regard to overall survival or progression-free survival, so no recommendation is made for that option. I think an important study that has been recently presented is the DESTINY-Gastric04 trial, which really has been practice-changing and has led to the recommendation for trastuzumab deruxtecan in patients that have HER2-positive metastatic gastric or GE junction adenocarcinoma. Now, this is a phase III trial in patients who retained HER2-positive disease after progressing on front-line trastuzumab-based treatments, and the comparator for this trial was trastuzumab deruxtecan versus ramucirumab plus paclitaxel. There was significant improvement and progression-free survival in patients that received trastuzumab deruxtecan. The patients that were excluded from the trial are patients that have pulmonary problems, interstitial lung disease; that is one of the toxicities of this particular agent, and close monitoring and prompt initiation of therapy such as glucocorticoid treatment in patients who develop this toxicity was also highlighted by the panel. So to summarize, the new guidelines highlight the possibility of FOLFIRI plus ramucirumab as a second-line option and then trastuzumab deruxtecan as a later-line option in patients that still retain HER2 expression. And that is very important because the trial did retest patients whether they expressed HER2. As we know, in a substantial number of patients, there is downregulation of HER2, and there is emerging data that the benefit for subsequent HER2-directed therapies is best noted in patients that still retain HER2 expression. Brittany Harvey: Great. So as our listeners have heard, there are many recommendations and new treatment options for advanced gastroesophageal cancer. Dr. Shah, earlier you highlighted the importance of biomarker testing, but I would like to hear in your view, what is the importance of this guideline and how will it impact both clinicians and patients with gastroesophageal carcinoma? Dr. Manish Shah: So as we have discussed throughout this podcast, the treatment for gastroesophageal cancer, both adenocarcinoma and squamous cell cancer, is increasingly complex, increasingly biomarker-driven. And I think the value of the guideline is to place all of that into context. So it provides the data for why certain biomarkers are important, what therapies should be indicated. Not only that, but if you are able to review the guideline, it provides the details of each of these studies and summarizes them in a meta-analysis fashion to sort of give you the context, because sometimes the individual studies can be maybe a little bit discordant or confusing and the guideline attempts to harmonize all that. And then also, I think the tables are very, very interesting because they give you actual numbers in terms of how many patients over a thousand would this benefit or how many patients over a thousand would this cause harm in terms of nausea, vomiting, or other things like that. So it gives you context for helping clinicians and patients weigh the potential benefits of the novel treatment strategies against the potential adverse events. And then finally, the guideline does also provide an algorithm that you are able to follow based on the biomarkers, and those are in figures 4 and 5. So I think overall, it is a very comprehensive guideline. It intends to make more manageable a very complex subject, and you know, I really encourage our listeners to review it after listening to the podcast. Dr. Lakshmi Rajdev: If I can add to that, I think that what is also really good about the guidelines is there are quick summaries. So if someone is busy in the clinic, of course, there is the opportunity to review the data supporting the guidelines in great depth in the manuscript, but what is also really good is that there are good summaries. In the event that you are very busy, you can easily identify what the recommendations should be for that particular patient based on these summaries. Brittany Harvey: Absolutely. Listeners are encouraged to review the full guideline, including those tables and figures that may be more helpful when they are looking for something quick to look at in the clinic as well. So, as you both mentioned, there have been a number of recent practice-changing trials in this area. So I imagine there is still a lot of ongoing research as well. So Dr. Shah, what are the outstanding questions regarding treatment options for patients with locally advanced unresectable, advanced, or metastatic gastroesophageal carcinoma? Dr. Manish Shah: I think we touched upon it a little bit. The guidelines are based on the data available, and they are primarily examining one novel therapy with chemotherapy in a specific biomarker population. But as you know, the biomarkers are not either/or; you are not either CLDN18.2 positive or PD-L1 positive. A portion of patients could have dual biomarkers, and you know, I think that we are generating data on how to manage those patients. At the recent GI Symposium in January this year, the ILUSTRO trial was presented by Dr. Shitara, which looked at combining zolbetuximab and chemotherapy with immunotherapy for dual-positive biomarkers, and that is leading to a phase III study that has begun to enroll. So unanswered questions are: how do we manage dual-positive biomarkers? The other thing that was mentioned is that the current data for mismatch repair deficiency involve chemotherapy plus immunotherapy. Only squamous cell cancer is there a study with a positive non-chemotherapy kind of backbone, that is CheckMate-648 that Dr. Rajdev mentioned. As we move forward, it will be good to get data on non-chemotherapy options in certain biomarker-positive populations. And then finally, another update, which is likely to be practice-changing, is the HERIZON-GEA-01 study that looked at zanidatamab, which is another biparatopic antibody that targets HER2, and that is likely to change practice. And as that data gets published, we may look to even do a rapid update for the current immunotherapy and targeted therapy guideline that is just being published. Dr. Lakshmi Rajdev: So, if I can add to that, there are numerous ADCs that look very interesting. There are bispecific antibodies; in fact, the zanidatamab is a bispecific antibody showing improved activity in patients with HER2-positive disease. So I think there are studies from Asia looking at CLDN CAR T-based therapies. So, I think that there are a lot of novel agents and a lot of excitement in the field. We know that the bemarituzumab study, unfortunately, the FGFR2 inhibitor failed to demonstrate any benefit, but I think that there are other agents that are being explored, so there are newer targets, newer agents, ADCs, bispecifics that could potentially change the field in the future. Brittany Harvey: Yes, we will look forward to the data to address these unanswered questions and new agents and inform future guideline updates. So, I would like to thank you both for all of your work to review the evidence here and update this important guideline, and for your time today, Dr. Rajdev and Dr. Shah. Dr. Lakshmi Rajdev: Thank you. Dr. Manish Shah: Thank you. Brittany Harvey: 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/gastrointestinal-cancer-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.

Dr. Bishal Gyawali and Dr. Tessa Cigler share the new, comprehensive, evidence-based update of the ASCO guideline on the use of hematopoietic colony-stimulating factors in patients with cancer. They discuss recommendations on primary prophylaxis, secondary prophylaxis, and treatment of febrile neutropenia along with stem cell mobilization, efficacy, safety, duration, dosing, and administration of CSFs – including biosimilars. They highlight where it is appropriate to use a CSF, and importantly, when not to use a CSF. They touch on the significance of individual patient considerations and cost implications, and future work to refine the risk factors for the development of complications of febrile neutropenia. Read the full guideline, "White Blood Cell Growth Factors: ASCO Guideline Update" at www.asco.org/supportive-care-guidelines TRANSCRIPT This guideline, clinical tools and resources are available at www.asco.org/supportive-care-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-25-02938     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'm interviewing Dr. Bishal Gyawali from Queen's University in Kingston, Ontario, Canada, and Dr. Tessa Cigler from Weill Cornell Medicine in New York, New York, co-chairs on "White Blood Cell Growth Factors: ASCO Guideline Update." Thank you for being here today, Dr. Gyawali and Dr. Cigler. Dr. Bishal Gyawali: Thank you very much for having me. It's a pleasure. Dr. Tessa Cigler: Hi there. Nice to be here as well. Brittany Harvey: Great. And then before we discuss this guideline, I'd 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. Cigler and Dr. Gyawali, 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 I'd like to dive into the guideline that we're here today to talk about. So first, what prompted an update to this guideline on the use of hematopoietic colony-stimulating factors in patients with cancer, and what is the scope of this updated guideline? Dr. Bishal Gyawali: The last version of the guidelines from ASCO on this topic was back in 2015, so it has been more than a decade since ASCO had a guideline on the use of G-CSF in patients with cancer receiving treatment. So it was due for an update because there has been a lot more evidence based on not necessarily new drugs, but evidence for proper timing of these agents and the duration of these agents, as well as there have been a lot of new biosimilars, and there are questions about are these biosimilars equivalent or how do we choose among these different options. One is that content of the evidence that has evolved over time in the last decade, but also I think the last time we had these guidelines, the ASCO guidelines were not incorporated to have those evidence GRADE tables. So the quality of the ASCO guidelines itself has evolved over the years, so we wanted to have a new version of the guideline that includes not only the new evidence, but also contains those evidence GRADE tables that will help to quantify the benefits. And so I think it was high time, and even more than that, the newer ASCO guidelines for any guideline, they also include considerations of cost, access, equity, and all these factors that were not included in the previous version of the guideline. So I think it's only natural that with time the guideline should also evolve. Dr. Tessa Cigler: I agree completely, and just as a framework, as we all know, neutropenia and its complications, including febrile neutropenia and infections, are still an important toxicity of many myelosuppressive chemotherapies. And these neutropenic complications do require prompt evaluation and treatment and often hospitalization, and we know that hematopoietic colony-stimulating factors, which I'm going to refer to as growth factors, can reduce the duration and severity of neutropenia and the risk of febrile neutropenia, so it remains an important topic in the practice of clinical oncology. Brittany Harvey: Absolutely. It's an important topic for both clinicians and for patients who are receiving treatment for their cancer. And as you said, there was a substantial amount of literature to review here and updating everything to be in line with the GRADE evidence rating system, so there was a lot of work that you both put into this. So then next, I'd like to review the key recommendations of this guideline by clinical question. So first, what factors did the expert panel identify that should influence the decision to administer primary prophylaxis of febrile neutropenia with a CSF? Dr. Bishal Gyawali: Yeah, so I think that constitutes one of the most important recommendations in our guidelines about primary prophylaxis with G-CSF. And this is important because not only it's about when to use it, it's also about when not to use it, as in the ASCO "Choosing Wisely" campaign has also made some recommendations about this. So our guideline recommendations are also aligned with that. So first of all, we recommend that primary prophylaxis with G-CSF is recommended when the risk of febrile neutropenia because of the chemotherapy regimen is equal to or more than 20% unless an alternative chemotherapy regimen with comparable efficacy and safety that does not need G-CSF is available. And the quality of evidence to make this recommendation is high, so we give a strong strength of recommendation for this. Having said that, even for patients where the risk of febrile neutropenia is not necessarily 20%, it's a little lower, but because of other patient-related factors, the patient is at a higher risk of complications from febrile neutropenia, such as age, comorbidities, and other factors, in such case primary prophylaxis with G-CSF should be offered. And we also make a recommendation that if G-CSF is not affordable or available, then antibiotic prophylaxis can also be offered, but the evidence quality for this is low, and the strength of recommendation is very conditional. A couple of things to highlight here would be that, I think Dr. Cigler can attest to that, we ran into lots of problems about finding the data for the evidence base to say what are the patient-related factors that actually make them at a higher risk of febrile neutropenia, you know, like how did that 20% benchmark come about? Why 20%? Or when we say even if it's less than 20%, if based on other comorbidities, if the risk is higher, we tried to dig into that evidence. For example, we're talking about our "Box 1" in the guideline, what is the evidence for each item we have included under that "Box 1"? And we tried to do a lot of search to find the evidence for that, and some of them do have strong evidence, and that will tie into our future research ideas as well. And some of them actually don't have such solid evidence too, so that was one of the reasons why we ran into lots of problems about how do we quantify whether someone is at a high risk of febrile neutropenia and where that 20% benchmark comes from. Dr. Tessa Cigler: And definitely, because there's not very clear data, our guidelines definitely leave room for physician discretion in all these situations. Brittany Harvey: Absolutely. I find that in a lot of these guidelines the key point is that there's a lot of shared decision-making with patients after talking through what risk factors they may have and what is best for them in their individual clinical scenario. So then moving on to secondary prophylaxis, what factors did the expert panel identify that should influence the decision to administer secondary prophylaxis of febrile neutropenia with a CSF? Dr. Tessa Cigler: So for patients who've already experienced a neutropenic complication from a previous cycle of chemotherapy, the question is which patients should then receive prophylactic G-CSF for subsequent cycles of chemotherapy. And without a lot of evidence again to guide us, the panel really felt strongly that secondary prophylaxis should be used when a treatment delay or when a reduced dose of chemotherapy would be thought to compromise cure rates or survival outcomes. We do note that in many situations, certainly a dose reduction or a delay would be a very reasonable alternative or an additional strategy to G-CSF administration. Dr. Bishal Gyawali: Yeah, I think it's more like if there is going to be compromise in outcomes without using G-CSF, as in if we can't maintain the dose intensity and that's going to lead to inferior outcomes, then we should. But if we can reduce the dose intensity and treatment frequency and still have the same outcomes, then I guess in simple words, we're just trying to say use it when it's absolutely needed, or you can also look into other alternatives that might not need G-CSF but you could maintain the same outcomes. Brittany Harvey: Understood. It's helpful to review those options for clinicians and showing that there's not just one way to address potential neutropenic complications for later cycles of chemotherapy. So then following those recommendations for prophylaxis, what does the expert panel recommend regarding CSFs for the treatment of febrile neutropenia? Dr. Bishal Gyawali: This is an important question because this ties strongly with the "Choosing Wisely" campaign. In other words, primary and secondary prophylaxis we talked about when CSF should be used; here we make a sort of negative recommendation in that we say when CSF should not be used, because this is where we see most overuse or overtreatment with G-CSF. So first, we say that we should not be using a CSF routinely simply because a patient has neutropenia. If they are afebrile but they only have neutropenia, we recommend against using CSF just to boost neutrophil counts; that's not a meaningful metric. Then the second recommendation we make is CSF should not be routinely used as an adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. So the first one was neutropenia, no fever, don't use it. The second one is okay, there is neutropenia and fever, but the treatment for that is use of antibiotic therapy, and so in such situations routinely we should not be using G-CSF just to boost the neutrophil count. And that is tied on to the third recommendation where if the patient has fever and neutropenia but is also at a very high risk for infection-related complications or who have other prognostic factors that we think will lead to poor outcomes for the patient, then in such situations, a CSF can be used as an adjunctive treatment. But we talk about the data in the manuscript, but the data show that the most that this will do is reduce the days of hospitalization by a couple of days. It actually does not have any data that it's going to improve the mortality rates. So as of now, we use the word "may be offered," it's not "should be offered," it's "may be offered" if there are other factors that we think will make the patient at the very poor risk of mortality outcomes, and the evidence quality here therefore is low and our strength of recommendation is conditional. And we also have a box that lists those items that we think might be associated with poor prognosis for the patients, but again the data for those, are they really hard evidence? No. And that is also tied with our future research recommendation that we should study more about these factors that might lead to these poor outcomes. Dr. Tessa Cigler: And again, allowing for discretion of the treating physician. Brittany Harvey: Absolutely. It's just as important to know when not to use CSFs routinely, and those risk factor boxes that you mentioned are available in the full manuscript along with the full list of recommendations, and our listeners can refer to that; a link will be in the show notes of the episode . Dr. Tessa Cigler: Just so you know, the panel, we really discussed those criteria a lot and agonized over them and gave you our best recommendations. Brittany Harvey: Definitely, and it sounds like there was varying degrees of evidence to support a lot of those risk factors, and so it's really important that the evidence supports those, but also there was expert consensus of the panel in reviewing each of those factors individually to come up with recommendations that can be applicable for all clinicians. Dr. Bishal Gyawali: If I may add, we're proud of our panel because I think our panel is quite inclusive of people representing different specialties within cancer care, as in we had radiation oncologist, we had infectious disease expert, pharmacists, and most importantly, we also had patient partners. Brittany Harvey: Absolutely. Having a multidisciplinary panel is really important for each and every guideline. So then, this is probably relevant now, but addressing a few more specific sections addressed in the guideline, what is the role of CSFs as adjuncts to progenitor cell transplantation? Dr. Tessa Sigler: Great question, and so, as solid tumor oncologists, Dr. Gyawali and I really leaned heavily on our hematology experts within the panel. The panel decided that a CSF should be used alone after chemotherapy or in combination with a CXCR4 inhibitor to mobilize peripheral blood progenitor cells. Clearly the choice of mobilization strategy depends on the type of cancer and the type of transplantation. The panel noted that a CSF should be routinely administered after autologous stem cell transplantation to reduce the risk of severe neutropenia, and that a CSF may be administered after allogeneic stem cell transplant to reduce the duration of severe neutropenia. Again, this last recommendation has not a lot of evidence to support it, and so we kind of tempered our language that it may be administered or can be considered based on clinical judgment of the physician and the clinical status of the patient. Brittany Harvey: And that really highlights the need for a multidisciplinary panel, because as you are solid tumor oncologists, you need the hematologists to make recommendations for all sorts of patients and make sure that these guidelines are comprehensive.   So then moving on to another smaller subset population, for patients receiving concomitant chemotherapy and radiation therapy, are CSFs recommended? Dr. Bishal Gyawali: I think there is very little evidence for patients who are receiving radiation therapy alone, so there is no evidence to suggest the use of CSF in patients with radiation therapy alone. The bigger question is in patients who are receiving both chemo and radiation together, chemoradiotherapy. In those patients, up until now, the classical recommendation has been to avoid G-CSF use. I think in our updated guidelines we discuss a couple newer trials that are trying to address this issue, but in the totality of evidence, we still stick with the same recommendation as before, which is CSFs are not recommended in patients receiving concomitant chemotherapy and radiation therapy, especially those involving the mediastinum because the biggest evidence of harm is for these patients. Dr. Tessa Cigler: I agree completely. Brittany Harvey: Definitely. It's important to recognize when that balance of benefits and harms leans more towards harms, and so that this should not be recommended for those patients. So there are several different CSFs that are recommended in the guideline, including biosimilars. So do the recommended CSFs differ in efficacy or safety? Dr. Tessa Cigler: So as supported by evidence, and the panel all agreed, that the various forms of CSFs, including the biosimilars, really have the same evidence for efficacy and for safety, and that the choice of agent really should depend on cost, availability, accessibility, patient convenience, and sometimes disease subtypes and treatment regimens. But, in essence, these can be used interchangeably without concern for efficacy or toxicity differences. Dr. Bishal Gyawali: I completely agree. I think in terms of efficacy outcomes, I don't think there is anything to choose between these agents. The choice between these agents would largely depend on different patient and treatment-related factors: cost, availability, affordability, feasibility. We even discuss things like where does the patient live, as in how frequently the patient can commit to the cancer center, and we also discussed things like even for the daily shots of filgrastim, patients can be taught and they can get it by themselves at home. So we discussed all these factors, but in a nutshell, the choice within these agents primarily depends not on efficacy factors, but simply based on all these other factors that are equally important but which can lead to informed decision-making about what is best for a given patient. But we mention it explicitly that the biosimilars, there is nothing to choose between them, especially the biosimilars; it's about price competition and what you can get at an affordable rate. Brittany Harvey: Understood. It's great to have many different options for patients so that there's something that can work for them based off access, cost, and all these factors that you listed. As you mentioned, it may be easier for some patients to get their treatment at home rather than in clinic, and so having different options and reviewing those with patients is very important. Dr. Bishal Gyawali: As we are having this conversation, I'm thinking that we might be a very unique guideline in that I don't think in many other settings you have this many options that you are asking about, you know, choices between equally good options and making decisions based on cost. I don't think there are any other areas in oncology where we have the privilege of making these decisions based on cost and convenience and all these factors, as well as we might be one of those guidelines where we have, as discussed before, so many recommendations about when not to do things and trying to promote judicial use of treatments. Dr. Tessa Cigler: As you might imagine, our panel discussions were very lively. Dr. Bishal Gyawali: Yes. But Dr. Cigler, do you recall any other guideline where there is so much discussion about when not to use things and how we have so many biosimilar options and we can choose the one that's most appropriate? I don't recall any other. Dr. Tessa Cigler: I agree with you. Brittany Harvey: It's certainly a unique guideline in that regard. So we'll move into the last clinical question that the expert panel addressed. But what does the expert panel recommend for the initiation, duration, dosing, and administration of CSFs? Dr. Bishal Gyawali: Yeah, I think there has been some new data in this regard that were not available in the previous guideline. For example, we have new trials testing a shorter duration of filgrastim injections compared to the standard of care. So we have some data, we call this 'de-escalation of treatment'. So we have more data supporting de-escalation of treatment. We have some data for lower dose of pegfilgrastim, we have data for lower duration of filgrastim, we have also some new data about timing of treatment, as in there has been some newer data presented about the relationship of timing of the drug and the frequency of adverse events from G-CSF such as bone pain. There is also the question about, for patients who don't live near the cancer center, can they get their pegfilgrastim shot on the day of chemo while they are in the cancer center? So all these questions that are very pragmatic and important questions, but were not answered before, we're glad that we had more evidence to talk about all these factors and give a more solid recommendation to our users of the guideline. Brittany Harvey: Definitely. And listeners can review the full list of dosing and administration recommendations in Table 2 in the guideline, and that will be linked in the show notes of the episode. So then I really want to thank you both for reviewing all of these recommendations. There's certainly a large amount of clinical questions and recommendations that you went through. I'd like to next ask, in your view, what is the importance of this updated guideline and how will it impact both clinicians and patients? Dr. Bishal Gyawali: I think the importance of this updated guideline is that, as mentioned before, we talk about newer data that have come up with regards to not just the most important two questions as in when to use it as primary prophylaxis and when to use it as secondary prophylaxis and when to use it as treatment, but also with regards to the duration and timing and dosing and multiple options and how these all factors as well as patient-related factors should be combined to make an informed decision, the most appropriate decision for the patient. And as mentioned before, we have the GRADE tables that were not in the previous version of this guideline. So I think even those users that are familiar with the 2015 guideline, I think they will find very novel content in this new updated guideline, and they will find it useful for their practice. I would encourage the readers to not only read the headlines of the box recommendations, but also read the full text of these guidelines because we have worked really hard to incorporate the latest evidence and also interpret them contextually. The discussion regarding de-escalation, patient considerations, cost implications; usually, people just skip these portions when they read a guideline. But I think these are also one of the most important paragraphs in our guideline, so they have been written with very careful thought, and I think reading the whole guideline is very much worth your time. Dr. Tessa Cigler: As you can imagine, I agree completely, having just spent several months thinking about these guidelines and all their nuances. Brittany Harvey: Certainly, this guideline is definitely a very comprehensive update, and that nuance in the manuscript is really important for clinicians to understand and read through and understand when it's appropriate to make certain decisions. So then to wrap us up, I'd like to ask, what are the outstanding questions and active research areas regarding the use of white blood cell growth factors in patients with cancer? Dr. Tessa Cigler: As you all know from clinical practice and that we've said several times already in this podcast is that the risk factors for the development of complications of febrile neutropenia are still not clearly worked out. And one of the things that is, I think, really needed in clinical practice is the development of predictive algorithms or biomarkers to really allow us to understand who might be more at risk and to allow for the clinician to be able to tailor the use of G-CSF as needed. Brittany Harvey: Yes, and so we'll look forward to future updates in this space to inform new recommendations and an updated guideline in the future. So I want to thank you both so much for your work to develop this comprehensive guideline. It was certainly a lot of effort, and thank you for your time today, Dr. Gyawali and Dr. Cigler. Dr. Tessa Cigler: Oh, my pleasure. It's nice to be here and to speak with you all. Dr. Bishal Gyawali: Yeah, it was great to speak with both of you but also through you to the audience, and we had a great time. Thank you. Brittany Harvey: And then 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/supportive-care-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've 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.

Listen to JCO's Art of Oncology article, "Mother's Grief" by Dr. Margaret Cupit-Link, who is an assistant professor of pediatric hematology/oncology at Cardinal Glennon Children's Hospital of St. Louis University. The article is followed by an interview with Cupit-Link and host Dr. Mikkael Sekeres. Dr Cupit-Link shares a pediatric oncologist's experience of a patient's death through the new lens of motherhood. TRANSCRIPT AOO 26E03 Narrator: Mother's Grief, by Margaret Cupit-Link, MD, MSCI  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 it is today to have joining us our third place Narrative Medicine Contest winner, Maggie Cupit-Link, an assistant professor of Pediatric Hematology Oncology at Cardinal Glennon Children's Hospital of St. Louis University to discuss her Journal of Clinical Oncology article, "Mother's Grief." Both Maggie and I have agreed to call each other by first names. Maggie, thank you for contributing to the Journal of Clinical Oncology and for joining us to discuss your winning article. Maggie Cupit-Link: Thank you so much for having me and for choosing my article. It's an honor to get to speak with this group. I know a lot of our listeners have a lot in common with us in our profession, so I'm excited to be here. Mikkael Sekeres: We're excited to have you. You are such a terrific writer. Tell us about yourself. Where are you from, and walk us through where you are at this stage of your career? Maggie Cupit-Link: I grew up in a small town in Mississippi called Brookhaven, and I ended up attending college in Memphis, Tennessee, which is important to note because I was a pre-med student when I got diagnosed with childhood cancer, Ewing sarcoma, at the age of 19. And so that really shaped my career goals. And I was treated at St. Jude Children's Research Hospital, which is very formative as well, given that I was surrounded by childhood cancer patients. I ended up doing my medical school at the Mayo Clinic Medical School in Minnesota, which was very cold for me but a wonderful experience. And then went to St. Louis to WashU, St. Louis Children's for my residency, and then back to Memphis for my fellowship at St. Jude. But now I'm back in St. Louis at the other hospital, Cardinal Glennon, which is affiliated with St. Louis University. And my husband's originally from St. Louis, so it was always a dream of his to be back here. And once I ended up here, I really have loved St. Louis as well. So this is home for us and our two babies who are ages one and two, and they are one year and one day apart exactly. Mikkael Sekeres: Oh my word. Well, you are definitely in the thick of it, aren't you? Maggie Cupit-Link: It's a very busy, chaotic life, but I'm very grateful. And so that makes it worth it. Mikkael Sekeres: That sounds fantastic. Well, I'm calling in from Miami today, so believe me, the thought of being in Rochester, Minnesota is not very appealing in mid-February. Maggie Cupit-Link: I believe that. I'm glad I'm not there right now. Mikkael Sekeres: Gee, I didn't know about your history of having cancer yourself. What was it like to return for fellowship at the place where you yourself were treated? Maggie Cupit-Link: That was an incredible experience for me. It was very emotional as well. I remember the first day of fellowship getting a tour and crying throughout the tour. More tears of joy, but it was, it was really surreal. It was really special. And I got to learn from some of the doctors who treated me, which made it really special as well. I'm really glad I got to train there and to be at a place with such a large volume of pediatric oncology patients was a really great learning experience. Mikkael Sekeres: I wonder, infrastructures, buildings change over a few years, particularly in medical centers. Was there ever a moment when you were talking to a patient who was sitting in the same chair where you were sitting when you were a patient? And was that something that you were open to sharing with people? Maggie Cupit-Link: All the time, on all accounts. Yes. The infrastructure has changed. It continues to grow significantly, but the clinic hadn't changed at that time. I think it will in the next couple of years. But the solid tumor clinic where I was treated was exactly the same. And there were many times where I took care of sarcoma patients and Ewing sarcoma patients who were teenagers as I had been in the very same rooms and times where I learned from my own oncologist as he was teaching me and training me. So it made it really special. It made empathy a big part of my experience. And I think it is for all of our experiences in oncology in particular, but I think that empathy has always been a huge part of my job and something that comes to me naturally, which is a gift. But as is sort of alluded to in my piece that we're discussing today, can be difficult at times. Empathy can also sometimes be a curse when it's hard to turn off, and that's been something as a mother now that I've really had to learn to cope with is like figuring out when my empathy might not serve me in moments and might not serve the patient in moments, and when it is an asset and a gift. Mikkael Sekeres: Empathy at the deepest possible level, having walked the same path your patients have walked as well. Really a remarkable story, Maggie. Maggie Cupit-Link: I'm very blessed to get to be alive and well, but especially to get to have a job that's so meaningful to me and hopefully can share my experience in a way that helps my patients. Mikkael Sekeres: And you share it through writing as well. When did you start writing narrative pieces? Maggie Cupit-Link: I started writing a lot when I was a cancer patient for more like a journal experience. And I had a CaringBridge page, which is one of these social media pages where families update their friends a lot on what's going on. And I started journaling daily, and then ended up publishing a book of my experience as a patient. I had also done a lot of writing of letters to my grandfather who's a retired professor of Christian philosophy because during my illness, I was really struggling with my faith and having a lot of questions as we all do when encountering children with cancer, "Why? Why God?" And so the book is actually called Why God? Suffering Through Cancer Into Faith, and it's a collection of narratives that I exchanged with my grandfather. And his part is more philosophical, and mine is more raw and emotional and expressive of the grief that I was feeling at the time as a patient. So that was the first big time I did narrative medicine, but I've found myself continuing to do so as a way to cope and process things that I go through. And the most recent one before the one we're discussing today was a piece about fertility that was published in JCO Cancer Stories and also I got to do the podcast for that piece. And that was about my experience losing fertility as a patient and how that has impacted what I tell patients about fertility and how I counsel them about possible fertility loss. And the plot twist there is that I actually have two miracle babies that I birthed for some reason after 13 years of menopause. So now I'm not infertile, but I'm very passionate about fertility as well. Mikkael Sekeres: Well, I remember that essay. I also remember how impactful that was to a lot of people who read it and how helpful it was. And gave a lot of people hope. Maggie Cupit-Link: I think hope is very, very important and necessary in the realm of cancer. Mikkael Sekeres: My word, you have so much that you could potentially share with your patients on their journey. Have you also been open to sharing your faith with them? Maggie Cupit-Link: Absolutely. I am. I think that it's something I'm really cautious not to push on anyone, but whenever patients bring up faith and want to talk about that or when they introduce that as a topic and make it clear that that's something that they are thinking about, then I'm definitely very open about that too. Mikkael Sekeres: Well, that must be a comfort to them. Maggie Cupit-Link: I hope so. It's a comfort to me as well. For me, I don't know how I would do this job and lose patients and children to death if I didn't believe in something more. Mikkael Sekeres: It's beautifully said. In this essay, you make a close connection to your patient and his mother when you write, "I imagined my own son contained in a hospital room, attached to an IV pole, vomiting from chemotherapy. I could feel the warmth of his skin against mine and the weight of his body on my chest. And as I looked back at Tristan's mother, I could only support her decision to hold her baby." What is the importance of this connection to patients, and are there any downsides? In other words, you know, in medical school, we're often taught to keep a distance, or there was an essay I wrote with Tim Gilligan, who's a GU oncologist and this incredible communicator, where we wonder if all the communication classes we're exposed to in medical school actually undo our natural communication and our natural connection because we figure, "Gee, if we have to take all these classes on communication, maybe we've got to communicate differently." What is the importance of this connection to patients, and are there any downsides? Like, should we keep a distance or not? Maggie Cupit-Link: I don't know if we should, but I know that I can't. This is my gift and my curse. I think that taking care of someone with a sick baby, especially as a parent, is so human and so full of emotion that it's not possible for me not to feel that connection. Now, I do think there's a point at which I have to be careful that what I'm doing and what I'm expressing doesn't make it harder for them. I think it's important for them to know that I feel for them and that I am having these feelings, but I don't want it to become about me when I'm trying to help them. So I once in one of these medical school situations was told that the moment the family begins to comfort me might be a moment that I've known I've gone too far. And so I think that's a rule of thumb I think about is like, if I'm crying in this moment with this family, does that make them feel loved, or does that make them feel like they need to worry about me? And I think most of the time it just makes them feel loved, but that's sort of the tension there. I think when it comes to me too, I've been unable so far to put up boundaries to protect myself emotionally. I don't know that I'm capable of that, but more importantly, I don't think that's authentic for me. And so I don't do that. I'm trying to process and grieve so that I can cope and continue to be the doctor and person that I am. But I refuse to put up emotional walls because I don't think that will serve the patient or be authentic to who I am as a person. Mikkael Sekeres: You bring up a couple of really important notions, and the first is authenticity, being true to ourselves. And if we're not true to ourselves, our patients will see through that and wonder if we're not being true to them. And also having our antennae up to get the pulse of the room, to see how people are reacting to what we're doing and making sure that we're serving our patient's needs more than we're serving our own needs when we're actually in the clinic room with our patients. Maggie Cupit-Link: Definitely, I agree. And and those scenarios in medical school, I remember just thinking to myself that it didn't make a lot of sense to me and that I was lucky that this class wasn't meant for me, that I'll just do what I feel is appropriate. And I always did really well in the simulations, but I had no way to articulate why I knew what to do. It just, for me, I was so lucky that part came naturally, and I think it does in many of us who find medicine as a calling. But I don't know how to teach or learn that. Mikkael Sekeres: Well, you've seen it from the other side as well. I mean, you strike me as being a naturally empathic person and someone who's tuned into other people's emotions. But you've also been there. You're more tuned in than I am, having been someone who's had cancer. I've certainly had close family members who've had cancer, my mom has lung cancer, for example. So I've been in the role of somebody in the room who's supporting somebody with cancer, but I haven't myself had cancer the way you have. Maggie Cupit-Link: It definitely impacts my empathy. And I think that I was surprised after becoming a mother how much that also changed things for me and impacted my empathy further. Until you're a parent, you really don't know the depth and intensity of your love for a child or a person. And it was only then that I realized how heartbreaking it might be to lose a child. It's very difficult to suppress that empathy. And that's when it might not be helpful sometimes is when I'm leaving work and thinking about someone who lost their baby and knowing that no matter how much I empathize with them, it's not going to fix it. It's been the first time in my career and maybe my life where I've had to tell myself that maybe it's okay not to have empathy in this moment. Like, maybe I should turn it off for a little bit so that I can relax and enjoy my baby. Mikkael Sekeres: My God, it's such an interesting perspective. I think as oncologists, we have this different perspective on illness and, and if we're smart about it, if we're really focused and in the moment, we appreciate the aspects of life and realize how precious they can be. And that can be a lovely thing and something we pass on to our kids. I will tell you, my own children have accused me of brushing off some of their maladies with the refrain, "Well, it may hurt you, but it's not leukemia." Maggie Cupit-Link: I've heard that's common with physician's children, but it takes a lot to get a rise out of the parent. Mikkael Sekeres: You write at one point in the essay, "At first, I believed that I had no right to grieve in this way, that it was his mother's grief, Tristan's mother, not mine. I reminded myself that I was not Tristan's mother. I did not give birth to him or name him." Now, we recently published an essay about grieving called "Are You Bereaved?" by Trisha Paul, where she also wonders whether we as oncologists have a right to grieve. What do you think? Do we? Maggie Cupit-Link: I have to note that Trisha and I were co-fellows together in our training, so I'm happy that you mentioned her. And I need to go read that essay. I haven't read that one, so I will. It's weird to wonder if we have the right to grieve. My grandmother is a psychologist, and I remember as a child saying like, "I know I shouldn't feel this way, but" about some random thing. And I remember her saying, "Feelings aren't 'should'. Feelings just 'are'." So like, maybe it doesn't matter if we should or shouldn't, but if we are grieving, we're grieving. I think in some ways it feels like I don't have the right to grieve because I have this wonderful, happy life. And this can be true of survivorship as well when I'm taking care of many children who won't get to be survivors, especially because I care for a lot of sarcoma patients. But I often wonder like, "Am I allowed to be this happy," or "am I allowed to not be happy because there's so much grief in their lives?" So it's hard. I feel this tension often like, I'm not allowed to grieve as much as this mom, but also I better be really, really happy because I'm okay and my baby's okay. It's hard when we compare our emotions to other people's who are going through different things. But it, but it's hard not to wonder, like, "Am I allowed to feel this way?" "Am I supposed to feel this way?" For me, that's when writing is helpful. Just writing down what I feel in great detail helps me move through the feelings, I guess. Mikkael Sekeres: Part of the processing of it. You described the code call for your patient vividly. You know, you draw us as readers into your essay and into that moment. We've all been in that moment. I remember when I was just talking to somebody about when I was in the intensive care unit, when I was a resident, and how at that time, a psychiatrist actually met with us every week to help us process what we were seeing in the intensive care unit, which was really remarkably forward thinking for how long ago I trained. Maggie Cupit-Link: That's really great. Mikkael Sekeres: How did you process it in real time and afterwards though? Maggie Cupit-Link: That day, even now, an aspect of me was dreading this conversation because I feel nauseated when I think back to that day, to that code, and I feel like I'm going to cry. And I don't feel like that in every code, but I think it was because of the parallels between the little boy and my baby. To note, my baby, Houston, he is a big, bald, fat faced baby with a binky in his mouth at all times, and Tristan was a fat, bald baby with a binky in his mouth at all times. And so even though there was a bit of an age difference, when I saw Tristan, I just thought of Houston, and I couldn't separate that. I feel often when I'm doing a lumbar puncture or running a code in real time on a patient, I can sort of dehumanize to the degree that's helpful where I just do what needs to be done and put aside the ick feelings. But with that child, in that code, I couldn't. And luckily I didn't have to do anything but stand there and tell them when to stop or just be supportive, but I felt sick. I felt like I couldn't do anything to help. I didn't feel like a doctor in that moment. I felt like a family member of that child. And that was really difficult. I was so lucky, and I don't know how much the piece reflects this, but the other doctor who was there, the other oncologist, is a mentor of mine who's older than me and wiser than me and very experienced. And I call her my 'work mom' lovingly. She was there, and she stepped in and helped me and checked on me and made me feel like I could handle things. It would have been much worse without her there. Mikkael Sekeres: We're fortunate when we do have our friends and colleagues to help process this because if you're not in this field, at that moment it's hard to understand just how deeply we can also feel the pain that our patients are going through. Maggie Cupit-Link: Absolutely. Mikkael Sekeres: And I do hope you'll retain that description of Houston for when you give the speech at his wedding because I'm sure he'd appreciate that. Maggie Cupit-Link: The big fat bald binky baby. Yes. Houston is now in his 'mama phase' where if I'm not holding him at all times, he fake cries, "Mama," until I do pick him up. So it's been exhausting physically, but I must pick him up. Mikkael Sekeres: I have to say it has been such a pleasure having you, Maggie Cupit-Link, join us to discuss your essay, "Mother's Grief." Thank you so much for submitting your article and for joining us today. Maggie Cupit-Link: Thank you so much for having me, and thank you for everyone for reading. 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 JCO's 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 Margaret Cupit-Link is an assistant professor of pediatric hematology/oncology at Cardinal Glennon Children's Hospital of St. Louis University.   Additional Reading:  It Mattered Later Why, God?: Suffering Through Cancer into Faith, by Margaret Carlisle Cupit, et al

Today, in honor of Black History Month, we're exploring what happens when inequity itself becomes a risk factor for breast cancer in the Black community — shaping who gets screened, how quickly they're diagnosed and, ultimately, who survives. Our guest, Dr. Lori Pierce, is a renowned radiation oncologist, former ASCO president and Komen Scholar, and national leader in advancing equity in cancer care. She has dedicated her career to improving outcomes of women with breast cancer, with a focus on the underserved, by transforming not just treatments but the systems that deliver them. Her perspective is rigorous, compassionate and urgently needed.

In this episode of JCO Article Insights, host Dr. Melis Canturk summarizes the article, "Phase 2 Trial of Ribociclib plus Letrozole in Women with Recurrent Low-Grade Serous Cancer of the Ovary, Fallopian Tube, or Peritoneum: A GOG Partners Trial," by Slomovitz et al.  TRANSCRIPT Melis Canturk: Hello, and welcome to JCO Article Insights. I'm your host, Melis Canturk, and today we will be discussing the JCO article, "Phase 2 Trial of Ribociclib plus Letrozole in Women with Recurrent Low-Grade Serous Cancer of the Ovary, Fallopian Tube, or Peritoneum: A GOG Partners Trial." Building on the fact that more than 95% of low-grade serous carcinoma are estrogen receptor positive and often exhibit abnormalities in the CDK4/6 signaling pathway, researchers launched the GOG 3026 trial. This study investigated the effectiveness of pairing the CDK4/6 inhibitor ribociclib with letrozole, an aromatase inhibitor, adapting a therapeutic approach that has already transformed the treatment landscape for hormone receptor-positive metastatic breast cancer. Low-grade serous ovarian cancer is a rare malignancy characterized by its hormonally driven nature and relative resistance to traditional platinum-based chemotherapy. While it's associated with longer survival than high-grade serous carcinoma, recurrent disease presents a significant clinical challenge due to low response rates to standard treatments. The GOG 3026 trial was an open-label, single-arm, multicenter, phase 2 study that enrolled 51 women with measurable, recurrent, low-grade serous ovarian cancer. To ensure diagnostic accuracy, all cases underwent central pathology review. Participants were required to be at least 18 years old with an ECOG performance status of 0 to 2. While there was no limit on the number of prior therapies, patients were excluded if they had previously used CDK4/6 inhibitors. Prior endocrine therapy was permitted only if the patient had discontinued it at least 6 months before the study and had not experienced disease progression while on that specific therapy. Additionally, women with intact ovarian function were required to undergo ovarian suppression. The treatment regimen consisted of 600 mg of oral ribociclib daily for the first 21 days of a 28-day cycle, paired with a continuous daily dose of 2.5 mg of letrozole. The trial's primary endpoint was the investigator-assessed objective response rate. The results were clinically meaningful. The confirmed overall response rate was 30.6%, which included one complete response and 14 partial responses. The clinical benefit rate, which includes stable disease, reached 84%. These outcomes are particularly notable given the heavily pretreated study population, where nearly 40% of patients had received three or more prior lines of systemic therapy. Durability and survival data further underscored the potential of this combination. Among those who responded to treatment, the median duration of response was 21.2 months. The median progression-free survival was 14.5 months, and the median overall survival reached 44.5 months. In terms of safety, the profile was consistent with previous CDK4/6 inhibitor studies. The most common grade 3 and 4 adverse event was neutropenia, occurring in 47% of patients. However, it was asymptomatic and managed through dose modification. Only 4% of patients discontinued the trial due to adverse events, and no dose-limiting toxicities were observed. When comparing these results to other therapeutic benchmarks, the ribociclib-letrozole combination demonstrated more favorable outcomes than historical endocrine monotherapy. It yields response rates of only 13% to 14%. Furthermore, while MEK inhibitors like trametinib or the combination of avutometinib defactinib show similar response rates, the ribociclib-letrozole regimen displayed significantly better tolerability. Specifically, only 4% of patients in this trial discontinued the therapy due to adverse events, compared to much higher discontinuation rates seen with MEK inhibitor strategies. In conclusion, the GOG 3026 trial successfully establishes ribociclib plus letrozole as a clinically active and well-tolerated regimen for recurrent low-grade serous ovarian cancer. By achieving durable disease control in a heavily pretreated, relatively chemoresistant population, this combination may redefine the therapeutic paradigm for this rare cancer. These findings support the continued evaluation of CDK4/6 endocrine strategies as a preferred chemotherapy-sparing option that prioritizes both disease control and patients' quality of life. Thank you for tuning into JCO Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future 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.  

In this episode of JCO Article Insights, host Dr. Melis Canturk summarizes the article, "Atezolizumab With Bevacizumab and Nonplatinum Chemotherapy for Recurrent Ovarian Cancer: Final Results From the Placebo-Controlled AGO-OVAR 2.29/ENGOT-ov34 Phase III Trial," by Harter et al. TRANSCRIPT Melis Canturk: Hello, and welcome to the JCO Article Insight. I'm your host, Melis Canturk, and today we will be discussing the JCO article, "Atezolizumab With Bevacizumab and Nonplatinum Chemotherapy for Recurrent Ovarian Cancer: Final Results From the Placebo-Controlled AGO-OVAR 2.29/ENGOT-ov34 Phase III Trial." While integrating immune checkpoint inhibitors has revolutionized the treatment of various gynecologic cancers, these agents have historically shown limited single agent activity in ovarian cancer. Despite a strong biological rationale for combining immunotherapy with chemotherapy and bevacizumab to enhance T-cell infiltration and normalized tumor vasculature, several phase III trials have failed to demonstrate a significant survival benefit in this setting. The AGO-OVAR 2.29/ENGOT-ov34 trial was launched to definitely evaluate whether adding the PD-L1 inhibitor atezolizumab to this combination could improve long-term outcomes for patients experiencing early relapse. This international, double-blind, randomized phase III trial enrolled 574 patients with epithelial ovarian, fallopian tube, or peritoneal cancer. Eligible participants had to be in their first or second relapse within 6 months of completing platinum therapy or in their third relapse regardless of the treatment-free interval. All patients received bevacizumab and an investigator selected chemotherapy backbone, either paclitaxel or doxorubicin. They were randomly assigned to receive either 840 mg of atezolizumab or a placebo every 2 weeks until disease progression or for a maximum of 2 years. The study population was an all-comer group, though patients were stratified by their PD-L1 status, previous bevacizumab use, and the number of prior treatment lines. The trial did not meet its primary end points, as the addition of atezolizumab failed to significantly improve overall survival or progression-free survival in the intention-to-treat population. For the primary end point of overall survival, the median was 14.2 months with atezolizumab compared to 13 months with the placebo. Progression-free survival was similarly insignificant, with a median of 6.4 months in the experimental arm versus 6.7 months in the control arm. Furthermore, the objective response rates were nearly identical between the groups, recorded at 40% for atezolizumab and 44% for the placebo. Interestingly, exploratory subgroup analyses revealed potential signals of benefit in specific populations, even though the overall trial was negative. Patients who had been previously treated with bevacizumab appeared to derive a greater benefit from the addition of atezolizumab than those who were bevacizumab-naïve. Additionally, outcomes seemed more favorable for patients receiving a paclitaxel chemotherapy backbone compared to those receiving doxorubicin. However, PD-L1 status did not appear to be a predictive marker for success, as hazard ratios for survival were similar regardless of whether the tumor was PD-L1 positive or negative. The safety profile of the triple combination was consistent with the known toxicities of the individual drugs. Grade 3 or higher adverse events occurred in 73% of the atezolizumab group and 70% of the placebo group. While the experimental arm saw higher incidences of immune-mediated events, such as thyroid-related issues, these were generally manageable. Serious adverse events were more frequent in the atezolizumab arm than in the placebo arm, but discontinuation rates due to toxicity were relatively low and comparable between the two groups. In conclusion, the AGO-OVAR 2.29 trial confirms that adding atezolizumab to bevacizumab and nonplatinum chemotherapy does not provide a statistically significant survival advantage for patients who receive nonplatinum chemotherapy for recurrent ovarian cancer. This study contributes to the growing body of evidence showing that immune checkpoint inhibitors have yet to find a definitive role in the standard treatment of recurrent ovarian cancer. Future research will likely focus on more sophisticated molecular stratification and the use of novel agents, such as bispecific antibodies, to overcome the challenging tumor microenvironment of low-grade serous ovarian cancer. Thank you for tuning into JCO Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future 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.  

Dr. Monty Pal and Dr. Ari Rosenberg discuss the evolution of treatment strategies in head and neck cancers, including the challenges of treating both HPV-positive and HPV-negative disease and the emergence of blood-based biomarkers to advance personalized therapy across different subtypes. 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, professor, and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles. Today, we're going to explore the evolving landscape of treatment strategies in head and neck cancer management, including locoregionally advanced head and neck squamous cell carcinoma, which happens to be on the rise in United States, in part due to spike in HPV-mediated oropharyngeal cancers. We're also going to discuss the emerging strategies of using blood-based biomarkers to really advance personalized therapy. Joining me for this discussion is Dr. Ari Rosenberg. He's a medical oncologist focused on head and neck cancer, and he's an associate professor – congratulations on the recent promotion – at the University of Chicago. The University of Chicago has really produced luminaries in this field, Dr. Rosenberg included. I've had the pleasure of getting to know Dr. Ezra Cohen over the years, who really had his grounding there, and of course Everett Vokes, former ASCO President. I'm really looking forward to this conversation, Ari. Thanks so much for joining us. Dr. Ari Rosenberg: Thanks, Monty. Thanks for the invitation. Dr. Monty Pal: You got it. And just a quick note for our listeners, our full disclosures are going to be in the transcript at the end of this episode. So let's start with the basics, if you don't mind. So, head and neck cancers are very diverse and they're challenging, right? In the sense that they're near vital organs, the treatments, you know, as we all saw during fellowship, if not now in clinical practice. They can really have such a major impact on vital organ function, speech, swallowing, et cetera. Can you just comment on head and neck cancers that are on the rise in the U.S.? I alluded to this briefly. Particularly, we've heard this in the context of colorectal cancer and so forth. Are you actually seeing younger adults being affected by this? Dr. Ari Rosenberg: Yeah, thanks for that. The vast majority of head and neck cancers are head and neck squamous cell carcinomas, as I'm sure many of the listeners recall as well from fellowship or their current training. And as you alluded to, the organ function, long-term and functional quality of life outcomes are quite important, particularly in the context that these develop in high value real estate, parts of our head and neck area that we use for speaking, swallowing, all sorts of other essential functions as well. As you also alluded to, we think of this in two different particular subtypes of head and neck cancer. The historical head and neck cancer from 50, 60 years ago was almost exclusively related to carcinogen exposure, tobacco, alcohol use, and that subtype of carcinogen-induced head and neck cancer has been slowly declining. However, over the last now several decades, we've been seeing an increase in primary oropharyngeal squamous cell carcinoma, mostly tonsil, base of tongue. These are attributable to HPV, human papillomavirus exposure. And that's now the majority of the head and neck cancers that we tend to see in our clinic. As you also alluded to, these have very different prognoses as well. HPV-related head and neck cancer has a much more favorable prognosis where much of the interest has been in can we de-intensify to optimize long-term function? But then the non-HPV-related head and neck cancer, or what we call HPV-negative head and neck cancer, continue to be very, very challenging. We only managed to cure about half of these folks, with many of these patients developing the current disease. These patients, in addition to being difficult to treat, also have major impacts both in terms of the treatments they undergo as well as their disease that can impact their function and quality of life. And you hinted at this a little bit, but we have been seeing an increase in younger patients with HPV-negative head and neck cancer as well, which is quite concerning. Younger patients, oftentimes never smokers, never drinkers, who are developing non-HPV-negative head and neck cancer. And that's been a little bit of a more recent trend that we've been seeing as well. So, definitely a lot of work to be done to optimize and improve outcomes across all of these different head and neck cancer subtypes. Dr. Monty Pal: I mean, I'm just curious, you know, in the context of colorectal cancer, one of the things that we talk about is the potential role of the microbiome driving some of these young-onset cancers with, you know, perhaps there being an impact on, for instance, inflammation and the gut and what have you. Tell me about head and neck cancer. Is this anything known as to why younger patients might be getting diagnosed with non-HPV type cancers? It's odd to me. Dr. Ari Rosenberg: Yeah, it's a great question. A lot of people are working on it. I think we folks have hypotheses, but it hasn't totally panned out exactly what's going on there. It does have a little bit more of a tendency towards women, whereas historically head and neck cancer is much more common in men than it is in women. But lots of people working on that, whether it's related to chronic inflammation, whether it's related to the microbiome. Whether it's related to dental exposure, dental work. So, a lot of folks trying to parse that out because I agree with you, it needs to be identified alongside improving treatment paradigms for these patients, the young ones and the older patients as well. Dr. Monty Pal: Interesting, interesting. You know, one of the phenomena that was sort of coming around when I was in training 25 years ago was this role of sort of induction therapy for head and neck cancers. And of course, it's really come full circle now to include checkpoint inhibitors and so forth. Tell me a little bit about this and how you apply it, maybe in an HPV-mediated context, maybe in a non-HPV context. Dr. Ari Rosenberg: Yeah, absolutely. Induction chemotherapy, as you alluded to, or neoadjuvant chemotherapy, depending on what the locoregional treatment approach is. Similar to other cancer types where systemic control early on has many potential advantages in this setting. Now, in head and neck cancer, even though induction chemotherapy is quite active in head and neck cancer, both HPV-positive and HPV-negative with pretty good response rates. A survival advantage for all comers with local regionally advanced disease remains unproven. There's been two randomized trials, both underpowered, but essentially did not show a survival advantage, showing that induction chemotherapy for all patients with locoregionally advanced and neck cancer can't be justified for a survival advantage. That being said though, there remains a number of potential advantages of giving induction or neoadjuvant chemotherapy, of course, improving systemic control and debulking the disease early on has potential advantages, and predicting the responsiveness to subsequent radiation treatment. We know for some time in head and neck cancer that the percentage of shrinkage or the response to induction chemotherapy actually predicts outcome related to radiation as a dynamic biomarker where response can be used to select patients, for example, for de-escalated radiation has been an area of active investigation, active research. And it also remains a key opportunity to evaluate predictive biomarkers and understanding pre and post treatment to better understand the biology. I'll just add to your question that recently over this past year, we also saw phase 3 data for neoadjuvant immunotherapy for a subset of head and neck cancer that is surgically resectable. And so that's reintroducing the potential benefit in the immunotherapy era of incorporating immunotherapy in the neoadjuvant or the induction setting as part of the evolving treatment paradigm for these diseases. Dr. Monty Pal: That's really interesting. And you kind of alluded to already several topics that I plan to hit on, you know, for instance, the role of immune checkpoint inhibitors, induction, chemotherapy, and so forth. And you started to touch on biomarkers. And of course, I think that's something near and dear to many of us in academic oncology. One thing that we've started talking a lot about in the context of colorectal cancer is circulating tumor DNA. How do you think this might fit in the context of head and neck cancer? Can you give us a flavor for that? Dr. Ari Rosenberg: Yeah, absolutely. In head and neck cancer, the current landscape is most developed for circulating tumor DNA for HPV-related head and neck cancer. The advantage of HPV-related head neck cancer is that you have a distinctive HPV DNA that does tend to spill out into the peripheral blood and can be detected using various different blood-based assays. And because of that advantage as a tissue agnostic approach, it turns out that a number of HPV DNA plasma assays are actually quite sensitive and quite specific. And a number of them have indeed been commercialized. Of course, not only for detecting a baseline, but also grading responsiveness during treatment and probably most importantly in the post-treatment surveillance setting, the detection of HPV DNA in the plasma remains a very important and substantial predictor of developing recurrent disease. There's been a number of trials that have been emerging looking at ctDNA and HPV-related head and neck cancer, using it, for example, as a strategy to deescalate patients. That was something we saw this past ASCO from the Dana-Farber group, and also using it to early detect recurrence and potentially intervene earlier for patients with minimal residual disease positivity. So, that remains evolving and as many folks are, I think, already using it in the clinic. But ctDNA also has a lot of potential for HPV-negative head and neck cancer. This is actually a bit more challenging to develop because you don't have that HPV DNA that you can track predictably because the tumor is an HPV- negative disease are much more heterogeneous, but there are a number of data that are coming out both for personalized assays such as Signatera or some of the other assays that require tumor. Unlike colon cancer, which you referenced, where most patients get surgery upfront, in head and neck cancer, many of the patients receive non-surgical pre-chemoradiation. So sometimes the amount of tumor available to generate a personalized assay is more limited and can be one of the challenges that we see in head neck cancer. But certainly that also seems to be emerging. And there's also further assays that are being developed for HPV-negative head neck cancers, such as methylomic signatures and others that may be tissue informed or tissue agnostic. And these are also emerging, particularly in the post-treatment surveillance setting as strong predictors of recurrent disease. So while we're certainly behind some of these other more common tumor types, colon cancer, lung cancer, we're right there with them and more and more trials are going report out, including a number of trials in our upcoming [University of Chicago] Head and Neck Cancer Symposium where I'll be presenting some data and others in the field will be presenting some data looking at ctDNA both for HPV-positive and for HPV- negative to try to improve outcomes for these patients. Dr. Monty Pal: That's so interesting. I've got to tell you that in kidney cancer, what I deal with day to day is a very low shedding disease, right? So techniques as opposed to ctDNA looking for tumor-informed information, that might be less preferred to something like methylomics where you might not necessarily be so contingent on what's happening in the primary tumor. I'm really interested in you mentioning that. Just a point of clarification, this is something I'm trying to wrap my head around. You'd mentioned circulating tumor HPV DNA, right? I assume this is markedly different from just looking for HPV titers in the patient, right? So is this actually incorporated elements of HPV within, you know, essentially host genome, if you will? Dr. Ari Rosenberg: Yeah, correct. This is circulating tumor HPV DNA. And we think of it biologically as a plasma-based tumor DNA biomarker that's specific for HPV-related head and neck cancers. Dr. Monty Pal: Got it, got it. It makes me wonder whether or not this might be applicable to diseases like cervical cancer and so forth where there's also extensively, you know, biology driven by HPV. Is that fair? Dr. Ari Rosenberg: Yes, definitely. And in the head and neck cancer field, much of this ctDNA actually was derived from a different viral mediated head neck cancer, is less common in the U.S., but nasopharyngeal cancer, which is oftentimes associated with EBV. That has been a biomarker for quite some time in nasopharyngeal cancer. Of course, in places where EBV-associated nasopharyngeal cancer, is endemic, such as East Asia, this has been around for quite some time, but we've been using that in the U.S., and there's been trials that have used EBV DNA plasma to predict recurrence and stratify for adjuvant treatment, for example. And so now with HPV, it's much more applicable to our US population because the vast majority of our head and neck cancer patients that we see in the US that are viral mediated in the US tend to be HPV-related. So having assays that we can use to improve outcomes for that biological subset remains of particular interest for us. Dr. Monty Pal: Yeah, that's fascinating. By the way, for the fellows listening, there's tons of boards pearls here that Dr. Rosenberg shared, EBV-associated cancers, the role of HPV and treatment association. So if you're recertifying anytime soon, I definitely think there's notes to take from this conversation indeed. I wanted to shift gears a little bit. And obviously, you're a prolific researcher. I don't think anyone goes through their fellowship in medical oncology without recounting these experiences of our head and neck patients really suffering from treatment-related toxicities. It's a real challenge. And I'm just wondering, I know a big body of work that you're focused on is really using multimodality treatment paradigms to perhaps reduce the cumulative treatment burden of patients with head and neck cancers. Can you talk about that a little bit? Dr. Ari Rosenberg: Yeah, definitely. Thanks for the question. And before I start going into some of the strategies, I'll just say that head and neck cancer, this is particularly for the fellows that are listening as well, just in reference to your prior comment, that this is really a multidisciplinary disease. At our center, all head and neck cancer patients are seen upfront at that first visit by all three specialties, med onc, rad onc, and surgery, because the choice and sequencing of modalities to optimize not only survival, but also functional quality of life outcome is so critical. And I think that's probably the biggest takeaway for anyone who treats a lot of head and neck cancer or will be treating a lot of head and neck cancer in the clinic. But in terms of more specific attempts at trying to optimize some of those parameters that you described, we really think about these separately in terms of HPV-positive and HPV-negative head and neck cancer. For HPV-positive head and neck cancer, the cure rates are quite high with chemo radiation, although not for everyone. There's still about 15, 10 to 15 % of folks that will develop a recurrence. But for the vast majority of patients, standard chemoradiation is quite a cure to therapy, but the toxicity associated with that can be quite substantial. And so there's been a number of attempts to try to deescalate treatment. It turns out that deescalating everyone with locoregionally advanced HPV-positive head and neck cancer is not a good strategy because it's not able to select out the patients that really do need full dose treatment. And we have seen some negative trials that show inferior outcomes when everyone is deescalated. But what does remain promising is again, trying to select out who the best candidates are for deescalated treatment. The folks at MSK have hypoxia imaging that they're using in trials that looks quite promising to select for the more favorable deescalatable biology. At our center, we've been interested in using induction chemotherapy to stratify response and select patients for deescalated treatment with excellent survival outcomes and reduce toxicity with deescalated treatment. And more recently, ctDNA that us and other groups, such as the Dana-Farber group, is using. And that also looks quite promising. Again, how do you select the patient who will do well with less radiation versus the ones that really need the full doses and volumes of radiation? And then for HPV-negative head and neck cancer, this is a much trickier disease because already the survival outcomes are not like we want it to be. Trying to figure out how to improve survival outcomes remains an important thing. Using immunotherapy seems to be one of the key cornerstones to that. But these are patients that also suffer from a lot of toxicity related to their treatment. We completed a trial not too long ago that we published this past year where we, in HPV-negative head and neck cancer patients, de-intensified the radiation for responders to neoadjuvant chemoimmunotherapy. And those patients did similar, if not even a little bit better, than the non-responders who got full dose treatment. So something that does warrant further investigation as well. How do we not only improve survival for those patients, but also reduce some of the long-term toxicities? Dr. Monty Pal: This is brilliant. I'm taking so many notes as you were mentioning these items. There are so many areas where I think the research crosses over. I already mentioned, know, ctDNA, for instance, and metabolomics and the places where that might apply to kidney cancer. The hypoxia imaging really caught my ear too. Obviously, kidney cancer is disease highly predicated on hypoxia. So thank you for all of this. We've got about a minute or so. So, I'm going to ask you for a really tall task here. Can you tell us what you foresee being some of the biggest challenges that sort of lie ahead and head and neck cancer. You've already kind of alluded to it with ongoing research, but if you had to pick maybe 2, 3 problems, the very most that we really need to get to and head and neck cancer, what would that be? Dr. Ari Rosenberg: Yeah, that's a great question. Obviously, lots of things to be done, but if I'm going to limit it to just a couple, I would say number one is really trying to improve the survival for HPV negative local regionally advanced head and neck cancer. We talked early on about how we are seeing, you know, of course we see many of these people that were smokers and drinkers, but also seeing these in younger patients, in patients without a history of tobacco use. Some of these are very biologically aggressive and we need better treatments beyond surgery, beyond chemo radiation, beyond immunotherapy to improve outcomes for these patients and cure more of them. So, I would say that's one big area. And the other is, which we didn't speak about so much in this talk, but remains one of the biggest challenges that we see in the clinic is the recurrent metastatic head and neck cancer patients. This is an incredibly challenging disease to treat, not only with poor survival, but also with substantial impacts on quality of life and function. mean, these are bad recurrences that cause a lot of pain, functional deficits, really impacts quality of life as well. So developing novel therapies, many of which are currently in clinical trials and many of which are currently continuing to be developed, remains so critical. How do we develop better systemic therapies, better targeted therapies, better biomarkers for recurrent metastatic head neck cancer to improve their survival and quality of life and functional outcomes. Those are the two big areas that require the most work at this time within the head and neck cancer field. Dr. Monty Pal: That's brilliant. I mean, I have to tell you I could probably talk to you all day about this, such a fascinating topic. It's a very exciting time in the field. Thank you, Dr. Rosenberg, for all your incredible contributions and thanks for sharing with us your insights on the ASCO Daily News Podcast. Dr. Ari Rosenberg: Yeah, and thanks for the introduction. Hope to do it again soon. Dr. Monty Pal: And many thanks to our listeners for your time today. If you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. More on today's speakers:      Dr. Monty Pal   @montypal  Dr. Ari Rosenberg @AriRosenbergMD 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. Ari Rosenberg:     Stock and Other Ownership Interests: Privo Technologies Consulting or Advisory Role: Nanobiotix, EMD Serono, Vaccitech, Novartis, Eisai, Astellas Pharma, Regeneron, RAPT Therapeutics, Geovax Labs, Janssen, Summit Therapeutics Speakers' Bureau: Coherus Biosciences Research Funding (Inst.): Hookipa Biotech, EMD Serono, Purple Biotech, Bristol-Myers Squibb/Celgene, BeiGene, Abbvie, Astellas Pharma, Pfizer, Janux Therapeutics

JCO PO author Dr. Foldi at UPMC Hillman Cancer Center and University of Pittsburgh School of Medicine shares insights into the JCO PO article, "Personalized Circulating Tumor DNA Testing for Detection of Progression and Treatment Response Monitoring in Patients With Metastatic Invasive Lobular Carcinoma of the Breast." Host Dr. Rafeh Naqash and Dr. Foldi discuss how serial ctDNA testing in patients with mILC is feasible and may enable personalized surveillance and real-time therapeutic monitoring. 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 am your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Associate Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, we are thrilled to be joined by Dr. Julia Foldi, Assistant Professor of Medicine in the Division of Hematology-Oncology at University of Pittsburgh School of Medicine and the Magee-Womens Hospital of the UPMC. She is also the lead and corresponding author of the JCO Precision Oncology article entitled "Personalized Circulating Tumor DNA Testing for Detection of Progression and Treatment Response Monitoring in Patients with Metastatic Invasive Lobular Carcinoma of the Breast." At the time of this recording, our guest's disclosures will be linked in the transcript. Julia, welcome to our podcast, and thank you for joining us today. Dr. Julia Foldi: Thank you so much for having me. It is a pleasure. Dr. Rafeh Naqash: Again, your manuscript and project address a few interesting things, so we will start with the basics, since we have a broad audience that comprises trainees, community oncologists, and obviously precision medicine experts as well. So, let us start with invasive lobular breast carcinoma. I have been out of fellowship for several years now, and I do not know much about invasive lobular carcinoma. Could you tell us what it is, what some of the genomic characteristics are, why it is different, and why it is important to have a different way to understand disease biology and track disease status with this type of breast cancer? Dr. Julia Foldi: Yes, thank you for that question. It is really important to frame this study. So, lobular breast cancers, which we shorten to ILC, are the second most common histologic subtype of breast cancer after ductal breast cancers. ILC makes up about 10 to 15 percent of all breast cancers, so it is relatively rare, but in the big scheme of things, because breast cancer is so common, this represents actually over 40,000 new diagnoses a year in the US of lobular breast cancers. What is unique about ILC is it is characterized by loss of an adhesion molecule, E-cadherin. It is encoded by the CDH1 gene. What it does is these tumors tend to form discohesive, single-file patterns and infiltrate into the tumor stroma, as opposed to ductal cancers, which generally form more cohesive masses. As we generally explain to patients, ductal cancers tend to form lumps, while lobular cancers often are not palpable because they infiltrate into the stroma. This creates several challenges, particularly when it comes to imaging. In the diagnostic setting, we know that mammograms and ultrasounds have less sensitivity to detect lobular versus ductal breast cancer. When it comes to the metastatic setting, conventional imaging techniques like CT scans have less sensitivity to detect lobular lesions often. One other unique characteristic of ILC is that these tumors tend to have lower proliferation rates. Because our glucose-based PET scans depend on glucose uptake of proliferating cells, often these tumors also are not avid on conventional FDG-PET scans. It is a challenge for us to monitor these patients as they go through treatment. If you think about the metastatic setting, we start a new treatment, we image people every three to four cycles, about every three months, and we combine the imaging results with clinical assessment and tumor markers to decide if the treatment is working. But if your imaging is not reliable, sometimes even at diagnosis, to really detect these tumors, then really, how are we following these patients? This is really the unique challenge in the metastatic setting in patients with lobular breast cancer: we cannot rely on the imaging to tell if patients are responding to treatment. This is where liquid biopsies are really, really important, and as the field is growing up and we have better and better technologies, lobular breast cancer is going to be a field where they are going to play an important role. Dr. Rafeh Naqash: Thank you for that easy-to-understand background. The second aspect that I would like to have some context on, to help the audience understand why you did what you did, is ctDNA, tumor informed and non-informed. Could you tell us what these subtypes of liquid biopsies are and why you chose a tumor informed assay for your study? Dr. Julia Foldi: Yes, it is really important to understand these differences. As you mentioned, there are two main platforms for liquid biopsy assays, circulating tumor DNA assays. I think what is more commonly used in the metastatic setting are non-tumor informed assays, or agnostic assays. These are generally next-generation sequencing-based assays that a lot of companies offer, like Guardant, Tempus, Caris, and FoundationOne. These do not require tumor tissue; they just require a blood sample, a plasma sample, essentially. The next-generation sequencing is done on cell-free DNA that is extracted from the plasma, and it is looking for any cell-free DNA and essentially, figuring out what part of the cell-free DNA comes from the tumor is done through a bioinformatics approach. Most of these assays are panel tests for cancer-associated mutations that we know either have therapeutic significance or biologic significance. So, the results we receive from these tests generally read out specific mutations in oncogenic genes, or sometimes things like fusions where we have specific targeted drugs. Some of the newer assays can also read out tumor fraction; for example, the newest generation Guardant assay that is methylation-based, they can also quantify tumor fraction. But the disadvantage of the tumor agnostic approach is that it is a little bit less sensitive. Opposed to that, we have our tumor informed tests, and these require tumor tissue. Essentially, the tumor is sequenced; this can either be whole exome or whole genome sequencing. The newer generation assays are now using whole genome sequencing of the tumor tissue, and a personalized, patient-specific panel of alterations is essentially barcoded on that tumor tissue. This can be either structural variants or it can be mutations, but generally, these are not driver mutations, but sort of things that are present in the tumor tissue that tend to stay unchanged over time. For each particular patient, a personalized assay, if you want to call it a fingerprint or barcode, is created, and then that is what then is used to test the plasma sample. Essentially, you are looking for that specific cancer in the blood, that barcode or fingerprint in the blood. Because of this, this is a much more sensitive way of looking for ctDNA, and obviously, this detects only that particular tumor that was sequenced originally. So, it is much more sensitive and specific to that tumor that was sequenced. You can argue for both approaches in different settings. We use them in different settings because they give us different information. The tumor agnostic approach gives us mutations, which can be used to determine what the next best therapy to use is, while the tumor informed assay is more sensitive, but it is not going to give us information on therapeutic targets. However, it is quantified, and we can follow it over time to see how it changes. We think that it is going to tell us how patients respond to treatment because we see our circulating tumor DNA levels rise and fall as the cancer burden increases or decreases. We decided to use the tumor informed approach in this particular study because we were really interested in how to determine if patients are having response to treatment versus if they are going to progress on their treatment, more so than looking for specific mutations. Dr. Rafeh Naqash: When you think about these tumor informed assays and you think about barcoding the mutations on the original tumor that you try to track or follow in subsequent blood samples, plasma samples, in your experience, if you have done it in non-lobular cancers, do you think shedding from the tumor has something to do with what you capture or how much you capture? Dr. Julia Foldi: Absolutely. I think there are multiple factors that go into whether someone has detectable ctDNA or not, and that has to do with the type of cancer, the location, right, where is the metastatic site? This is something that we do not fully understand yet: what are tumors that shed more versus not? There is also clearance of ctDNA, and so how fast that clearance occurs is also something that will affect what you can detect in the blood. ctDNA is very short-lived, only has a half-life of hours, and so you can imagine that if there is little shedding and a lot of excretion, then you are not going to be detecting a lot of it. In general, in the metastatic setting, we see that we can detect ctDNA in a lot of cases, especially when patients are progressing on treatment, because we imagine their tumor burden is higher at that point. Even with the non-tumor informed assays, we detect a lot of ctDNA. Part of this study was to actually assess: what is the proportion of patients where we can have this information? Because if we are only going to be able to detect ctDNA in less than 50 percent of patients, then it is not going to be a useful method to follow them with. Because this field is new and we have not been using a lot of tumor informed assays in the metastatic setting, we did not really know what to expect when we set out to look at this. We did not know what was going to be the baseline detection rate in this patient population, so that was one of the first things that we wanted to answer. Dr. Rafeh Naqash: Excellent. Now going to this manuscript in particular, what was the research question, what was the patient population, and what was the strategy that you used to investigate some of these questions? Dr. Julia Foldi: So, we partnered with Natera, and the reason was that their Signatera tumor-informed assay was the first personalized, tumor-informed, really an MRD assay, minimal residual disease detection assay. It has been around the longest and has been pretty widely used commercially already, even though some of our data is still lacking. but we know that people are using this in the real world. We wanted to gather some real-world data specifically in lobular patients. So, we asked Natera to look at their database of commercial Signatera testing and look for patients with stage 4 lobular breast cancer. The information all comes from the submitting physicians sending in pathologic reports and clinical notes, and so they have that information from the requisitions essentially that are sent in by the ordering physician. We found 66 patients who were on first-line or close to first-line endocrine-based therapies for their metastatic lobular breast cancer and had serial collections of Signatera tests. The way we defined baseline was that the first Signatera had to be sent within three months of starting treatment. So, it is not truly baseline, but again, this is a limitation of looking at real-world data is that you are not always going to get the best time point that you need. We had over 350 samples from those 66 patients, again longitudinal ctDNA samples, and our first question was what is the baseline detection rate using this tumor informed assay? Then, most importantly, what is the concordance between changes in ctDNA and clinical response to treatment? That is defined by essentially radiologic response to treatment. Dr. Rafeh Naqash: Interesting. So, what were some of your observations in terms of ctDNA dynamics, whether baseline levels made a difference, whether subsequent levels at different time points made a difference, or subsequent levels at, let us say, cycle three made a difference? Were there any specific trends that you saw? Dr. Julia Foldi: So, first, at baseline, 95 percent of patients had detectable ctDNA, which is, I think, a really important data point because it tells us that this can be a really useful test. If we can detect it in almost all patients before they start treatment, we are going to be able to follow this longitudinally. And again, these were not true baseline samples. So, I think if we look really at baseline before starting treatment, almost all patients will have detectable ctDNA in the metastatic setting. The second important thing we saw was that disease progression correlated very well with increase in ctDNA. So, in most patients who had disease progression by imaging, we saw increase in ctDNA. Conversely, in most patients who had clinical benefit from their treatment, so they had a response or stable disease, we saw decrease in ctDNA levels. It seems that what we call molecular response based on ctDNA is tracking very nicely along with the radiographic response. So, those were really the two main observations. Again, this is a small cohort, limited by its real-world nature and the time points that ctDNA assay was sent was obviously not mandated. This is a real-world data set, and so we could not really look at specific time points like you asked about, let us say, cycle three of therapy, right? We did not have all of the right time points for all of the patients. But what we were able to do was to graph out some specific patient scenarios to illustrate how changes in ctDNA correlate with imaging response. I can talk a little bit about that. Dr. Rafeh Naqash: That was going to be my question. Did you see patients who had serial monitoring using the tumor informed ctDNA assay where the assay became positive a few months before the imaging? Did you have any of those kinds of observations? Dr. Julia Foldi: Yes, so I think this is where the field is going: are we able to use this technology to maybe detect progression before it becomes clinically apparent? Of course, there are lots of questions about: does that really matter? But it seems like, based on some of the patient scenarios that we present in the paper, that this testing can do that. So, we had a specific scenario, and this is illustrated in a figure in the paper, really showing the treatment as well as the changes in ctDNA, tumor markers, and also radiographic response. So, this particular patient was on first-line endocrine therapy and CDK4/6 inhibitor with palbociclib. Initially, she had a low-level detectable ctDNA. It became undetectable during treatment, and the patient had a couple of serial ctDNA assays that were negative, so undetectable. And then we started, after about seven months on this combination therapy, the ctDNA levels started rising. She actually had three serial ctDNA assays with increasing level of ctDNA before she even had any imaging tests. And then around the time that the ctDNA peaked, this patient had radiographic evidence of progression. There was also an NGS-based assay sent to look for specific mutations at that point. The patient was found to have an ESR1 mutation, which is very common in this patient population. She was switched to a novel oral SERD, elacestrant, and the ctDNA fell again to undetectable within the first couple months of being on elacestrant. And then a very similar thing happened: while she was on this second-line therapy, she had three serial negative ctDNA assays, and then the fourth one was positive. This was two months before the patient had a scan that showed progression again. Dr. Rafeh Naqash: And Julia, like you mentioned, this is a small sample size, limited number of patients, in this case, one patient case scenario, but provides insights into other important aspects around escalation or de-escalation of therapy where perhaps ctDNA could be used as an integral biomarker rather than an exploratory biomarker. What are some of your thoughts around that and how is the breast cancer space? I know like in GI and bladder cancer, there has been a significant uptrend in MRD assessments for therapeutic decision making. What is happening in the breast cancer space? Dr. Julia Foldi: So, super interesting. I think this is where a lot of our different fields are going. In the breast cancer space, so far, I have seen a lot of escalation attempts. It is not even necessarily in this particular setting where we are looking at dynamics of ctDNA, but in the breast cancer world, of course, we have a lot of data on resistance mutations. I mentioned ESR1 mutation in a particular patient in our study. ESR1 mutations are very common in patients with ER-positive breast cancer who are on long-term endocrine therapy, and ESR1 mutations confer resistance to aromatase inhibitors. So, that is an area that there has been a lot of interest in trying to detect ESR1 mutations earlier and switching therapy early. So, this was the basis of the SERENA-6 trial, which was presented last year at ASCO and created a lot of excitement. This was a trial where patients had non-tumor-informed NGS-based Guardant assay sent every three to six months while they were on first-line endocrine therapy with a CDK4/6 inhibitor. If they had an ESR1 mutation detected, they were randomized to either continue the same endocrine therapy or switch to an oral SERD. The trial showed that the population of patients who switched to the oral SERD did better in terms of progression-free survival than those who stayed on their original endocrine therapy. There are a lot of questions about how to use this in routine practice. Of course, it is not trivial to be sending a ctDNA assay every three to six months. The rate of detection of these mutations was relatively low in that study; again, the incidence increases in later lines of therapy. So, there are a lot of questions about whether we should be doing this in all of our first-line patients. The other question is, even the patients who stayed on their original endocrine therapy were able to stay on that for another nine months. So, there is this question of: are we switching patients too early to a new line of therapy by having this escalation approach? So, there are a lot of questions about this. As far as I know, at least in our practice, we are not using this approach just yet to escalate therapy. Time will tell how this all pans out. But I think what is even more interesting is the de-escalation question, and I think that is where tumor informed assays like Signatera and the data that our study generated can be applied. Actually, our plan is to generate some prospective data in the lobular breast cancer population, and I have an ongoing study to do that, to really be able to tease out the early ctDNA dynamics as patients first start on endocrine therapy. So, this is patients who are newly diagnosed, they are just starting on their first-line endocrine therapy, and measure, with sensitive assays, measure ctDNA dynamics in the first few months of therapy. In those patients who have a really robust response, that is where I think we can really think about de-escalation. In the patients whose ctDNA goes to undetectable after just a few weeks of therapy with just an endocrine agent, they might not even need a CDK4/6 inhibitor in their first-line treatment. So, that is an area where we are very interested in our group, and I know that other groups are looking at this too, to try to de-escalate therapy in patients who clear their ctDNA early on. Dr. Rafeh Naqash: Thank you so much. Well, lots of questions, but at the same time, progress comes through questions asked, and your project is one of those which is asking an interesting question in a rarer cancer and perhaps will lead to subsequent improvement in how we monitor these individuals and how we escalate or de-escalate therapy. Hopefully, we will get to see more of what you are working on in subsequent submissions to JCO Precision Oncology and perhaps talk more about it in a couple of years and see how the space and field is moving. Thanks again for sharing your insights. I do want to take one to two quick minutes talking about you as an investigator, Julia. If you could speak to your career pathway, your journey, the pathway to mentorship, the pathway to being a mentor, and how things have shaped for you in your personal professional growth. Dr. Julia Foldi: Sure, yeah, that is great. Thank you. So, I had a little bit of an unconventional path to clinical medicine. I actually thought I was going to be a basic scientist when I first started out. I got a PhD in Immunology right out of college and was studying not even anything cancer-related. I was studying macrophage signaling in inflammatory diseases, but I was in New York City. This was right around the time that the first checkpoint inhibitors were approved. Actually, some of my friends from my PhD program worked in Jim Allison's lab, who was the basic scientist responsible for ipilimumab. So, I got to kind of first-hand experience the excitement around bringing something from the lab into the clinic that actually changed really the course of oncology. And so, I got very excited about oncology and clinical medicine. So, I decided to kind of switch gears from there and I went back to medical school after finishing my PhD and got my MD at NYU. I knew I wanted to do oncology, so I did a research track residency and fellowship combined at Yale. I started working early on with the breast cancer team there. At the time, Lajos Pusztai was the head of translational research there at Yale, and I started working with him early in my residency and then through my fellowship. I worked on several trials with him, including a neoadjuvant checkpoint inhibitor trial in triple-negative breast cancer patients. During my last year in fellowship, I received a Conquer Cancer Young Investigator Award to study estrogen receptor heterogeneity using spatial transcriptomics in this subset of breast cancers that have intermediate estrogen receptor expression. From there, I joined the faculty at the University of Pittsburgh in 2022. So, I have been there about almost four years at this point. My interests really shifted slowly from triple-negative breast cancers towards ER-positive breast cancers. When I arrived in Pittsburgh, I started working very closely with some basic and translational researchers here who are very interested in estrogen signaling and mechanisms of resistance to endocrine therapy, and there is a large group here interested in lobular breast cancers. During my training, I was not super aware even that lobular breast cancer was a unique subtype of breast cancers, and that is, I think, changing a little bit. There is a lot more awareness in the breast cancer clinical and research community about ILC being a unique subtype, but it is not even really part of our training in fellowship, which we are trying to change. But I have become a lot more aware of this because of the research team here and through that, I have become really interested also on the clinical side. And so, we do have a Lobular Breast Cancer Research Center of Excellence here at the University of Pittsburgh and UPMC, and I am the leader on the clinical side. We have a really great team of basic and translational researchers looking at different aspects of lobular breast cancers, and some of the work that I am doing is related to this particular manuscript we discussed and the next steps, as I mentioned, a prospective study of early ctDNA dynamics in lobular patients. I also did some more clinical research work in collaboration with the NSABP looking at long-term outcomes of patients with lobular versus ductal breast cancers in some of their older trials. And so, that is, in a nutshell, a little bit about how I got here and how I became interested in ILC. Dr. Rafeh Naqash: Well, thank you for sharing those personal insights and personal journey. I am sure it will inspire other trainees, fellows, and perhaps junior faculty in trying to find their niche. The path, as you mentioned, is not always straight; it often tends to be convoluted. And then finding an area that you are interested in, taking things forward, and being persistent is often what matters. Dr. Julia Foldi: Thank you so much for having me. It was great. Dr. Rafeh Naqash: It was great chatting with you. And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Host Dr. Davide Soldato and guests Dr. David Einstein and Dr. Ravi Madan discuss JCO article, "National Cancer Institute's Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations," underscoring the need for a consensus on clinical trial designs implementing novel endpoints in this population, the importance of PSA doubling time as a prognostic factor and with an emphasis on treatment de-escalation to limit toxicity and improve patient outcomes. TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. 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 Dr. David Einstein and Dr. Ravi Madan. Dr. Einstein is a medical oncologist specializing in genitourinary malignancy working at Beth Israel Deaconess Medical Center, part of the DFCI Cancer Center, and an assistant professor at Harvard Medical School. Dr. Madan is a senior clinician at the National Cancer Institute (NCI), where he focuses on conducting clinical research in prostate cancer, particularly in the field of immunotherapy. Today, we will be discussing the article titled, "National Cancer Institute's Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations." So, thank you for speaking with us, Dr. Einstein and Dr. Madan. David Einstein: Thanks for having us. This is a great pleasure. Ravi Madan: Appreciate being here. Davide Soldato: So, I just want to start from a very wide angle. And the main question is why did you feel that there was the need to convey a consensus and a working group to talk about this specific topic: biochemically recurrent prostate cancer? What has been the change in current clinical practice and in the trial design that we are seeing nowadays? And so, why was it necessary to convey such a consensus and provide considerations on novel clinical trials? David Einstein: Yeah, so I think it's very interesting, this disease state of biochemically recurrent prostate cancer. It's very different from other disease states in prostate cancer, and we felt that there was a real need to define those differences in clinical trials. Years ago, metastatic castration-resistant prostate cancer was the primary disease state that was explored, and over time, a lot of things shifted earlier to metastatic disease defined on a CAT scan and bone scan to an earlier disease state of metastatic castration-sensitive prostate cancer. And the clinical trial principles from late-stage could be applied to MCSPC as well. However, BCR is very different because the patients are very different. And for those reasons, there are unique considerations, especially in terms of toxicity and treatment intensity, that should be applied to biochemically recurrent prostate cancer as opposed to just using the principles that are used in other disease states. And for that reason, we thought it was very important to delineate some of these considerations in this paper with a group of experts. Davide Soldato: Thanks so much. So, one of the main changes that have been applied in recent years in clinical practice when looking at biochemically recurrent prostate cancer is the use of molecular imaging and particularly of PSMA PET. So, first of all, just a quick question: was the topic of the consensus related on which threshold of PSA to use to order a PET scan to evaluate this kind of patient? David Einstein: Yeah, thanks for that question. It's a super important one. The brief answer is that no, we did not address questions about exactly when clinicians would decide to order scans. We were more concerned with the results of those scans in how you define different disease states. But I think as a broader question, I think a lot of folks feel that finding things on a scan equates that with what we used to find on conventional scans. And fundamentally, we actually sought to redefine that disease space as something that's not equivalent to metastatic disease, and rather coined the term "PSMA-positive BCR" to indicate that traditional BCR prognostic criteria and factors still apply, and that these patients have a distinct natural history from those with more advanced metastatic disease. Ravi Madan: And if I may just add that the National Cancer Institute is running a trial where we're prospectively monitoring PSMA-positive BCR patients. And that data is clearly showing that, much like what we knew about BCR a decade ago, PSMA findings in BCR patients do not change the fact that overall, BCR is an indolent disease state. And the findings, which are usually comprised of five- to seven-millimeter lymph nodes, do not endanger patients or require immediate therapy. And so, while PSMA is a tool that we can be using in this disease state, it doesn't really change the principal approach to how we should manage these patients. And as Dr. Einstein alluded to, there is a drive to create a false equivalency between PSMA-positive BCR and metastatic castration-sensitive prostate cancer, but that is not supported by the data we're accumulating or any of the clinical data as it exists. Davide Soldato: One thing that it's very important and you mentioned in your answer to my question was actually the role of PET scan and conventional imaging, so CAT scan and bone scan that we have used for years to stage patients with metastatic prostate cancer. And you mentioned that there is a distinction among patients who have a positive PET scan and a BCR, and patients who have a positive conventional imaging. And yet, we know that sometimes the findings of the PET scan are not always so clear to interpret. So, I just wanted to understand if the consensus reached an agreement as to when to use conventional imaging to potentially resolve some findings that we have on PET scan among thess patients with BCR? David Einstein: Yeah, I think there's a number of questions actually buried within that question. One of which is: does PSMA PET result in false positives? And the answer has definitely been yes. There's a known issue with false-positive rib lesions. And so, first and foremost, we need to be very careful in calling what truly is suspicious disease and what might actually not be cancer or might be something that is totally separate. So I think that's the first part of the answer to that question. The second is to what extent do we need to use paired PET and conventional imaging to define this disease state? In other words, do you have to have positive findings on one and negative findings on the other in order to enter this definition? The challenge there, as we discussed, is that logistically, oftentimes it's hard to get patients to do multiple sets of scans to actually create that definition. Sometimes it's difficult to get insurers to pay for such scans. And finally, it's hard to sometimes blind radiologists to the results of one scan in reading the other. So, we did have some deliberations about to what extent you could use some of the CAT scan portion of a PSMA PET in order to at least partially define that. We also talked about using bone scans to confirm any bone findings seen on PET. But I think another important part of this is not just the baseline imaging, but also what's going to be done serially on a study in order to define responses and progression. And that's sort of a whole separate conversation about to what extent you can interpret changes in serial PET. Ravi Madan: And just to pick up on the key factor here, I think that the PSMA PET in BCR is pretty good at defining lymph node disease, and that's actually predominantly 80 to 90 percent of the disease seen on these findings. It might be pretty good at also defining other soft tissue findings. The real issues come to bone findings. And one thing the group did not feel was appropriate was to just define only PSMA-positive bone findings confirmed on a CT bone window. There's not really great data on that, but the working group felt that, when in the rare situation, because it is relatively rare, a PSMA-positive finding is in a bone, a bone scan should be done. And it's worth noting that Phu Tran, who is a co-author and a co-leader of this working group, his group has already defined that underlying genomics of conventionally based lesions, such as bone scan, are more aggressive than findings on next-gen imaging, such as PSMA. So, there is also a genomic underlying rationale for defining the difference between what is seen on a PET scan in a bone and what is seen on a bone scan. Davide Soldato: Coming back to this issue of PET PSMA sometimes identifying very small lesions where we don't see any kind of correlates on conventional imaging or where we see only very little alteration on the bone scan or in the CT scan, was there any role that was imagined, for example, for MRI to distinguish this type of findings on the PET scan? Ravi Madan: So, I think that, again, what can be identified on a PSMA frequently cannot be seen on conventional imaging. We didn't feel that it was a requirement to get an MRI or a CT to necessarily confirm the PSMA findings. I think that generally, we have to realize that in this disease state, that questionable lesions are going to be seen on any imaging, including PSMA. We've actually probably put way too much faith in PSMA findings thus far, as Dr. Einstein alluded to with some of the false positives we're seeing. So, I think that these false positives are going to have to be baked into trials. And in terms of clinical practice, it highlights the need to again, not overreact to everything we see and not necessarily need to biopsy everything and put patients' health in jeopardy to delineate a disease that's indolent anyway. Davide Soldato: Thanks so much. That was very clear. So, basically, the main driver was really also the data showing that if we have a BCR, so a patient with a biochemically recurrent disease that is positive on the conventional imaging, this is usually associated with a different aggressiveness of the disease. But coming back to a comment that you made before, Dr. Madan, you said that even if we talk about PSMA-positive BCR, we are still talking about BCR and the same criteria should apply. So, what we have used for years in this space to actually try to stratify the prognosis of patients is the PSA doubling time, so how quickly the PSA rises over time. So, coming back to that comment, was the consensus on the PSA doubling time basically retained as what we were using before, so defining patients with a doubling time less than 12 months, 10 months, 9 months, as patients with a higher risk of progressing in terms of developing metastatic disease? Ravi Madan: Yes, so that's a very important point. And the working group defined high-risk BCR as a PSA doubling time less than six months. And this really comes from Johns Hopkins historical data, which shows that if your doubling time is three months or less, there's about a 67 percent chance of metastasis at five years. If it's between three and six months, it's 50 percent. And if it's over six months, if it's between six and nine months, it's roughly only 27 percent. There are trials that are accruing with eligibility criteria that they may describe as high-risk that are beyond six months, but the data as really it's been defined in the literature highlights that truly high-risk BCR is less than six months. And the working group had a consensus on that opinion, and that was our recommendation. David Einstein: And I think an important follow-on to that is that's regardless of PET findings, right? And so, we present a couple of case studies of patients with positive PET findings who have a long doubling time, in whom the disease is in fact indolent, as you would have expected from a traditional BCR prognostic standpoint. Obviously, there are patients in whom they have fast doubling times, and even if they do not have PET findings, that doesn't make them not high-risk. Ravi Madan: And just to follow up that point, I will let you know a little bit of a free preview that my colleague Melissa Abel from the NCI will be presenting PSMA findings in the context of PSA doubling time at ASCO GU if that data is accepted. Davide Soldato: Looking forward for those data because I think that they're going to clarify a lot of the findings that we have in this specific population. And coming back to one of the points that we made before, so PET PSMA has a very high ability to discriminate also a very low burden of disease, which we currently refer to as oligometastatic biochemically recurrent prostate cancer, which is not entirely defined as an entity. But what we are seeing both in some clinical trials, which use mainly conventional imaging, but also what we're starting to see in clinical practice, is that frequently we use the metastasis-directed therapy to treat these patients. So, just a little bit of a comment on the use of this type of strategy in clinical practice and if the panel thought of including this as, for example, a stratification criteria or mandated in the design of novel clinical trials in the field of BCR? David Einstein: Yeah, I think that's an incredibly important point. You know, fundamentally, there's a lot of heterogeneity in practice where some folks are using local salvage approaches, some are using systemic therapies, in some cases surveillance may be reasonable, or some combination of these different strategies. We certainly have phase two data from multiple trials suggesting that met-directed therapy may help buy patients time off of treatment until subsequent treatments are started. And that in and of itself may be an important goal that we can come back to in discussing novel endpoints. I think what our panel acknowledged was that, in some sense, the clinical practice has gotten even farther ahead than where the data are, and this is being offered pretty routinely to patients in practice. And so, what became clear was that we, in developing clinical trials, cannot forbid investigators from doing something that would be within their usual standard of care, even if it might not be supported by the most robust data. But at minimum, it definitely should be used as a stratification factor, or in some trial designs, you can do met-directed therapy after a primary endpoint is assessed. And that offers a compromise between testing, say, the effect of a systemic therapy but also not excluding patients and investigators from doing what they would have done had they not been on a study. Ravi Madan: And I would just like to follow up your phrasing in the question of "oligometastatic prostate cancer." We have a figure in the paper and it highlights the fact that, unfortunately, that term in prostate cancer is imaging agnostic. And we've already discussed in this podcast, as well as in the paper, that imaging used to define a metastatic lesion, whether it's PSMA or conventional imaging, carries with it a different clinical weight and a different prognosis. So, we feel in the working group, that the correct term for this disease state of PSMA-positive BCR is just that: PSMA-positive BCR. We also have to realize that when we talk about oligometastatic disease, while it's imaging agnostic, it seems to be numerically based, whether it's five or three or 10 depending on the trial. But PSMA-positive BCR does not have a limit in terms of the number of lesions. And so again, we just feel that there is an important need to delineate what we're seeing in this disease state, which again is PSMA-positive BCR, and that should be differentiated frankly from oligometastatic disease defined on other imaging platforms. David Einstein: Right, and that also makes clear that patients can have polyfocal disease on PET that still is not what we would consider metastatic, but goes beyond the traditional definition of oligometastatic. So, in other words, just because someone has PET-detected disease only, that does not automatically equate with oligometastatic. Davide Soldato: Thanks so much. So, you were speaking a little bit, Dr. Einstein, about the different types of treatment that we can propose or not propose to this patient because you mentioned, for example, that in clinical practice MDT, so metastasis-directed therapy, is becoming more and more used. For these patients, we can potentially use systemic treatments, which include androgen deprivation therapy, which can be given continuously or in an intermittent fashion. And recently, we can also use novel systemic therapies, for example, enzalutamide, to treat this type of patient. So, given that the point of the consensus was really to provide consideration for novel clinical trials in this space, what was the opinion on the panel regarding the control arm? So, if we're looking at a novel therapy in the BCR space, does the control arm need to include a therapy or not? And if so, which therapy? David Einstein: Yeah, this is a super important question and one that's subject to a lot of discussion, especially in light of recent data from EMBARK. What we came to a consensus around was the fact that neither MDT nor systemic therapy should be required as a control arm on BCR trials. And we can talk about a number of reasons for that. There's also the pragmatics of what investigators might actually accrue patients to and what they would consider their standard of care, and that's important to factor in, too. I think that one of the major goals of our working group was outlining what kinds of trials we would like to see in the future and where the limitations of the current data stand. For example, EMBARK proposes a strategy of a single treatment discontinuation and resumption at a predefined threshold indefinitely. That's probably not how most people are practicing. Most folks are probably using some version of intermittent therapy as they would have before this trial, but we actually don't have any data supporting that. Moreover, we don't have data comparing different intermittent strategies to one another. We don't know what the right thresholds are, we don't know how much time we buy patients off treatment, and we don't know to what extent MDT modifies that. And so, those are all really important questions to be asking in future versions of these trials. I'd say my second point would be that a lot of drug development is happening with novel therapies that are not hormonal, trying to bring them into this space. And when you think about trying to compare one of those types of therapies to a hormonal therapy on short-term endpoints, the hormonal therapy is always going to win. Hormonal therapy is almost universally effective, it will bring down PSAs, and it will prolong, quote-unquote, "progression." The downside of that is that hormonal therapy doesn't actually modify the disease, it suppresses it, and it tends to have fairly transient effects once you remove it. And so, part of our goal was in trying to figure out some novel endpoints that would allow these novel types of therapies to be examined head-to-head against a more traditional type of hormonal therapy and have some measurement of some of the more long-term impacts. Davide Soldato: So, jumping right into the endpoints, because this is a very relevant and I think very well-constructed part of the paper that you published. Because in the past we have used some of these endpoints, for example, metastasis-free survival, as potentially a proxy for long-term outcomes. But is this the right endpoint to be using right now, especially considering that frequently this outcome is measured using conventional imaging, but we are including in these trials patients who are actually negative on conventional imaging but have a positive PSMA when they enter this type of trial? David Einstein: Yeah, there's a number of challenges with those types of endpoints. One of which is, as you say, we're changing the goalposts a little bit on how we're calling progression. We still don't exactly understand what progression on PET means, and so that's something that is challenging. That said, we're also cognizant of the fact that many times investigators are likely to get PET scans in the setting of rising PSA, and that's going to affect any endpoint that relies purely on conventional imaging. So, there's some tension there between these two different sets of goalposts. One thing that we emphasize is that not only are there some challenges in defining those, but also there're challenges in what matters to a patient. So, if a progression event occurs in the form of a single lesion on a PET scan or even a conventional image, that might be relevant for a clinical trial but might be less relevant for a patient. In other words, that's something that, in the real world, an investigator might use serial rounds of metastasis-directed therapy or intermittent therapy to treat in a way that doesn't have any clinical consequences for the patient necessarily. In other words, they're asymptomatic, it's not the equivalent of a metastatic castration-resistant disease progressing. And so, we also need to be cognizant of the fact that if we choose a single endpoint like PFS, that there's going to be many different versions of progression, some of which probably matter clinically more than others, and some of which are more salvageable by local therapies than others. Ravi Madan: So I think the working group really thoughtfully looked at the different options and underscored perhaps strengths and weaknesses, and I think that's presented as you mentioned in the paper. But I think it's also going to depend on the modality, the approach of the therapeutic intervention. In some cases if it's hormone-based, then maybe PSA is providing some early metrics, maybe metastasis-free survival is more relevant in a continuous therapy, but intermittent therapies might have a different approach. There's emerging immunotherapy strategies, radiopharmaceutical strategies, they might have some more novel strategies as well. I think we have to be open-minded here, but we also have to be very clear: we do not know what progression is on a PSMA scan. Just new lesions may not carry the clinical significance that we think, and we may not know what threshold that ultimately becomes clinically relevant is. So, I do think that there was some caution issued by the working group about using PSMA as an endpoint because we still do not have the data to understand what that modality is telling us. Again, I'm optimistic that the National Cancer Institute's prospective data set that we've been collecting, which has over 130 patients now, will provide some insights in the months and years ahead. Davide Soldato: So, just to ask the question very abruptly, what would you feel like the best endpoint for this type of trials is? I understand that is a little bit related to the type of treatments that we're going to use, whether it's intermittent, whether it's continuous, but do we have something that can encapsulate all of the discussion that we have up until this point? David Einstein: Yeah, so that's a perfect segue to the idea of novel endpoints, which we feel are very important to develop in these novel disease spaces. So, one thing that we discussed was an endpoint called treatment-free survival, which conceptually you can think of as exactly what it sounds like, but statistically you actually have to do some work to get there. And so essentially, you imagine a series of Kaplan-Meier curves overlaid: one about overall survival, one time to next therapy, one time on initial therapy. You can actually then take the area under those curves or between those curves and essentially sum it up using restricted mean survival time analysis. And that can give you a guide about the longitudinal experience of a patient: time spent on treatment versus off treatment; time spent with toxicity versus without toxicity. And importantly, each one of those time-to-event metrics can be adjusted depending on exactly what the protocol is and what is allowed or not allowed and what's prespecified as far as initiation of subsequent therapies. So, we felt that this was a really important endpoint to develop in this disease space because it can really capture that longitudinal aspect. It can really reward treatments that are effective in getting durable responses and getting patients off of therapy, because unfortunately, PFS-based endpoints generally reward more or longer systemic therapy versus shorter or no systemic therapy, and that's sort of an artificial bias in the way those endpoints are constructed. So, I think that there are challenges of course in implementing any new endpoint, and some of the things that are really critical are collecting data about toxicity and about subsequent therapies beyond what a typical trial might collect. But I think in this kind of disease space, that longitudinal aspect is critical because these are really patients who are going to be going through multiple rounds of therapy, going to be going on and off treatments, they're going to be using combinations of local and systemic therapies. And so, any one single endpoint is going to be limited, but I think that really highlights the limitations of using PFS-based endpoints in this space. Ravi Madan: I also think that in the concept of treatment-free survival lies one of the more powerful and, honestly, I was surprised by this, that it was so universally accepted, recommendations from the committee. And that was that the general approach to trials in this space should be a de-escalation of the EMBARK strategy as it's laid out with relatively continuous therapy with one pause. And so, I think again, buried in all of this highlights the need for novel endpoints like treatment-free survival. We get to the fact that these are patients who are not at near-term clinical risk from symptoms of their disease, so de-escalating therapies does not put them at risk. And if you look at, for example, lower-volume metastatic castration-sensitive prostate cancer, it's become realized that we need to de-escalate, and there are now trials being done to look at that. Historically, we know that BCR is an indolent disease process for the vast majority of patients who are not at near-term risk from clinical deterioration. So, therefore, we shouldn't wait a decade into abundant BCR trials to de-escalate. The de-escalation strategy should be from the outset. And that was something the committee really actually universally agreed on. David Einstein: And that de-escalation can really take multiple forms. That could be different strategies for intermittent therapy, different start-stop strategies. It could also mean actually intensifying in the short-term with the goal long-term de-intensification, kind of analogous to kidney cancer where we might use dual checkpoint inhibitors up front with some higher upfront toxicity but with the hope of actually long-term benefit and actually being able to come off treatment and stay in remission. Those kinds of trade-offs are the types of things that are challenging to talk about. There's not a one-size-fits-all answer for every patient. And so, that's why some of these endpoints like treatment-free survival would be really helpful in actually quantifying those trade-offs and allowing each patient to make decisions that are concordant with their own wishes. Davide Soldato: Thanks so much. That was very clear, especially on the part of de-escalation, because, as you were mentioning, I think that we are globally talking about a situation, a clinical situation, where the prognosis can be very good and patients can stay off treatment for a very long period of time without compromising long-term outcomes. And I think that well-constructed de-escalation trials, as you were mentioning and as the consensus endorsed, are really needed in this space also to limit toxicity. This brings us to the end of this episode. So, I would like to thank again Dr. Einstein and Dr. Madan for joining us today. David Einstein: We really appreciate the time and the thought, and I think that even starting these types of discussions is critical. Even just recognizing that this is a unique space is the beginning of the conversation. Ravi Madan: Yeah, and I want to thank JCO for giving us this forum and the opportunity to publish these results and all the expert prostate cancer investigators who were part of this committee. We produced some good thoughts for the future. Davide Soldato: We appreciate you sharing more on your JCO article titled, "National Cancer Institute's Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations." 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 opinion of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Listen now to the latest episode of JCO Cancer Stories: The Art of Oncology, North Star, by Dr Manuela Spadea. As a pediatric oncologist, Spadea shares a luminous, gut-honest reflection that reminds us that beyond protocols and outcomes, the deepest medicine is presence. TRANSCRIPT Narrator: North Star, by Manuela Spadea, 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. What a pleasure it is to have joining us today Manuela Spadea, an assistant professor of pediatrics at the University of Turin in Italy and consultant oncologist at the Regina Margherita Children's Hospital in Turin, Italy. We will discuss her Journal of Clinical Oncology article and second place winner in our Narrative Medicine Contest, "North Star." At the time of this recording, our guest has no disclosures. We have agreed to address each other by first names. Manuela, thank you for contributing to the Journal of Clinical Oncology and to our Narrative Medicine Contest, and especially for joining us to discuss your winning article today. Manuela Spadea: Hi Mikkael. Thank you for having me today. It is a pleasure and an honor being invited to speak with you. Mikkael Sekeres: No, the pleasure and honor is mine, I promise. You know, on these podcasts, I often like to ask our guests to tell us something about yourself. Where are you from, and walk us through your career and where you are right now. Manuela Spadea: Sure. I am from Italy. I work in Turin, where I work as a consultant pediatrician, a consultant oncologist, and also as an assistant professor of pediatrics. So my work is divided in these two duties: clinical duties on one hand and on the other hand, research and also teaching activities. I was drawn to choose pediatric oncology because this sits at the intersection of science and humanity, in my opinion, of course. I think that in pediatric oncology, we face different and several challenges, so we need to perform at our best in diagnosis, treatment, and whatever. But also, we are asked to not forget being human and to connect always with our children and their families. So it was basically this intersection, this connection between science, research on one hand, and humanity and heart on the other hand that led me to what I am today. Mikkael Sekeres: It is a fantastic explanation, and it is interesting how you have framed that, that there is an aspect of arts and humanities that you have found in focusing on pediatric hematology oncology. I do think that is more so than what we face in adult oncology. Manuela Spadea: I think that it is kind of different because if you think about our world and you think about a sentence, just putting the words 'child', 'cancer', and 'death' in the same sentence is very hard to think about. An adult is someone that has already had the chance and the gift to grow up. Mikkael Sekeres: Huh. It is an interesting perspective on it. Manuela Spadea: Yeah. A child is someone who is growing up and cancer stays in between his possibility to become an adult or not. Mikkael Sekeres: So the emotional burden right out of the gate of having a child with cancer and the possibility of death and the reaction to the compromise of a full life and the shortening of a full life automatically invokes that extra step of humanity and arts and how we have to approach a medical situation. I had not heard somebody put that into a concise phrase like that before, but you are absolutely right. When did you start writing narrative pieces? Manuela Spadea: I started writing when I was an adolescent, basically. And writing for me was a way to cope with whatever kind of feeling I felt during my life and during what I experienced as a human beforehand. But thereafter, when I became a clinician, writing was a way to cope with difficult shifts or hard nights in which you are asked to make very hard decisions as a clinician. Mikkael Sekeres: Often, either on this podcast or outside of it, doctors will approach me and want to get into writing and write a piece. And I think what many people do not realize is it is entirely possible later in life to start writing and to be very skilled at it. Many of our authors for JCO's Art of Oncology, though, have been writing their entire lives. It is not like they woke up one morning and decided, "Today I am going to write and I am going to write creatively." We have all been working on it for decades. Manuela Spadea: Sure. Mikkael Sekeres: I wonder who are some of your favorite authors or are there writers who have influenced your own writing? Manuela Spadea: I would go with Paulo Coelho and Alda Merini. The reasons are very different because from Paulo Coelho, I learned how to express life as a journey and how to use and exploit, of course, symbolic images to express what we want to tell to our readers. From Alda Merini, I learned that pain and suffering are worthy of being mentioned and they still deserve a place in our writings. And she taught me how to collocate, how to find the right place and the right words to express pain and suffering that are parts of our life, of course, in pediatric oncology, of course, and are worthy being expressed in a manner that can reach our readers and touch them. Mikkael Sekeres: Well, as you have beautifully in your essay, I wonder if you could give us an example of a symbolic image. Manuela Spadea: For example, referring to my essay, "North Star." I chose the North Star because it is a very important image because it recalls to us about being a fixed point in a collapsing world. Basically, it is the world of our children that is collapsing and you are the one who represents this fixed point, this anchor. Mikkael Sekeres: So in your essay, which our entire editorial staff just loved, you write about, and I am going to quote you to you, which is always a little bit awkward, but here I go. You write about "the unbearable beautiful vulnerability of being a North Star for a child with cancer." And you write, "We never call it that, of course, not in rounds, not in protocols, but that is what we become: a fixed point in a collapsing sky. When nothing else makes sense, when numbers fail and outcomes blur, they look to us, not because we promise survival, but because we promise we won't leave." Wow. I mean, that is an incredible collection of sentences. I wonder, in our relationships with our patients, when does that happen? When do we become a North Star? Manuela Spadea: I think that we become a North Star when our patients experience our humanity because they can trust us, not only for our degrees or our experience as clinicians, physicians, researcher, whatsoever. They trust us as a North Star when they feel that we are empathetic with them, when they know that we are feeling what they are experiencing. And so they leave their feelings to us, they share their feelings and they begin to connect with us. Mikkael Sekeres: When does that happen in the timeline of when we meet a patient? Is that something that can happen at our very first meeting where a patient may identify us or a member of our team as their North Star, or is that something that only happens over time as we build trust and build empathy? Manuela Spadea: It is definitely something that happens over time, day by day. Sometimes, but only occasionally, in my opinion, it can happen on the very first days, for example, the days in which we give them the diagnosis. But these are only small occasions because in the majority of cases, in my experience, the trust is built day by day. Mikkael Sekeres: There are also times that doesn't happen, though, right? What are those scenarios like when either patients do not need us to be a North Star or when that deep connection never happens? Manuela Spadea: I think that these are very challenging situations. It can happen when outcomes blur, of course, because sometimes patients are experiencing too much suffering and they cannot share with us because they are not able of sharing with us their feelings. Sometimes it is just because you are not their North Star. Sometimes it is inexplicable, basically. "I do not trust you, not because you are not what I am looking for, but because I do not feel I can trust you. And I do not know how to explain because I cannot trust you." Mikkael Sekeres: It is interesting. It is complicated to develop that relationship where you become a North Star. It sounds like what you are saying is it is a combination of trust, first and foremost, honesty, attentiveness to a patient's needs, and time. Manuela Spadea:Sure. Mikkael Sekeres: In your piece, you write about a couple of patients you have treated, Eva and Cecilia, and you write, "In both Eva's and Cecilia's journeys, I was not the most experienced doctor in the hospital. I wasn't the one who had written the protocol they were enrolled in or published the paper that dramatically shifted their chances. But I was the one who stayed, the one they chose. Incredibly, this is both a gift and a responsibility." There is a lot in those sentences, Manuela. You give patients the agency to identify us as a North Star, not us. Can you talk about that a little bit? Manuela Spadea: I think that there is a word in pediatric oncology that could be used as recurrent. And this word is 'impossible'. Why I chose this word? Because we live impossible diagnosis. Let's be honest. Impossible diagnosis, impossible suffering, impossible losses. When you face the impossible, being a North Star without being burned out by this, it is accepting that you are going to face uncertainty just being present. Because you are not the one that will change the outcome, or you can't be sure that that child will have the chance to survive. So if you give the possibility to face the uncertainty, being sure that whenever it goes, you can just be present for your patient and remember every day to your patient that you are there for them. So basically you win. And on the other hand, you also need to protect yourself because being a North Star is a responsibility, as I wrote. And a responsibility can be overwhelming for the one who is responsible for that child. So in that case, the only thing that can protect you is taking the part of being a North Star with boundaries. So you should also try to maintain your objectivity as a clinician and protect that objectivity that allows you to also serve as a good clinician. Mikkael Sekeres: So I wonder if I could follow up on that a little bit. It is a lot of work to be a North Star, isn't it? I mean, we have to choose our words and our actions so very carefully when we are in a room with a patient and that patient's family. Do you think serving as a North Star contributes to burnout or is it actually the opposite? It keeps our work vibrant and real? Manuela Spadea: Good question. I think that it is both, indeed. I think that burning out comes not by being a North Star, but by being a North Star in isolation, without caring about yourself, without finding a way to cope with your grief, with your sense of fear because we are human, so it is basically we experience these feelings. I mean, if we do not have a way to cope and to protect our feelings, we can absolutely go into burnout. On the other hand, it can be very important thing for our work because it can give our work the possibility to be vibrant and real because we are allowed to take the journey of our patient in a moment in which their journey is very unbearable. This is also not only a responsibility, but also a very important place that we have in their lives. This is very beautiful for me. This is astonishing because we are allowed to enter our patients' lives in a very difficult moment, and we can walk with them. Basically, being present and walking through what cancer journeys reserve for them. Mikkael Sekeres: Well, I think that is a lovely place to end our podcast. What a real pleasure it has been to have Manuela Spadea, who is an assistant professor of pediatrics at the University of Turin, Italy, and consultant oncologist at the Regina Margherita Children's Hospital in Turin, Italy, to discuss her essay, "North Star." Manuela, thank you so much for submitting your article both to JCO and to our contest, and for joining us today. Manuela Spadea: Thank you, Mikkael. It has been an honor to share these stories with you. 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 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 Manuela Spadea is an Assistant Professor of Pediatrics at the University of Turin, Italy, and Consultant Oncologist at the Regina Margherita Children's Hospital, in Turin, Italy.

En este episodio especial de Código Tumoral, la Dra. Julieta Gómez, oncóloga médica de México, conversa con el Dr. Diego Ballén, oncólogo médico de Colombia y el Dr. Jorge Gallardo, oncólogo médico de la Clínica Las Condes y miembro del grupo de trabajo SLAGO, en Santiago de Chile. Juntos presentan un análisis de los avances más relevantes del Congreso Anual de la Sociedad Americana de Oncología Clínica sobre tumores gastrointestinales del 2026, llevado a cabo en San Francisco, California (EE. UU.), del 8 al 10 de enero.Cáncer gástrico o de la unión gastroesofágicaNEOSUMMIT-01MATTERHORNILUSTROLUCERNACáncer colorrectalAgonista del receptor GLP-1 frente a aspirina para la prevención primaria del cáncer colorrectal: evidencia de una comparación directa en el mundo real, en la cual los agonistas del receptor GLP-1 se asociaron con una reducción relativa del 26% en la incidencia de cáncer colorrectal en comparación con la aspirina. Estos hallazgos, junto con su perfil de seguridad favorable, sugieren un potencial impacto en salud pública y respaldan la necesidad de validación prospectiva en ensayos clínicos aleatorizados.[5]Análisis de las diferencias moleculares, clinicopatológicas y en los resultados entre el cáncer colorrectal (CCR) con dMMR/MSI-H de inicio temprano (

Dr. Pedro Barata and Dr. Ugwuji Maduekwe discuss the evolving treatment landscape in gastroesophageal junction and gastric cancers, including the emergence of organ preservation as a selective therapeutic goal, as well as strategies to mitigate disparities in care. Dr. Maduekwe is the senior author of the article, "Organ Preservation for Gastroesophageal Junction and Gastric Cancers: Ready for Primetime?" in the 2026 ASCO Educational Book. TRANSCRIPT Dr. Pedro Barata: Hello, and welcome to By the Book, a podcast series from ASCO that features compelling perspectives from authors and editors of the ASCO Educational Book. I'm Dr. Pedro Barata. I'm a medical oncologist at University Hospitals Seidman Cancer Center and an associate professor of medicine at Case Western Reserve University in Cleveland, Ohio. I'm also the deputy editor of the ASCO Educational Book. Gastric and gastroesophageal cancers are the fifth most common cancer worldwide and the fourth leading cause of cancer-related mortality. Over the last decade, the treatment landscape has evolved tremendously, and today, organ preservation is emerging as an attainable but still selective therapeutic goal. Today, I'm delighted to be speaking with Dr. Ugwuji Maduekwe, an associate professor of surgery and the director of regional therapies in the Division of Surgical Oncology at the Medical College of Wisconsin. Dr. Maduekwe is also the last author of a fantastic paper in the 2026 ASCO Educational Book titled "Organ Preservation for Gastroesophageal Junction and Gastric Cancers: Ready for Prime Time?" We explore these questions in our conversations today.  Our full disclosures are available in the transcript of this episode as well. Welcome. Thank you for joining us today. Dr. Ugwuji Maduekwe: Thank you, Dr. Barata. I'm really, really glad to be here. Dr. Pedro Barata: There's been a lot of progress in the treatment of gastric and gastroesophageal cancers. But before we actually dive into some of the key take-home points from your paper, can you just walk us through how systemic therapy has emerged and actually allowed you to start thinking about a curative framework and really informing surgery decision-making? Dr. Ugwuji Maduekwe: Great, thank you. I'm really excited to be here and I love this topic because, I'm terrified to think of how long ago it was, but I remember in medical school, one of my formative experiences and why I got so interested in oncology was when the very first trials about imatinib were coming through, right? Looking at the effect, I remember so vividly having a lecture as a first-year or second-year medical student, and the professor saying, "This data about this particular kind of cancer is no longer accurate. They don't need bone marrow transplants anymore, they can just take a pill." And that just sounded insane. And we don't have that yet for GI malignancies. But part of what is the promise of precision oncology has always been to me that framework. That framework we have for people with CML who don't have a bone marrow transplant, they take a pill. For people with GIST. And so when we talk about gastric cancers and gastroesophageal cancers, I think the short answer is that systemic therapy has forced surgeons to rethink what "necessary" really means, right? We have the old age saying, "a chance to cut is a chance to cure." And when I started out, the conversation was simple. We diagnose the cancer, we take it out. Surgery's the default. But what's changed really over the last decade and really over the last five years is that systemic therapy has gotten good enough to do what is probably real curative work before we ever enter the operating room. So now when you see a patient whose tumor has essentially melted away on restaging, the question has to shift, right? It's no longer just, "Can I take this out?" It's "Has the biology already done the heavy lifting? Have we already given them systemic therapy, and can we prove it safely so that maybe we don't have to do what is a relatively morbid procedure?" And that shift is what has opened the door to organ preservation. Surgery doesn't disappear, but it becomes more discretionary. Necessary for the patients who need it, and within systems that can allow us to make sure that we're giving it to the right patients. Dr. Pedro Barata: Right, no, that makes total sense. And going back to the outcomes that you get with these systemic therapies, I mean, big efforts to find effective regimens or cocktails of therapies that allow us to go to what we call "complete response," right? Pathologic complete response, or clinical complete response, or even molecular complete response. We're having these conversations across different tumors, hematologic malignancies as well as solid tumors, right? I certainly have those conversations in the GU arena as well. So, when we think of pathologic CRs for GI malignancies, right? If I were to summarize the data, and please correct me if I'm wrong, because I'm not an expert in this area, the traditional perioperative chemo gives you pCRs, pathologic complete response, in the single digits. But then when you start getting smarter at identifying biologically distinct tumors such as microsatellite instability, for instance, now you start talking about pCRs over 50%. In other words, half of the patients' cancer goes away, it melts down by offering, in this case, immunotherapy as a backbone of that neoadjuvant. But first of all, this shift, right, from going from these traditional, "not smart" chemotherapy approaches to kind of biologically-driven approaches, and how important is pCR in the context of "Do I really need surgery afterwards?" Dr. Ugwuji Maduekwe: That's really the crux of the entire conversation, right? We can't proceed and we wouldn't be able to have the conversation about whether organ preservation is even plausible if we hadn't been seeing these rates of pathologic complete response. If there's no viable tumor left at resection, did surgery add something? Are we sure? The challenge before this was how frequently that happened. And then the next one is, as you've already raised, "Can we figure that out without operating?" In the traditional perioperative chemo era, pathologic complete response was relatively rare, like maybe one in twenty patients. When we go to more modern regimens like FLOT, it got closer to one in six. When you add immunotherapy in recent trials like MATTERHORN, it's nearly triple that rate. And it's worth noting here, I'm a health services-health disparities researcher, so we'll just pause here and note that those all sound great, but these landmark trials have significant representation gaps that limit and should inform how confidently we generalize these findings. But back to what you just said, right, the real inflection point is MSI-high disease where, with neoadjuvant dual-checkpoint blockade, trials like NEONIPIGAS and INFINITY show pCR rates that are approaching 50% to 60%. That's not incremental progress, that's a whole new different biological reality. What does that mean? If we're saying that 50% to 60% of the people we take to the OR at the time of surgery will end up having no viable tumor, man, did we need to do a really big surgery? But the problem right now is the gold standard, I think we would mostly agree, the gold standard is pathologic complete response, and we only know that after surgery. I currently tell my patients, right, because I don't want them to be like, "Wait, we did this whole thing." I'm like, "We're going to do this surgery, and my hope is that we're going to do the surgery and there will be no cancer left in your stomach after we take out your stomach." And they're like, "But we took out my stomach and you're saying it's a good thing that there's no cancer." And yes, right now that is true because it's a measure of the efficacy of their systemic therapy. It's a measure of the biology of the disease. But should we be acting on this non-operatively? To do that, we have to find a surrogate. And the surrogate that we have to figure out is complete clinical response. And that's where we have issues with the stomach. In esophageal cancer, the preSANO protocol, which we'll talk about a little bit, validated a structured clinical response evaluation. People got really high-quality endoscopies with bite-on biopsies. They got endoscopic ultrasounds. They got fine-needle aspirations and PET-CT, and adding all of those things together, the miss rate for substantial residual disease was about 10% to 15%. That's a number we can work with. In the stomach, it's a lot more difficult anatomically just given the shape of people's stomachs. There's fibrosis, there's ulceration. A fair number of stomach and GEJ cancers have diffuse histology which makes it difficult to localize and they also have submucosal spread. Those all conceal residual disease. I had a recent case where I scoped the patient during the case, and this person had had a 4 cm ulcer prior to surgery, and I scoped and there was nothing visible. And I was elated. And on the final pathology they had a 7 cm tumor still in place. It was just all submucosal. That's the problem. I'm not a gastroenterologist, but I would have said this was a great clinical response, but because it's gastric, there was a fair amount of submucosal disease that was still there. And our imaging loses accuracy after treatment. So the gap between what looks clean clinically and what's actually there pathologically remains very wide. So I think that's why we're trying to figure it out and make it cleaner. And outside of biomarker-selected settings like MSI-high disease, in general, I'm going to skip to the end and our upshot for the paper, which is that organ preservation, I would say for gastric cancer particularly, should remain investigational. I think we're at the point where the biology is increasingly favorable, but our means of measurement is not there yet. Dr. Pedro Barata: Gotcha. So, this is a perfect segue because you did mention the SANO, just to spell it out, "Surgery As Needed for Oesophageal" trial, so SANO, perfect, I love the abbreviation. It's really catchy. It's fantastic, it's actually a well-put-together perspective effort or program applying to patients. And can you tell us how was that put together and how does that work out for patients? Dr. Ugwuji Maduekwe: Yeah, I think for those of us in the GI space, we have SANO and then we also have the OPRA for rectum. SANO for the upper GI is what takes organ preservation from theory to something that's clinically credible. The trial asked a very simple question. If a patient with a GEJ adenocarcinoma or esophageal adenocarcinoma achieved what was felt to be a clinical complete response after chemoradiation, would they actually benefit from immediate surgery? And the question was, "Can you safely observe?" And the answer was 'yes'. You could safely observe, but only if you do it right. And what does that mean? At two years, survival with active surveillance was not inferior to those who received an immediate esophagectomy. And those patients had a better early quality of life. Makes sense, right? Your quality of life with an esophagectomy versus not is going to be different. That matters a lot when you consider what the long-term metabolic and functional consequences of an esophagectomy are. The weight loss, nutritional deficiencies that can persist for years. But SANO worked because it was very, very disciplined and not permissive. You mentioned rigor. They were very elegant in their approach and there was a fair amount of rigor. So there were two main principles. The first was that surveillance was front-loaded and intentional. So they had endoscopies with biopsies and imaging every three to four months in the first year and then they progressively spaced it out with explicit criteria for what constituted failure. And then salvage surgery was pre-planned. So, the return-to-surgery pathway was already rehearsed ahead of time. If disease reappeared, take the patient to the OR within weeks. Not sit, figure out what that means, think about it a little bit and debate next steps. They were very clear about what the plan was going to be. So they've given us this blueprint for, like, watching people safely. I think what's remarkable is that if you don't do that, if you don't have that infrastructure, then organ preservation isn't really careful. It's really hopeful. And that's what I really liked about the SANO trial, aside from, I agree, the name is pretty cool. Dr. Pedro Barata: Yeah, no, that's a fantastic point. And that description is spot on. I am thinking as we go through this, where can this be adopted, right? Because, not surprisingly, patients are telling you they're doing a lot better, right, when you don't get the esophagus out or the stomach out. I mean, that makes total sense. So the question is, you know, how do you see those issues related to the logistics, right? Getting the multi-disciplinary team, getting the different assessments of CR. I guess PETs, a lot of people are getting access to imaging these days. How close do you think this is, this kind of program, to be implemented? And maybe I would assume it might need to be validated in different settings, right, including the community. How close or how far do you think you see that being applied out there versus continuing to be a niche program, watch and wait program, in dedicated academic centers? Dr. Ugwuji Maduekwe: I love this question. So I said at the top of this, I'm a health equity/health disparities researcher, and this is where I worry the most. I love the science of this. I'm really excited about the science. I'm very optimistic. I don't think this is a question of "if," I think it's a question of "when." We are going to get to a point where these conversations will be very, very reasonable and will be options. One of the things I worry about is: who is it going to be an option for? Organ preservation is not just a treatment choice, and I think what you're pointing out very rightly is it's a systems-level intervention. Look at what we just said for SANO. Someone needs to be able to do advanced endoscopy, get the patients back. We have to have the time and space to come back every three to four months. We have to do molecular testing. There needs to be multi-disciplinary review. There needs to be intensive surveillance, and you need to have rapid access to salvage surgery. Where is that infrastructure? In this country, it's mostly in academic centers. I think about the panel we had at ASCO GI, which was fantastic. And as we were having the conversation, you know, we set it up as a debate. So folks were debating either pro-surveillance or pro-surgery. But both groups, both people, were presenting outcomes based on their centers. And it was folks who were fantastic. Dr. Molena, for example, from Memorial Sloan Kettering was talking about their outcomes in esophagectomies [during our session at GI26], but they do hundreds of these cases there per year. What's the reality in this country? 70% to 80% to 90%, depending on which data you look at, of the gastrectomies in the United States occur at low-volume hospitals. Most of the patients at those hospitals are disproportionately uninsured or on government insurance, have lower income and from racial and ethnic minority groups. So if we diffuse organ preservations without the system to support it, we're going to create a two-tiered system of care where whether you have the ability to preserve your organs, to preserve bodily integrity, depends on where you live and where you're treated. The other piece of this is the biomarker testing gap. One of the things that, as you pointed out at the beginning, that's really exciting is for MSI-high tumors. Those are the patients that are most likely to benefit from immunotherapy-based organ preservation. But here's the problem. If the patient isn't tested at time of initial diagnosis before they ever see me as a surgeon, the door to organ preservation is closed before it's ever open. And testing access remains very inconsistent across academic networks. And then there's the financial toxicity piece where, for gastrectomy, pancreatectomy, I do peritoneal malignancies, more than half of those patients experience significant financial toxicity related to their cancer treatment. We're now proposing adding at least two years, that's the preliminary information, right? It's probably going to be longer. At least a couple of years of surveillance visits, repeated endoscopies, immunotherapy costs. How are we going to support patients through that? We're going to have to think about setting up navigation support, geographic solutions, what financial counseling looks like. My patient for clinic yesterday was driving to see me, and they were talking about how they were sliding because it was snowing. And they were sliding for the entire three-hour drive down here. Are we going to tell people like that that they need to drive down to, right, I work at a high-volume center, they're going to need to come here every three months, come rain or snow, to get scoped as opposed to the one-time having a surgery and not needing to have the scopes as frequently? My concern, like I said, I'm an optimist, I think it is going to work. I think we're going to figure out how to make it work. I'm worried about whether when we deploy it, we widen the already existing disparities. Dr. Pedro Barata: Gotcha, and that's a fantastic summary. And as I'm thinking also of what we've been talking in other solid tumors, which one of the following do you think is going to evolve first? So we are starting to use more MRD-based assays, which are based on blood test, whether it's a tumor-informed ctDNA or non-informed. We are also trying to get around or trying to get more information response to systemic therapies out of RNA-seq through gene expression signatures, or development of novel therapeutics which also can help you there. Which one of these areas you think you're going to help this SANO-like approach move forward, or you actually think it's actually all of the above, which makes it even more complicated perhaps? Dr. Ugwuji Maduekwe: I think it's going to be all of the above for a couple of reasons. I would say if I had to pick just one right now, I think ctDNA is probably the most promising and potentially the missing piece that can help us close the gap between clinical and pathologic response. If you achieve clinical complete response and your ctDNA is negative, so you have clinical and molecular evidence of clearance, maybe that's a low-risk patient for surveillance. If you have clinical complete response but your ctDNA remains positive, I would say you have occult molecular disease and we probably need intensified therapy, closer monitoring, not observation. I think the INFINITY trial is already incorporating ctDNA into its algorithm, so we'll know. I don't think we're at the point where it alone can drive surgical decisions. I think it's going to be a good complement to clinical response evaluation, not a replacement. The issue of where I think it's probably going to be multi-dimensional is the evidence base: who are we testing? Like, what is the diversity, what is the ancestral diversity of these databases that we're using for all of these tests? How do we know that ctDNA levels and RNA-seq expression arrays are the same across different ancestral groups, across different disease types? So I think it's probably going to be an amalgam and we're going to have to figure out some sort of algorithm to help us define it based on the patient characteristics. Like, I think it's probably different, some of this stuff is going to be a little bit different depending on where in the stomach the cancer is. And it's going to be a little bit more difficult to figure out if you have a complete clinical response in the antrum and closer to the pylorus, for example. That might be a little bit more difficult. So maybe the threshold for defining what a clinical complete response needs to be is higher because the therapeutic approach there is not quite as onerous as for something at the GE-junction. Dr. Pedro Barata: Wonderful. And I'm sure AI, whether it's digitization of the pathology from the biopsies and putting all this together, probably might play a role as well in the future.  Dr. Maduekwe, it's been fantastic. Thank you so much for sharing your insights with us and also congrats again for the really well-done review published.  For our listeners, thank you for staying with us. Thank you for your time. We will post a link to this fantastic article we discussed today in the transcript of this episode. And of course, please join us again next month on the By the Book Podcast for more insights on key advances and innovations that are shaping modern oncology. Thank you, everyone. Dr. Ugwuji Maduekwe: Thank you. Thank you for having me. Watch the ASCO GI26 session: Organ Preservation for Gastroesophageal and Gastric Cancers: Ready for Primetime? 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. Ugwuji Maduekwe @umaduekwemd 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. Ugwuji Maduekwe: Leadership: Medica Health Research Funding: Cigna    

Featuring perspectives from Dr Stacey A Cohen, Dr Christopher Lieu and Dr Jenny Seligmann, moderated by Dr Lieu, including the following topics:  Introduction (0:00) Neoadjuvant Treatment for Localized Colorectal Cancer (CRC) — Dr Seligmann (2:39) Emerging Novel Approaches to Adjuvant Treatment for Localized CRC — Dr Lieu (33:18) Role of Circulating Tumor DNA Testing in Localized CRC — Dr Cohen (59:43) CME information and select publications

[Ep.317] Miedo y Asco. Un encuentro anunciado como catástrofe. Pronósticos apocalípticos, horas de suspenso...Donald Trump y Gustavo Petro se encontraron y, contra todo libreto mediático, el final fue menos dramático de lo esperado. En este episodio miramos cómo los medios narraron el miedo, cómo administraron la incertidumbre en un en vivo eterno de martes y cómo dejaron ver —sin filtros— una opinión pública dividida.Con Andrés Páramo, Juan Álvarez y María Paula MartínezInvitada: María Fernanda FitzgeraldPos producción: Mónica CastiblancoCollage: Santiago Rivas#presunto #CríticadeMedios #Análisis #mediosPresunto es un proyecto que analiza narrativas mediáticas. Gracias por apoyarnos vía Patreon. :)Notas del episodioEn Vivo de Coronell hablando sobre la puerta https://www.youtube.com/watch?v=auehzGs2evgLos Danieles, Epstein y Pastrano https://cambiocolombia.com/los-danieles/articulo/2026/2/epstein-y-pastrana/Silla Vacía, Epstein, Pastrana y Maxwellhttps://www.lasillavacia.com/en-vivo/nuevos-archivos-de-epstein-revelan-mensajes-entre-pastrana-y-maxwell/Foto Gerardo Reyes en Xhttps://x.com/GerardoReyesC/status/2002549105927815295Petro-Trump el espectador https://www.elespectador.com/opinion/columnistas/el-espectador/editorial-en-video-cita-petro-trump-no-es-hora-de-provocaciones/?outputType=ampTrump From Epstein, The daily Showhttps://youtu.be/cwXIq81eE24?si=D6VvsBNrrF0nC-32Steve Eder, New York Timeshttps://www.instagram.com/reel/DQ_-rQRj6vh/?igsh=MTIxN2JicTBwMmNhOQ%3D%3DFitzgerald on Epsteinhttps://www.instagram.com/reel/DURfnSSiXy2/?igsh=MWxyMjZiODBsbWdkNQ%3D%3D6 AM W, emisión del martes 3F, 6:30 am / Ahí está la franja divina sobre regalos y “tela ancestral” Hosted on Acast. See acast.com/privacy for more information.

Dr Stacey A Cohen from Fred Hutchinson Cancer Center in Seattle, Washington, Dr Jenny Seligmann from the University of Leeds in the United Kingdom and Dr Christopher Lieu from the University of Colorado Cancer Center in Aurora review clinical findings from the 2026 ASCO Gastrointestinal Cancers Symposium relevant to the management of localized colorectal cancer.CME information and select publications here.

Dr Stacey A Cohen from Fred Hutchinson Cancer Center in Seattle, Washington, Dr Jenny Seligmann from the University of Leeds in the United Kingdom and Dr Christopher Lieu from the University of Colorado Cancer Center in Aurora review clinical findings from the 2026 ASCO Gastrointestinal Cancers Symposium relevant to the management of localized colorectal cancer.CME information and select publications here.

Dr Stacey A Cohen from Fred Hutchinson Cancer Center in Seattle, Washington, Dr Jenny Seligmann from the University of Leeds in the United Kingdom and Dr Christopher Lieu from the University of Colorado Cancer Center in Aurora review clinical findings from the 2026 ASCO Gastrointestinal Cancers Symposium relevant to the management of localized colorectal cancer.CME information and select publications here.

Dr. Monty Pal and Dr. Atul Batra discuss the PLANeT study from India, which evaluated low-dose pembrolizumab in addition to neoadjuvant chemotherapy for triple-negative breast cancer, and its place among a growing body of international research on improving efficacy while reducing costs and toxicity with lower doses of immunotherapy. 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, professor, and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center, Los Angeles. My guest today, I think, is going to be a really riveting one. It's Dr. Atul Batra, who is an additional professor of medical oncology at the All India Institute of Medical Sciences, or AIIMS, in New Delhi. And he's also the senior author of the PLANeT study. It's a very compelling study that evaluated low-dose pembrolizumab in addition to neoadjuvant chemotherapy for triple-negative breast cancer. And it's really a big part of a growing body of research that's showing balanced efficacy when we use lower doses of immunotherapy instead of standard doses to reduce cost, as well as potentially toxicity. I think this has huge implications for our global audience, and I'm so thrilled to have you on the podcast today, Dr. Atul Batra, welcome. Dr. Atul Batra: Thank you, Dr. Pal. Dr. Monty Pal: And we'll just take it with first names from here since we're both friends. I have to give the audience some context. Atul, I had the great honor of visiting AIIMS New Delhi. For those that don't know, this is really, you know, the Harvard Medical School of India. It's the most competitive institution for medical training. And on the back end of that, there's also incredible resources when it comes to clinical trials and infrastructure. I just wanted to have you give the audience sort of a scope of the types of trials that you've been able to do at AIIMS New Delhi. Dr. Atul Batra: Thank you, Monty. So, I work at the All India Institute of Medical Sciences, and we had the honor and pleasure of having Monty here this month. And people are still in awe of his lectures that he delivered there. Coming back to our institute, so it's kind of a medical college. It's one of the oldest ones, it was built in 1956. We are lucky enough that we get the best of the residents and fellows because they have to go through an exam, a competitive exam, and mostly it's them who come to us and we're able to do some good work out here. Regarding the trials that we have conducted, we do conduct some investigator-initiated studies, and we try to answer the questions where we can help our own patients. Like, for example, this PLANeT study. Every other patient in the clinic was almost not able to afford Keytruda at the full dose, pembrolizumab, and we had a lot of evidence creeping in that a lower dose might be helpful. And that's how we planned this study. Before that, there are certain cancers that are peculiar to India, like gallbladder cancer, head and neck cancers. These are much more common in India as compared to the U.S., and there are some good studies that have been conducted from our own institute by our senior colleagues which have been presented at ASCO and published in the JCO. We also did the capecitabine hand-foot syndrome study that was known as the D-ToRCH study: 1% diclofenac gel that became the standard of care to prevent hand-foot syndrome.  So, that's kind of a brief overview of investigator-initiated studies. India is slowly and steadily becoming a partner of the global registration trials. And it's more recently, the last five years or so, we have seen that the number of phase 2 and phase 3 trials are increasing and we are able to offer now these trials as well to our patients. Dr. Monty Pal: That was a terrific overview. I just want to highlight for the audience, as we go through some of your discussions today around specific trials, the speed at which this can be done. Just for context, for me to accrue a clinical trial of 30 patients – I think many people have probably come across some of the work that I've done in the microbiome space – at a single institution, 30 patients, right, takes me about a year and a half, two years. We're going to go through some trials today where Dr. Batra and his team have actually, in fact, accrued close to 200 patients over a span of just a year, which is just remarkable by, I would say, any American standard. So, I see a real need for partnership and Atul, I'll kind of get back to that at the end. But without further ado, the focus of this podcast today, I think, is really this terrific presentation you gave in an oral session at ESMO and subsequently published in Annals of Oncology related to the PLANeT study. Would you give the listeners some context around what the study entailed and population and so forth? Dr. Atul Batra: So, we know the KEYNOTE-522 became the standard of care for triple-negative breast cancer, where Keytruda, when added at 200 mg, the standard dose every three weeks with neoadjuvant, increases the pCR from around 51% to 64% by a magnitude of around 13%. However, in India and other low-middle income countries, less than 5% of the patients actually have access to this dose of pembrolizumab. So, our standard of care was actually just chemotherapy till now. And this kind of led us to design this trial. There are data that come from previous trials conducted in India, from the Tata Memorial, done in head and neck space, some other studies done in Hodgkin's lymphoma, that a much lower dose, probably around one-tenth of the dose, works well in these cancers. So, that's where we designed the PLANeT study, where we gave the standard neoadjuvant chemotherapy in the control arm, and in the experimental arm we added 50 mg of pembrolizumab. This was given every six weeks for three doses. So, that's a total of 150 mg over the neoadjuvant period as compared to 1,600 mg that was given in the KEYNOTE-522 study. So, this was almost one-tenth of the study. Dr. Monty Pal: So, a tenth of the dose, which is just remarkable. I mean, that's just such an interesting concept. Dr. Atul Batra: And the results, when we – the primary outcome, this was a phase 2 study. We just wanted to see, is there a signal of activity? And to even our surprise, when we looked at the pathological complete response rates, in the control arm this was 40.5%, and in the experimental arm this was 53.8%. So, a difference came to around 13.3%; it was numerically, I mean, so much similar to what KEYNOTE-522 had with just these many doses. So, this was around 160 patients randomized over one year. We could randomize them in one year because of the load that we see. And the primary endpoint was met, and we could see that the path complete response did show a remarkable increase. We are still following these patients to see whether there is a difference in event-free survival at a longer follow-up. Until now, it's a small follow-up, so the number of events absolute, are different: four events in the experimental arm and 11 events in the control arm. So, we are seeing some signal even in this much short follow-up period as well. But we need to see more of what happens in the longer term. Dr. Monty Pal: That's so impressive. I wonder, with this lower dose, do you attenuate toxicity at all as far as you can gather? Dr. Atul Batra: So, although we shouldn't be doing kind of cross-trial comparisons, but if you look at thyroid dysfunction, we saw that around 10% of our patients had this thyroid dysfunction. This was compared to 15% in the KEYNOTE-522, that was a larger sample size though. But we're seeing that all the toxicities are somewhat less as compared to those in the standard dose. So, the exposure is less, but I mean, I can't really commit definitely on this. For this we would need much more data to say this with more confidence. Dr. Monty Pal: Yeah. I'm going to ask you a really tough question to follow up, and this is probably something that's on everyone's mind after reading a study like this. Is this something that is disease-specific that needs to be replicated across other histologies? The reason I ask this is, you know, you think about paradigms like, for instance, in the States we're toying between intravenous versus subcutaneous delivery of checkpoint inhibitors, and we have studies focused in specific histologies that might justify use across all histologies. With this particular phenomenon, do you think we need to do dedicated studies in renal cell or in colon cancer and other places where, you know, in selected settings we might use checkpoint inhibitors and then decide whether or not there's this dose equivalence, if you will? Dr. Atul Batra: That's a real tough one, though. But I'm happy to share that there are several ongoing studies within India currently. At our institute, my colleagues are leading studies in lung cancer space, cervical cancer. There was already a publication from Tata Memorial Hospital in head and neck cancers and we see that the signal has been consistent throughout. Regarding renal cancer, there was one study that was presented for sure at ASCO from CMC Vellore, that's again a center in South India. That was in RCC at a much lower dose. And for patients who cannot take the full dose, we actually are offering lower dose nivolumab in such patients and we are seeing responses. I mean, we haven't done those randomized trials again because the numbers are much lower in kidney cancers, we know. We could do this trial in triple-negative ones because we had support and we had numbers to conduct this trial. But I'm sure this should be a class effect. I mean, when we can get tumor-agnostic approvals, then some real-world data has come up in almost all tumors, we have seen that consistent effect across tumors. And as we speak of today, I'm also delighted to share that in India, yesterday, we had the first biosimilar of nivolumab and that's now available at a much, much lower price than the original patent product. There was a long ongoing lawsuit that was there, that's over now, and from yesterday onwards, I'm so happy to share here that we would have the first biosimilar of nivolumab that's available. That's going to bring the cost to almost like one-tenth already. Dr. Monty Pal: Wow. That's huge.  I'm going to be very selfish here for a second and focus on a study that is in the renal cell space that your group has done. You know, when it came out, I was really sort of intrigued by this study as well and it reflects sort of a different capability, I think, of AIIMS New Delhi, and that's in the, what I'm going to call, biomarker space. This, for the audience, was a prospective effort to characterize germline variants in patients with advanced kidney cancer. And it's something that we talk about a lot in the kidney cancer literature, whether or not we're missing a lot of these so-called hereditary patterns of RCC. Can you tell us a little bit about that study too? Dr. Atul Batra: Yeah, so that was led by one of our fellows, Chitrakshi Nagpal, and she's just completed her fellowship. And two years back we published that. So, that was done in almost 160 consecutive patients that we recruited over the span of just one year and we saw, apart from the common known mutations in RCC, that was around 5% or so, but a lot of other mutations were also seen that we don't generally see in kidney cancers and we see in other cancers like BRCA1, BRCA2 and others. We are still, I mean, doing those analyses to see whether we get more things out of there in the somatic: is there a loss of heterozygosity or was it just present and in there? Dr. Monty Pal: I thought it was a terrific study and again, I was just so blown away at the pace. I mean, as I look at 140 patients accrued over a span of one year, this is something that would take us perhaps three times as long at City of Hope, and that's with a very sort of, what I consider to be large and dedicated kidney cancer program. So, it really underscores, I think, the need for collaboration. And ever since I came back from my visit to you at AIIMS Delhi, I think I've just been sort of transformed in the sense of trying to think of better ways for us to collaborate. One tangible thing that I'm going to get cracking on is seeing whether or not perhaps we can form some partnerships through SWOG or what we call the NCTN, the National Clinical Trials Network here within the U.S. Talk to me about collaboration. I mean, you've been really terrific at this. How do you sort of envision collaboration enhancing the global landscape of oncology? Dr. Atul Batra: That's really amazing, Monty. That's what we need. We have the infrastructure, we have the manpower, we have patients. I mean, these are all high-volume centers. Unfortunately, we are a little less in numbers, so we are more clinically occupied as well. So, sometimes it's kind of tougher, but again, when it comes to helping out the patients, global collaboration, we need to kind of take you guys along with us and have our patients finish trials earlier. This is a win-win situation for patients, one, because they also get exposure or an option to participate in the clinical trials, and second, we can answer all these scientific questions that we have at a much faster pace. All those things can be done within a much shorter span of time for sure. We are so happy to hear that, and with open hands we are ready to collaborate for all these efforts. Dr. Monty Pal: That's awesome. You know, I came back thinking, gosh, this would be so ideal for some of these rare subtypes of kidney cancer. Prospective clinical trials that I'm running in that space where really we're threatened with closure all the time. And if we just sort of extended a hand to, you know, our partners in India and other countries, you know, I'm sure we could get this research done in a meaningful way and that's got to be a win for patients. Atul, I had such a terrific time chatting with you today. I'm looking forward to seeing lots more productivity from your group there. By the way, for our viewership here, take a look and see what AIIMS New Delhi is doing under the leadership of Dr. Batra and others. It is just a real powerhouse and I think that after doing so, you'll be enticed to collaborate as well.  I'm hoping this is the first of many times that we have you on the podcast. Thank you so much for joining. Dr. Atul Batra: Thank you so much for having me here, Monty. It was a pleasure as always speaking to you. And thank you again. Dr. Monty Pal: You got it.  Well, and thanks to our listeners. I encourage you to check out Dr. Batra's paper. We'll actually have a link to the study 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. Monty Pal   @montypal Dr. Atul Batra @batraatulonc 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. Atul Batra: Stock and Other Ownership Interests: Zydus Pharmaceuticals, Glenmark, Caplin Point Laboratories, Laurus Research Funding: AstraZeneca, Astellas Pharma, Alkem Laboratories

Dr. Joshua Reuss is back on the podcast to discuss the full update to the living guideline on stage IV NSCLC without driver alterations. He discusses the new evidence and how this impacts the latest recommendations on first-line and subsequent therapeutic options. Dr. Reuss emphasizes the need for shared decision-making between clinicians and patients. He shares ongoing research that the panel will review in the future for further updates to this living guideline, and puts the updated recommendations into context for clinicians treating patients with stage IV NSCLC. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2026.3.0" at www.asco.org/thoracic-cancer-guidelines" TRANSCRIPT This guideline, clinical tools and resources are available at www.asco.org/thoracic-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-25-02825    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. Joshua Reuss from Georgetown University, co-chair on "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2026.3.0." It is great to have you back on the show today, Dr. Reuss. Dr. Joshua Reuss: Happy to be here, Brittany. Brittany Harvey: 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. Reuss 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. Dr. Reuss, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations is updated on an ongoing basis. So, what prompted this latest update to the recommendations? Dr. Joshua Reuss: Our committee is tasked with making routine updates to the living guidelines and really keeping them living, right? So, evaluating new data as it is coming in to see, is this practice changing? Is this data that should inform and potentially alter our guideline recommendations so that practitioners and other care providers could really make the best treatment decisions for their patients? So that is something that happens on a more routine basis, but periodically, we are tasked with performing a more comprehensive update of our guideline where we really evaluate every one of our point recommendations, the data associated with these recommendations, to be sure that these are up to date, these are comprehensive, and to see if we need to alter anything in the language of these updates. Brittany Harvey: Excellent. Thank you for providing that background. And yes, this is truly a comprehensive update that goes through all the latest literature. Given that, I would like to review what has changed and what is new in the recommendations. So, what are the updated recommendations on first-line therapy for patients with stage IV non-small cell lung cancer without driver alterations? Dr. Joshua Reuss: So there are two main guidelines that we recommend from this panel. One is a driver mutation-positive guideline and the other is a driver mutation-negative guideline. And I think on first blush, one might look at kind of the recent flurry of approvals and new data and say, well, all the excitement, you know, is in the driver mutation-positive guideline. But I would say that the driver mutation-negative guideline is equally as important and really has several unique challenges associated with it. You know, first and foremost is that there are really a multitude of regimens that can be considered for any one patient. And how to choose between one can be quite difficult and a stressful challenge that clinicians can have, particularly since there are really no randomized studies comparing these regimens in a head-to-head fashion. In addition, you know, these guidelines are really broken down by two key factors. One is disease histology, so namely squamous versus non-squamous histology. And the other is PD-L1 status, broken down into one of three tertiles: PD-L1 high, which is greater than or equal to 50% expression; PD-L1 low, which is 1% to 49% expression; and then PD-L1 negative or unknown. So what you are really looking at, if you do that math, is really six unique patient subpopulations where we need to make a recommendation on one of the multitude of treatment regimens that is approved. And what that means is you are oftentimes really looking at subset and sub-subset level data to help inform clinicians in their treatment decision making, which can be quite challenging because as those small subsets of data is more and more parsed, there are many confounders that can be interjected there. And so I think the committee is tasked with really quite a challenge in terms of how to really communicate and broadcast that data in a way that informs clinicians in making a decision on what is the right treatment for their patient. Brittany Harvey: Absolutely. It can be challenging to interpret that subgroup data across several different studies that are reporting on different regimens and different outcomes. And I appreciate you mentioning the driver mutation-positive guideline as well. Listeners can check out the companion episode with Dr. Puri for more information on what is changed in the driver mutation-positive guideline. Based on that primer, what is new for first-line therapy for patients with stage IV non-small cell lung cancer without driver alterations? Dr. Joshua Reuss: Even though I will say there is not a lot of new trial data that was incorporated into this guideline, there were some updates and just some meaningful long-term data that we incorporated. I think first and foremost, there is a new top-level recommendation in this guideline pertaining to molecular testing, which is absolutely critical in both the driver mutation-positive and driver mutation-negative space. I think we tend to think that, oh, well, molecular testing really only pertains to then finding a driver mutation. But the lack of a mutation is absolutely critical as well, right? Because that is what leads us down the mutation-negative pathway. We also need this molecular testing to assess PD-L1 status. We are seeing emerging data on molecular mutations that might confer resistance to certain immunotherapy-based strategies. So the committee felt strongly that a recommendation on molecular testing is critical to include in both the driver mutation-positive guideline and the driver mutation-negative guideline. I will also say that we are now seeing five and six-year updates from some of the landmark trials of immunotherapy in driver mutation-negative non-small cell lung cancer. It is really incredible to see that in some of these trials, we are seeing very impressive durability of the treatment in the patient subsets that we are commenting on. In others, perhaps that durability is less clear, and I think that leads to challenges in making a recommendation on any one particular regimen. And I think that is nowhere more clear than in the squamous subset. I think that was one perhaps subtle change that is in this guideline where, particularly in the PD-L1 negative squamous population, the committee felt that no one regimen really was worthy of standing above the others. Sometimes I think it is important to really champion one unique regimen if we feel that the data is there to support it. But I think it is equally important to list multiple regimens where the data is less clear. I think another point is that while perhaps there were no new regimens that we have added or that led to other clear changes in the prioritization of one regimen over another, there are other unique data subsets that I think come into play in making a decision and that really are important when looking at the discussion on any one recommendation from this guideline. For example, we know there is emerging data on perhaps the significance of molecular alterations in KEAP1 or STK11 and how that might influence frontline decision-making. You know, there is not a prospective phase III trial in this population, but I think we still need to use that data in certain scenarios to make recommendations for a particular patient. Another example of a trial that, again, did not change our recommendations, but I think one can incorporate in their decision making is the KEYNOTE-598 trial. Now, this is not a new study, but what it studied was pembrolizumab versus pembrolizumab plus ipilimumab in a PD-L1 high subset, and found that the addition of ipilimumab to pembrolizumab in the PD-L1 high population did not significantly improve clinical efficacy. And so while pembrolizumab plus ipilimumab is not an approved regimen, it is hard to extrapolate that to our combination treatments that are approved. I think some clinicians might find that data valuable when making a frontline treatment decision on a patient who has PD-L1 high status. So a bit of a whirlwind tour, but I think there are still multiple factors that went into this guideline that are important to review when making treatment decisions for any one patient. Brittany Harvey: Absolutely. I think what you just mentioned in having that upfront molecular testing is really key for individualized patient care. And the evidence summaries that you provide in addition to the recommendations are really important for clinicians to be able to refer to as they are making decisions in their clinic. So then beyond those changes for first-line therapy, what is updated for second-line and subsequent therapies? Dr. Joshua Reuss: For second-line and subsequent therapies, we did see one new treatment recommendation join these ranks, and that was telisotuzumab vedotin. Telisotuzumab vedotin, quite a mouthful. That is an antibody-drug conjugate. I like to think of that as smart chemotherapy, targeted chemotherapy, where you are trying to utilize some aspect of a marker that is selectively expressed or overexpressed on the cancer surface to then shepherd in the anticancer molecule, a highly potent chemotherapeutic in the case of currently approved antibody-drug conjugates, to exert antitumor killing effect. So in this case, the antibody-drug conjugate telisotuzumab vedotin targets MET overexpression. So telisotuzumab is an antibody targeting MET, and that is conjugated to an MMAE highly potent chemotherapeutic payload called vedotin. So we know MET can be selectively expressed and overexpressed in non-small cell lung cancer in both driver mutation-positive and mutation-negative subsets. The data that led to this approval was from the phase II LUMINOSITY trial which evaluated telisotuzumab vedotin, or Teliso-V, in many subsets. But the subset that really showed promise and was expanded was the EGFR wild-type, non-squamous, non-small cell lung cancer population with MET overexpression. And so in 78 patients with high levels of expression, the response rate here was 34.6%, median progression-free survival of 5.5 months, and a median overall survival of 14.6 months. With an overall acceptable safety profile; grade 3 or higher adverse events, neuropathy was perhaps the most common at 7%, also increased ALT at 3.5%, and pneumonitis at 2.9%. Now this was phase II data that led to an accelerated approval. There is an ongoing phase III study randomizing patients with high expression to Teliso-V versus docetaxel. That is the phase III TeliMET study. But it is nice that we now have another option for patients, perhaps a more biomarker-directed option with, again, this MET overexpression. And again, it further reinforces the importance of molecular testing in patients with traditionally driver mutation-negative non-small cell lung cancer, whether that is upfront or at progression, and in particular utilizing immunohistochemistry to assess MET expression in these patients. And this does join another ADC that we had previously made an update in our recommendation, which is trastuzumab deruxtecan, which is approved for those patients with HER2-overexpressing non-small cell lung cancer. So just again to reiterate the importance of molecular testing in patients both at the outset of their treatment and upon progression on frontline therapy. Brittany Harvey: Definitely. It is great to have this new antibody-drug conjugate join the treatment options, and as you mentioned, very important in this case to have that molecular testing done at the outset and at progression. So then in your view, what should clinicians know as they implement this living guideline, and how do these changes impact patients with non-small cell lung cancer? Dr. Joshua Reuss: Because there are so many different regimens that one can consider for any one patient, I think it is easy to become overwhelmed and stress on, "Am I making the right choice for my patient?" And I think one of the key take home points is that in many cases, there is no one right regimen. And I think one has to weigh several factors. It is the treatment schedule. It is the toxicity profile. It is the molecular profile of the patient. It is the patient preference. You know, there are so many factors here. And I would like to draw the reader and viewer's attention to an important section of these guidelines, particularly the Patient and Clinician Communication section, where we have a box focused on discussion points between patients and clinicians, which I think focuses on several of the high-level points that one can emphasize in making these decisions, ranging on things from: what are the goals of the treatment? What are the risks and benefits to any one approach? What are comorbidities that should be factored in? Common concerns, toxicity management, clinical trial consideration. All of these factors that I think are incredibly important in making that frontline treatment decision and implementing a regimen that both the clinician and, more importantly, the patient feels comfortable with. Brittany Harvey: It is really important that there is shared decision-making in these scenarios. And I think that patient-clinician communication section can tease out some of those preferences from the patient end and talk through the risks and benefits of different regimens as well. As we mentioned at the top of this episode, this guideline is a living guideline and updated on an ongoing basis. So what is the panel examining and keeping an eye on for future updates to this guideline? Dr. Joshua Reuss: So I think there are a lot of exciting new therapies and more up-to-date trials that we are anxiously awaiting the results of on our committee, and I think the oncology community in general is awaiting the results of. When we will have these results, I think, is a bit of an open-ended question, but I can give some insight on several of the trials that our committee is really keeping a close eye on. One that we have mentioned for several guideline iterations is the ECOG-ACRIN INSIGNA trial. This is a phase III clinical trial comparing pembrolizumab versus pembrolizumab plus carboplatin and pemetrexed chemotherapy in PD-L1 positive, non-squamous, non-small cell lung cancer. We talk about there being different regimens that can be considered in PD-L1 positive and PD-L1 high subsets, namely immunotherapy alone or immunotherapy plus chemotherapy, but there is no direct head-to-head comparison here. So this trial hopefully will answer that question. It has now finished accrual. There are other very interesting molecules and trials. I think another interesting compound is ivonescimab. This is a PD-1/VEGF bispecific antibody that is currently approved in China as monotherapy in patients with PD-L1 positive non-small cell lung cancer based off of the HARMONi-2 trial, where the progression-free survival of this bispecific antibody, ivonescimab, appeared superior to pembrolizumab. And we are looking closely at ongoing trials to see if these results will be replicated in an ex-China population. And if so, I think it could have a real impact and change on our guidelines. Still other very interesting things. There are obviously confirmatory studies for antibody-drug conjugates, such as the TeliMET study that I alluded to earlier, and many promising antibody-drug conjugates, both bispecific and trispecific antibody-drug conjugates, that hopefully can inform practice. And then there are several unique subsets of populations that I think we now are utilizing data on to make decisions, but a lot of that is retrospective in small subsets where we do not have that prospective data. And there are several trials ongoing in some of these subsets to try to gain clarity on what regimen may be the best for patients. One example is the phase III TRITON trial, which is looking at comparing CTLA-4 containing regimen, particularly the POSEIDON regimen of durvalumab plus tremelimumab and chemotherapy, versus the KEYNOTE-189 regimen, which is pembrolizumab plus carboplatin and pemetrexed, in patients with non-squamous, non-small cell lung cancer that have alterations in either KRAS, KEAP1, and/or STK11. There is a lot of both preclinical and clinical data to suggest that patients with these alterations in STK11 and KEAP1 may be more resistant to a PD-1 based treatment approach, and perhaps the incorporation of CTLA-4 can lead to a more meaningful response in this unique subset. Obviously, that data, it is retrospective, it is in small subsets. And when you add in a CTLA-4 molecule, you are also introducing greater risk for toxicity. So this trial is going to be very important in elucidating: is there a benefit in that unique subset? Does that data that we see retrospectively in this small subset hold true when evaluated in a prospective fashion? So while our guideline, our most recent comprehensive panel update, may not have had a lot of new data in it that has influenced frontline treatment decision-making, I think the future is bright and there are a lot of novel studies and novel treatments on the horizon that will hopefully improve the outcomes for our patients. Brittany Harvey: Absolutely. We will look forward to the results of those ongoing trials to provide more options and particularly clarity for patients with non-small cell lung cancer and to inform this guideline and its many updates to come. So I want to thank you so much for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Reuss. Dr. Joshua Reuss: Thank you so much. Brittany Harvey: 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/thoracic-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.  

Dr. Sonam Puri discusses the full update to the living guideline on stage IV NSCLC with driver alterations. She shares a new overarching recommendation on biomarking testing and explains the new recommendations and the supporting evidence for first-line and subsequent therapies for patients with stage IV NSCLC and driver alterations including EGFR, MET, ROS1, and HER2. Dr. Puri talks about the importance of this guideline and rapidly evolving areas of research that will impact future updates. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2026.3.0" at www.asco.org/thoracic-cancer-guidelines TRANSCRIPT This guideline, clinical tools and resources are available at www.asco.org/thoracic-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-25-02822    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'm interviewing Dr. Sonam Puri from Moffitt Cancer Center, co-chair on "Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO Living Guideline, Version 2026.3.0." It's great to have you here today, Dr. Puri. Dr. Sonam Puri: Thanks, Brittany. Brittany Harvey: And then just before we discuss this guideline, I'd 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. Puri, 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. So then, to dive into the content that we're here today to talk about, Dr. Puri, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer with driver alterations is updated on an ongoing basis. So, what data prompted this latest update to the recommendations? Dr. Sonam Puri: So Brittany, non-small cell lung cancer is one of the fastest-moving areas in oncology right now, particularly when it comes to targeted therapy for driver alterations. New data are emerging continuously from clinical trials, regulatory approvals, real-world experience, which is exactly why these are living guidelines. The goal is to rapidly integrate important advances as they happen, rather than waiting for years for a traditional update. Since the last full update of the ASCO Stage IV Non-small Cell Lung Cancer Guideline with Driver Alterations published in 2024, there have been seven new regulatory approvals and changes in first-line therapy for some driver alterations. [This version] of the "Stage IV Non-small Cell Lung Cancer Guidelines with Driver Alterations" represents a full update, which means that the panel reviewed and refreshed every applicable section of the guideline to reflect the most current evidence across therapies including sequencing and clinical decision-making. This is to ensure that clinicians have up-to-date practical guidelines that keep pace with how quickly the field is evolving. Brittany Harvey: Absolutely. As you mentioned, this is a very fast-moving space and this full update helps condense all of those versions that the panel reviewed before into one document, along with additional approvals and new trials that you reviewed during this time period. So then, the first aspect of the guideline is there's a new overarching recommendation on biomarker testing. Could you speak a little bit to that updated recommendation? Dr. Sonam Puri: Yeah, definitely. So the panel has discussed and provided recommendations on comprehensive biomarker testing and its importance in all patients diagnosed with non-small cell lung cancer. Ideally, biomarker testing should include a broad-based next-generation sequencing panel, rather than single-gene tests, along with immunohistochemistry for important markers such as PD-L1, HER2, and MET. These results really drive treatment decisions, both in frontline settings for all patients diagnosed with non-small cell lung cancer and in subsequent line settings for patients with non-small cell lung cancer harboring certain targetable alterations. Specifically in the frontline setting, it helps determine whether a patient should receive upfront targeted therapy or immunotherapy-based approach. We now have strong data that shows that complete molecular profiling results before starting first-line therapy is associated with better overall survival and actually more cost-effective care. Using both tissue and blood-based testing can improve likelihood of getting actionable results in a timely way, and we've also provided guidance on platforms that include RNA sequencing, which are specifically helpful for identifying gene fusions that might be otherwise missed with other platforms. On the flip side, outside of a truly resource-limited setting, single-gene PCR testing really should not be routine anymore. This is what the panel recommends. It's less sensitive and inefficient and increases the risk of missing important actionable alterations. Brittany Harvey: Understood. I appreciate you reviewing that recommendation. It really helps identify critical individual factors to match the best treatment option to each individual patient. So then, following that recommendation, what are the updated recommendations on first-line therapy for patients with stage IV non-small cell lung cancer with a driver alteration? Dr. Sonam Puri: Since the last full update in 2024, there have been four additional interim updates which were published across 2024 and 2025. Compared to the last version, there have been several updates which have been included in this full update. One of the most important shifts has been in first-line treatment of patients with non-small cell lung cancer harboring the classical, or what we call as typical, EGFR mutation. The current version of the recommendation is based on the updated survival data from the phase III FLAURA2 and MARIPOSA studies, based on which the panel recommended to offer either osimertinib combined with platinum-pemetrexed chemotherapy or the combination of amivantamab plus lazertinib in the first-line treatment of classical EGFR mutations. And these recommendations, as I mentioned, are grounded in the results of the FLAURA2 and MARIPOSA trials, both of which demonstrated improvement in progression-free survival and overall survival compared to osimertinib alone in patients with common EGFR mutations. That being said, the panel actually spent significant time discussing the toxicities associated with these treatments as well. These combination approaches come with higher toxicity, longer infusion time, increased treatment frequency. So while combination therapy is now recommended as preferred, the panel has recommended that osimertinib monotherapy remains a reasonable option, particularly for patients with poor performance status and for those who are not interested in treatment intensification after knowing the risks and benefits. Brittany Harvey: Absolutely. It's important to consider both those benefits and risks of those adverse events that you mentioned to match appropriately individualized patient care. So then, beyond those recommendations for first-line therapy, what is new for second-line and subsequent therapies? Dr. Sonam Puri: So this is a section that saw several major updates, particularly again in the EGFR space. The first was an update on treatment after progression on osimertinib for patients with classical EGFR mutation. Here the panel recommends the combination of amivantamab plus chemotherapy, and this recommendation was based on the phase III MARIPOSA-2 trial, which compared amivantamab plus chemotherapy with chemotherapy alone with progression-free survival as the primary endpoint. The study met its primary endpoint, showing an improvement in median PFS with the combination of amivantamab plus chemotherapy compared to chemotherapy alone. And as expected, the combination was associated with higher toxicity. So, although the panel recommends this regimen, the panel emphasizes that patients should be counseled on the side effects which may be moderate to severe with the combination therapy approach. In addition, a new recommendation was added for patients who are not candidates for amivantamab plus chemotherapy. In those cases, platinum-based chemotherapy with or without continuation of osimertinib may be offered, and the option of continuing osimertinib with chemotherapy was recommended and supported by data from a recently presented phase III COMPEL study, which randomized 98 patients with EGFR exon 19 deletion or L858R-mutated advanced non-small cell lung cancer who had experienced no CNS progression on first-line osimertinib, and these patients were randomized to receive platinum-pemetrexed chemotherapy with osimertinib or placebo. Although this study was small, it demonstrated a PFS benefit with continuation of osimertinib with chemotherapy, and this approach may be appropriate for patients without CNS progression who prefer or require alternatives to more intensive treatment strategies. Next was an update on options for patients with EGFR-mutated lung cancer after progression on osimertinib and platinum-based chemotherapy. Here the panel recommended that for patients whose disease has progressed after both osimertinib and platinum-based chemotherapy, a new drug known as datopotamab deruxtecan can be offered as a treatment option. And this treatment recommendation was based on evaluation of pooled data from the TROPION-Lung01 and TROPION-Lung05 study, in which in the pooled analysis about 114 patients with EGFR-mutant non-small cell lung cancer were treated with Dato-DXd, 57% of whom had received three or more prior lines of treatment, and what was observed was an overall response rate of 45% with a median duration of response of 6.5 months. So definitely promising results. Next, we focused on updates to subsequent therapy options for patients with another type of EGFR mutation known as EGFR exon 20 insertion mutations. In this section, the panel added sunvozertinib as a subsequent line option after progression on platinum-based chemotherapy with or without amivantamab. Sunvozertinib is an oral, irreversible, and selective EGFR tyrosine kinase inhibitor with efficacy demonstrated in the phase II WU-KONG6 study conducted in Chinese patient population. In this study, amongst 104 patients with platinum-pretreated EGFR exon 20 mutated non-small cell lung cancer, the observed response rate was 61%. Staying in the EGFR space, the panel added a recommendation for patients with acquired MET amplification following progression on EGFR TKI therapy. In these situations, the panel recommended that treatment may be offered with osimertinib in combination with either tepotinib or savolitinib. As our listeners may know, MET amplification occurs in approximately 10% to 15% of patients with EGFR-mutated non-small cell lung cancer when they progress on third-generation EGFR TKIs, and detection of MET amplification is done with various methods, such as tissue-based methods like FISH, NGS, and IHC, as well as ctDNA-based NGS with variable cut-offs. Over the last few years, several studies have informed this recommendation. I'm going to be discussing some of them. In the phase II ORCHARD trial, 32 patients with MET-amplified non-small cell lung cancer after progression on first-line osimertinib were evaluated, where the combination of osimertinib plus savolitinib achieved an overall response rate of 47% with a duration of response of 14.5 months. More recently, the phase II SAVANNAH trial reported outcomes in 80 patients with MET-amplified tumors after progression on osimertinib, and in this patient population, the combination of savolitinib and osimertinib achieved an overall response rate of 56% with a median PFS of 7.4 months. And lastly, the phase II single-arm INSIGHT 2 trial assessed the efficacy of osimertinib plus tepotinib in patients with advanced EGFR-mutant non-small cell lung cancer who had disease progression following first-line osimertinib therapy. And in this study, in a cohort of 98 patients with MET-amplified tumors confirmed by central testing, the overall response rate with the combination was 50% with a duration of response of 8.5 months. So definitely informing this guideline recommendation. Next, we had an update on recommendation in patients with ROS1-rearranged non-small cell lung cancer. For patients with ROS1-rearranged non-small cell lung cancer, the panel recommended specifically for patients who progressed after first-line ROS1 TKIs, the addition of taletrectinib as a new option alongside repotrectinib. And this recommendation was based on analysis of the results of the TRUST-I and TRUST-II studies, which showed that amongst 113 tyrosine kinase inhibitor-pretreated patients, taletrectinib achieved a confirmed overall response rate of 55.8% with a median duration of response of 16.6 months and a median PFS of 9.7 months, a very promising agent. Finally, for patients with HER2 exon 20 mutated non-small cell lung cancer, the panel added two new oral HER2 tyrosine kinase inhibitors, zongertinib and sevabertinib, as options in addition to T-DXd and after exposure to T-DXd. These recommendations are based on early phase data from two trials: the phase I Beamion LUNG-01 study, which evaluated zongertinib, and the phase I/II SOHO-01 study that evaluated sevabertinib. In this study, zongertinib demonstrated an overall response rate of 71% in previously treated patients, with an overall response rate of 48% amongst patients who had received prior HER2-directed ADCs including T-DXd. Sevabertinib in its early phase study showed an overall response rate of 64% in previously treated but HER2 therapy-naive patients, and an overall response rate of 38% in patients previously exposed to HER2-directed therapy. The panel believes that both agents had manageable toxicity profile and represent meaningful new options for this patient population. Brittany Harvey: Certainly, it's an active space of research, and I appreciate you reviewing the evidence underpinning all of these recommendations for our listeners. So, it's great to have these new options for patients in the later-line settings. And given all of these updates in both the first and the later-line settings, what should clinicians know as they implement this latest living guideline update, and how do these changes impact patients with non-small cell lung cancer? Dr. Sonam Puri: Some great questions, Brittany. I think for clinicians when implementing this update, I think about two practical steps. First is reiterating the importance of comprehensive biomarker testing. That is the only way to identify key drivers and resistance mechanisms that we are now targeting. And second, picking a first-line strategy that balances efficacy and toxicity and patient preference for your specific patient. I think informed decision-making, shared decision-making is more important than any time right now. It has always been important, but definitely very important now. For patients, this guideline brings recommendations on more personalized treatment options for both first-line and post-progression settings, which potentially means better outcomes. But it is also very important for our patients to continue to have informed conversations about side effects, time commitment, and what matters most to them with their providers. The panel in this version of the guideline specifically acknowledges the real-world barriers that prevent patients from receiving guideline-concordant therapy, including challenges with access to comprehensive molecular testing and treatment availability, and the panel emphasizes on the importance of shared decision-making, and we provide practical discussion points to help clinicians navigate these conversations with the patient. In addition, the panel has also addressed common real-world clinical complexities, such as treating elderly or frail patients, managing multiple chronic conditions, considerations around pregnancy and fertility, and certain disease scenarios such as oligoprogression or oligometastatic disease. And where available, the guideline summarizes this existing data to support informed individual decision-making in these complex situations. Brittany Harvey: Shared decision-making is really paramount, especially with all of the options and weighing the risks and benefits and considering the individual circumstances of each patient that comes before a clinician. We've talked a lot about all of the new studies that the panel has reviewed, but what other studies or areas of research is the panel examining for future updates to this living guideline as it continues to be updated on an ongoing basis? Dr. Sonam Puri: Yes, definitely, so much to look forward to, right? Looking ahead, the panel is closely monitoring several rapidly evolving areas that are likely to shape future updates of the guideline. This includes emerging data from ongoing later-phase studies, particularly the studies that are evaluating these new targeted agents moving to earlier lines of therapy, alongside studies evaluating additional combination strategies or more refined approaches to treatment sequencing. We're also closely watching advances in biomarker testing, the evolving understanding of resistance mechanisms, development of new targets, and promising therapeutic agents. I think ultimately the living guideline exists to help clinicians and patients navigate this rapidly evolving field, and we would like to ensure that scientific advances are rapidly translated into better, more personalized patient care. Brittany Harvey: Definitely. We'll look forward to those updates from those ongoing trials and future areas of research that you mentioned to provide better options for patients with non-small cell lung cancer and a driver alteration. So I want to thank you so much for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Puri. Dr. Sonam Puri: Thanks so much. Thanks so much for the opportunity. Brittany Harvey: 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/thoracic-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. There's also a companion episode with Dr. Reuss on the related living guideline on stage IV non-small cell lung cancer without driver alterations that listeners can find in their feeds as well. And if you've enjoyed what you've 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.  

Featuring perspectives from Dr Jaffer A Ajani, Dr Samuel J Klempner, Dr Rutika Mehta and Dr John Strickler, moderated by Dr Klempner, including the following topics:  Introduction (0:00) HER2-Targeted Approaches for Advanced Gastroesophageal Cancers — Dr Ajani (2:02) Faculty Panel Discussion: Cases and Questions from the Community (14:13) Targeting Claudin 18.2 in Advanced Gastroesophageal Cancers — Dr Strickler (37:29) Faculty Panel Discussion: Cases and Questions from the Community (49:21) Optimal Incorporation of Immunotherapeutic Strategies into Treatment for Patients with Metastatic Gastroesophageal Tumors — Dr Mehta (1:09:56) Faculty Panel Discussion: Cases and Questions from the Community (1:22:02) Other Novel Agents and Strategies Under Evaluation for Advanced Gastroesophageal Cancers — Dr Klempner (1:44:23) CME information and select publications

Dr Jaffer Ajani from The University of Texas MD Anderson Cancer Center in Houston, Dr Rutika Mehta from Weill Cornell Medicine/NewYork-Presbyterian Hospital in New York, New York, Dr John Strickler from Duke University in Durham, North Carolina, and Dr Samuel Klempner from Massachusetts General Hospital in Boston review relevant data supporting immunotherapy for patients with gastroesophageal cancers and review recently presented clinical findings from the 2026 ASCO Gastrointestinal Cancers Symposium.CME information and select publications here.

Dr Jaffer Ajani from The University of Texas MD Anderson Cancer Center in Houston, Dr Rutika Mehta from Weill Cornell Medicine/NewYork-Presbyterian Hospital in New York, New York, Dr John Strickler from Duke University in Durham, North Carolina, and Dr Samuel Klempner from Massachusetts General Hospital in Boston review relevant data supporting immunotherapy for patients with gastroesophageal cancers and review recently presented clinical findings from the 2026 ASCO Gastrointestinal Cancers Symposium.CME information and select publications here.

Dr Jaffer Ajani from The University of Texas MD Anderson Cancer Center in Houston, Dr Rutika Mehta from Weill Cornell Medicine/NewYork-Presbyterian Hospital in New York, New York, Dr John Strickler from Duke University in Durham, North Carolina, and Dr Samuel Klempner from Massachusetts General Hospital in Boston review relevant data supporting immunotherapy for patients with gastroesophageal cancers and review recently presented clinical findings from the 2026 ASCO Gastrointestinal Cancers Symposium.CME information and select publications here.

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.

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.

In this JCO Precision Oncology Article Insights episode, host Dr. Jiasen He summaries the article, "Longitudinal Evaluation of Circulating Tumor DNA as a Prognostic Biomarker to Detect Molecular Residual Disease in Germ Cell Tumors," by Hassoun et al. TRANSCRIPT Jiasen He: Hello, and welcome to the JCO Precision Oncology Article Insights. I'm your host, Jiasen He, and today, we'll be discussing the JCO Precision Oncology article, "Longitudinal Evaluation of Circulating Tumor DNA as a Prognostic Biomarker to Detect Molecular Residual Disease in Germ Cell Tumors," by Dr. Rebecca Hassoun and colleagues. Traditionally, treatment response for solid tumors has relied on imaging, which focuses on visible anatomic changes in the tumor. However, imaging does not always reflect molecular or cellular changes and cannot detect microscopic disease, which is clinically important and often linked to relapse. Liquid biopsy, on the other hand, is minimally invasive and can be used for cancer monitoring by analyzing circulating biomarkers in biofluids such as blood. One type of liquid biopsy is circulating tumor DNA, or ctDNA, which measures small fragments of DNA released by tumor cells into the bloodstream. ctDNA can allow precise monitoring of tumor-specific mutations and be a powerful tool for assessing treatment responses. ctDNA has already been applied in clinical settings for cancers such as non-small cell lung cancer and breast cancer, etcetera. However, there is still limited data on the use of ctDNA for germ cell tumors. Germ cell tumors are the most common malignancy affecting men aged 15 to 35 years. Accurate risk stratification and disease monitoring is key to risk-adapted therapy, maximizing the chance of cure while minimizing side effects. One unique tool we use currently for diagnosis, staging, and monitoring is serum tumor markers, such as AFP, beta-hCG, and LDH. However, these markers have limitations, including false elevation in certain clinical scenarios, and studies have shown that they can be normal in up to 40 percent of patients with germ cell tumor. This creates an unmet need for other sensitive and specific biomarkers to improve patient care. In this paper, the authors investigated the use of ctDNA in a cohort of patients with germ cell tumor at various disease time points. They compared ctDNA results with traditional serum tumor markers to evaluate whether ctDNA can predict relapse and survival outcomes. This multi-institutional retrospective study included patients with stage I, II, and III germ cell tumors, primarily testicular cancer, who had at least one ctDNA test result. ctDNA was evaluated longitudinally at different time points, including pre-orchiectomy, during the molecular residual disease, or MRD, window, defined as 1 to 12 weeks post-orchiectomy but before primary therapy, and during the surveillance window, defined as more than 12 weeks post-orchiectomy or follow retroperitoneal lymph node dissection or post-chemotherapy. ctDNA analysis was performed using a tumor-informed 16 multiplex PCR next-generation sequencing assay. A total of 324 plasma samples were analyzed from 74 patients in this cohort. The majority had stage I disease, around 40 percent, and nonseminomatous histology, around 70 percent. 15 patients were evaluated in the pre-orchiectomy window, and only one patient tested negative for ctDNA. This patient had stage I disease. The authors further assessed ctDNA positivity in both the MRD window and surveillance window, evaluating its association with event-free survival. They found that ctDNA outperformed serum tumor markers in both settings. ctDNA positivity was associated with significantly worse event-free survival compared with ctDNA-negative patients. Among the 14 patients with stage II to III disease who had ctDNA assessed in both the MRD window and surveillance window, nine patients consistently had a negative ctDNA or converted from positive to negative over time. In contrast, five patients demonstrated persistent ctDNA positivity, and all of these patients subsequently relapsed. Among the 38 patients who had both ctDNA and serum tumor marker tests during the MRD window, nine patients showed discordant biomarker results. Of these, 6 patients were ctDNA-negative but serum tumor marker-positive, and one of them experienced recurrence. Three patients were ctDNA-positive but serum tumor marker-negative, and one of these patients also recurred. During the surveillance window, 46 patients had both biomarkers available, and 10 showed discordant results. Three patients were ctDNA-negative but serum tumor marker-positive, and none of them recurred. In contrast, all seven patients who were ctDNA-positive but serum tumor marker-negative experienced recurrence. This intriguing data strongly support the potential role of ctDNA in patients with stage I, II, and III germ cell tumors. However, as the authors noted, the retrospective nature of the study presents limitations, as treatment approaches, imaging schedules, and the timing of testing were not standardized, and ctDNA testing varies among participating institutions. Larger prospective trials with standardized protocols and long-term follow-up will be essential to validate these findings and determine how ctDNA can be reliably integrated into clinical practice. Thank you for tuning in to JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future 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.

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.

Marta Gutiérrez habla del actor norteamericano que estrena Sin piedad. Cuenta cómo fueron sus inicios y aspectos como su religiosidad.

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

P. Federico (Guatemala)El premio más grande es ir con Jesús, independientemente de quién se acerca y/o quién no. El Señor aprovecha para irnos haciendo capaces en el trato con todo tipo de personas y circunstancias. Déjate curar, déjate moldear, déjate cambiar.[Ver Meditación Escrita] https://www.hablarconjesus.com/meditaciones-escritas/  

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  

Host Dr. Davide Soldato and guests Dr. Kerin Adelson and Dr. Maureen Canavan discuss JCO article "Association Between Systemic Anticancer Therapy Administration Near the End of Life with Health Care and Hospice Utilization in Older Adults: A SEER Medicare Analysis of End-of-Life Care Quality," highlighting adverse outcomes for patients who receive any type of systemic anticancer therapy(SACT) at EOL (end of life) and the need for better communication between oncologists and patients regarding expected risk and benefits of such treatments to properly align goals-of-care. 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 authors Dr. Maureen Canavan, epidemiologist and associate research scientist at Yale Cancer Outcomes, Public Policy and Effectiveness Research Center; and by Dr. Kerin Adelson, Chief Quality and Value Officer, medical oncologist, and clinical researcher on health services and clinical care delivery at MD Anderson Cancer Center. In the manuscript "Association Between Systemic Anticancer Therapy Administration Near the End of Life With Health Care and Hospice Utilization in Older Adults: A SEER-Medicare Analysis of End-of-Life Care Quality." that you recently published in the JCO, you performed an analysis that included more than 30,000 older adults in the SEER-Medicare database, and you observed that 7.6% of these patients received any systemic anticancer medication within 30 days of death. So, I wanted you to explain why you thought that this was a priority right now, and whether there was any previous data that was published in the literature, and if you think that there was any significant gap in the literature that led you to the research you just published. Dr. Kerin Adelson: We have published a series of articles looking at real-world trends  in patterns of care, particularly related to systemic anticancer therapy at the end of life. This has been gaining increasing focus in recent years because of the understanding that when patients stay on systemic anticancer therapy, that is often a surrogate for a lack of goal-concordant care. So, patients who continue to receive systemic therapy have worse quality of life, are more likely generally to have a medicalized death, and less likely to use hospice. And what our prior work has shown is that more and more we are seeing patients using immunotherapies and targeted therapies towards the end of life. No prior work had really comprehensively examined whether these novel therapies were associated with those same patterns of care increases in acute care utilization and decreases in hospice. Dr. Davide Soldato: So basically, the data that we had up until that point was mostly with cytotoxic chemotherapy, and the emergence of this new treatment, which frequently are thought to be less toxic and so less problematic also in the end of life, led to this research. Is that correct? Dr. Kerin Adelson: Correct. Dr. Maureen Canavan: I would also build on that. I think that as the landscape of cancer care changes, it is important to really understand the availability of treatments, but then also, as Kerin noted, it is important to focus on goal-concordant care. We have established literature, studies we have done and some other studies that have looked at cytotoxic chemotherapy, but with the emergence of these targeted therapies, we really did not know a few things. We did not know the rates of utilization in a large national population, and how that was associated with these elements of medicalized death like ED use, hospitalizations, acute care use. So this was really a question that we had going into it. How can we expand the knowledge base so that both patients and providers can be more cognizant when thinking about goals of care conversations and ensuring that that is in place? Dr. Kerin Adelson: And our work has kind of evolved to answer some critical questions. So, one of our early papers looked at different rates of systemic anticancer therapy at the end of life, and that is where we showed that we were seeing a lot more immunotherapy and targeted therapy. And then we asked the question, well, oncologists generally when they give these treatments, they are hoping that those treatments are going to work and help the patients live longer. So we did another paper where we actually looked at practices who were more aggressive near the end of life and whether they had better overall survival than practices that were less aggressive, accounting for the fact that there could be populations of patients who benefited. And in fact, we showed there was no survival difference. So then this paper sort of answered the question: Well, if it is not having benefit, is this treatment actually doing harm? And this study gets at that question: What are the harms of continuing patients on therapy past the point of benefit? Dr. Maureen Canavan: And I think building off of that, the use of the SEER-Medicare database is a quite robust database. So in this, we have very specific data we can track. We can track the exact type of treatment they had, you know, was it a targeted therapy? Was it immunotherapy? So looking at those subclasses of therapy. We were also able to directly link it within that time frame to the acute care utilization, a limitation that we had in some of our previous work that that data was not always available. So it is more focused in the sense that we were looking at older adults, so patients 66 years of age and older, but we were able to get those individual metrics. So to Kerin's point, we did not see the survival benefit. What do we see then for these medicalized death elements? So the higher rates of all of them across the board. Dr. Davide Soldato: So coming back to the cohort and to the data that you utilized, Dr. Canavan mentioned the use of the SEER system to analyze these data. You already mentioned that you included mostly older adults, so those aged 66 and more. And also there was a little bit of restriction regarding the fact that the patient needed to be covered by Medicare in the last year of death concerning Part A and Part B, and the last 30 days from death concerning Part D. So I just wanted to ask a little bit of a question regarding these findings and whether you think that we also need additional work, especially in the younger population because I think it is something that all of us who work in oncology have seen. The aggressiveness, and this is also something that you showed in your data, tends to increase as the age of the patient tends to decrease. So we tend to be more aggressive towards younger patients. So just a comment on that on the population and generalizability of the findings. Dr. Maureen Canavan: Yeah, I will start with the data question element. Thank you. I think there are a few things to point out for that. So in terms of the restriction to ensure that they had continuous Part D coverage, that was necessary for us to track their oral medication use during that time. So kind of an easy response. The Part A, Part B requirement, it is actually pretty widely used in studies of SEER-Medicare data, and that is you want to establish the patient population, that they are not getting treated with another insurance provider in some way that you are not able to track. So that ensures that we can track not only their systemic anticancer therapy use but also when we are trying to make sure that we are controlling for confounders like chronic conditions and stuff, we are able to track the presence of chronic conditions. So we wanted to make sure we were not biasing the data, so I think that was an important consideration. You do point out very wisely that there are then limitations with the generalizability, and I think we would be lacking if we did not account for that. But I think it is important to establish this baseline relationship association, and then you can step out, we will say, to more diverse populations. So I think we could potentially maybe try to relax the timeline to see if people that might have influx in and out of the Medicare system are still seeing those same rates. I think it is likely they would. But I think to the bigger point that you bring up is that establishing this within the older adults where, you know, we do see as they get older maybe less rates of systemic therapy, extending it to the younger population. There is a challenge with that in that just that data is not available to the robust level that SEER-Medicare is. Both Kerin and I have noted that there is the possibility to look within one specific insurance provider type. Again, recognizing the limitations of the generalizability, but always slowly pushing the needle, finding out more about younger adult populations. And I think this is maybe in an ideal world, but setting the precedent that we really do need to track this on a national scale within younger adults because they do have the need. We do see these higher rates of utilization, and really making sure again with the mindset always of the best interest of patients and the most informative to providers in how we are looking at care. So I think generalizability is definitely a goal. However, there are limitations of the availability of data for younger populations and I think that they are a necessary restraint that all researchers should acknowledge. Dr. Kerin Adelson: Yeah, I think it is important for our audience to understand that health services research and large database research is really limited by what databases are available and what are the characteristics of those databases. So we have done a lot of work in an electronic health record database, and there you can get certain kinds of granularity that you may not be able to get in a payer or a claims-based database. But what you do not get is that comprehensive look at, say, what happens if a patient goes to another practice. Claims-based databases offer you that, but research on US populations is limited by our payment system. So when you look at younger patients, there are so many different insurance companies that when you are trying to get that comprehensive view, it can be hard or very expensive actually. These commercial insurers will sell their data to different databases. So for us, the largest single payer in the United States is the US government, and that is for patients who are over age 65, and that is why you see lots of US-based studies done in the Medicare population. Interestingly, a recent paper by a Canadian group showed very, very similar patterns. It was a significantly smaller study but, right, Canada is a single-payer system and so they were able to really look at all ages, and we did see the same patterns of care in a different payment system. Dr. Davide Soldato: Going back a little bit to the type of treatments that were observed in your manuscript, so we start from a 7.6% of patients who received any type of systemic anticancer therapy within 30 days from death. And when we split the different categories that you analyzed, which I think is a very strong aspect of your manuscript, we see that more or less 50% of the patients received chemotherapy, 20% more or less received immunotherapy, more or less 20% targeted therapy, and then there is a combination of those agents. So just wanted to have a little bit of your opinion compared also to the data that you already published and that you mentioned before. Was this in line with previous data? Was there anything surprising about this? We saw a little bit of a raise in the use of immunotherapy and targeted therapy as you were saying, but still, there is a very high proportion of chemotherapy, 50%. Dr. Kerin Adelson: So I think that really, really reflects the time period in which we studied where immunotherapies were gaining ground. There was tons of excitement and we were seeing this shift. I bet if we do the same study in five years that chemotherapy percent may even go down to half, and we are going to see more and more targeted and immunotherapies, and that is just reflecting the pattern of drug discovery that we are seeing. Dr. Davide Soldato: Coming to the real question that you wanted to answer with this manuscript, so is systemic anticancer therapy associated with worse outcomes in terms of healthcare utilization and use of hospice resources? Was there any hint that for example immunotherapy was related to less of these adverse outcomes? Dr. Kerin Adelson: So I will be honest, I was a little bit surprised that the combination of chemotherapy and immunotherapy was that much more strongly correlated with acute care use at the end of life. You know, I had really thought most likely that what we would see were similar rates. And we did. Each different type of systemic anticancer therapy was associated with significantly higher odds of ending up in the hospital, going to the ICU, dying in the hospital, going to the ED. But that group that got dual therapy was that much higher, you know, over three times the risk. And that surprised me because what it suggested is that there is likely a component of treatment toxicity that is leading to some of the acute care use. It is not simply just a constellation of patients who have not yet transitioned towards hospice or palliative care or end-of-life care who are then more likely to end up in the hospital. But the fact that we see a difference between, say, single-agent immunotherapy and dual combination with chemotherapy does suggest that the treatments are actually contributing to some of what we are seeing. Dr. Davide Soldato: But still, all of the treatments that you evaluated were still associated with higher healthcare utilization. Like there was no signal that, for example, giving immunotherapy at the end of life was not associated with these adverse outcomes. Correct? Dr. Kerin Adelson: Correct. And you will find oncologists out there who will say, actually, these treatments are so good that they might actually lower rates of hospitalization because they keep patients healthy. And certainly, that may be true upstream or earlier in the course of disease, but at the end of life, any form of systemic anticancer therapy is really a surrogate marker for lack of transition towards what is likely appropriate end-of-life therapy. And I just want to point out that time spent in the hospital, going back and forth to invasive procedures, going to the intensive care unit, even going back and forth to an infusion center, that is time that is not spent at home with loved ones for people who have very little time left to live. Dr. Davide Soldato: Thank you very much. That was exactly the point that I wanted you to stress because I think it is really the most important message that we can get as oncologists from this manuscript. Like there is no treatment that is not associated with potentially harming our patient and, as you were saying, taking off time with loved ones in a critical period of the life of these individuals who have been diagnosed and treated for cancer. So, basically what we saw in the paper was a 7.65% utilization of systemic anticancer therapy. And I might imagine that for some oncologists or for some hematologists that might not actually be that much. Like they could potentially say, "Okay, but it is like 7%, it is not that high. I would have expected something higher." So I just wanted a little bit of perspective regarding also quality metrics that we have available for these types of indicators at end-of-life care. What would be the appropriate percentage of people receiving any type of treatment within 30 days from death? Dr. Maureen Canavan: A couple caveats, as a data person I always like to give those. This was among all cancer patients, so not necessarily patients that had been on active treatment. So I think that number was actually quite lower than when we looked in another study about patients that had chemo within the last year, so on, you know, active treatment. So I think that is an element to take into consideration is that those numbers will vary based on who your denominator population is. So that is important to consider. Additionally, the National Quality Forum, they call for reducing rates of systemic therapy at end of life. But I think they, similar to how I would be, are cautious to point out this is the exact number, or it should be zero. Because there are cases where you have to go in line with patient preferences. And if a patient is very adamant that they want to continue treatment, that needs to be a decision that comes between them and their provider. So, you know, the zero, though sounding ideal to us who want to encourage transitions and encourage goals of care conversation is a nice number, it is not a realistic. So, to evade your question completely, I do not think there is a set number. But the goal is to make sure that both patients, providers, everyone is informed and is making the best holistic decision. So there is this natural tendency, I think, to keep fighting both for the patient and the provider to try to beat something, but recognizing the point at which we are beyond a benefit of treatment and what would be most beneficial to the patient in terms of getting back to that idea of, you know, the time with their families and whatnot. So is the number zero? No. Could it probably be lower than we have? I think yes, definitely. Dr. Kerin Adelson: I completely agree with everything Dr. Canavan said. I think one of the other challenges is that this data isn't being tracked and publicly reported across the world. And so what that optimal rate is, is a little unclear. We see different rates also depending on the population included. So one of the things Dr. Canavan said is our database included patients who were likely treated long ago for cancer and cured of their cancer. So they were less likely to die on systemic therapy. But until everybody starts tracking and reporting, it is really hard to know where we are as a country or really as a global population, and then what are the bars that we want to achieve in driving down the rates. I think some data shows that probably something in the range of 10% or below, you know, for patients who have more active cancer is probably where we should be going and driving towards. But until we have more public reporting of these metrics and consistency in how we measure them, it is really hard to come up with a single number. Dr. Davide Soldato: I have the impression that sometimes there is also a little bit of difficulty for the oncologist or the hematologist to really understand who are the patients who are approaching end of life. So there has been some data and you also report some of them in the discussion of the manuscript regarding, for example, prompts inside of the electronic health records or the use of artificial intelligence to try to predict what is the disease course. So just wanted a little bit of perspective if you think that these tools could potentially be helpful and if you think that we will be able at a certain point to implement them in routine clinical care. Dr. Kerin Adelson: I have been working on trying to do this actually at MD Anderson and coming up with a really reliable data tool that will tell us who are the patients who are going to die in short order after receiving systemic anticancer therapy. And it is not that easy, I will say. So, you know, I think we all want this amazing machine learning model that is incredibly reliable. But like any statistical test, there are problems, right? So a very sensitive test that is going to identify high, high risk of dying at the end of life is going to be compromised by false positives. And when an oncologist knows that the test might be a false positive, it becomes very hard for them to take action on it. Similarly, you know, a very, very specific test is going to be compromised by false negatives. So in that case, you could end up having patients who are at risk for dying and still treating them with chemotherapy. And so, you know, I think in the end we need some tools. It will be great if machine learning becomes very reliable and we have the right structured data elements in our electronic health records to give these reliable prediction tools. But I think there are some basic things that we all know, and those are the markers of chronicity of cancer. So patients who have had multiple lines of therapy already, right? Past the point of clinical trial benefit. Patients who have lost significant amounts of weight. Patients who are not getting out of bed and have worse performance status. Patients who are increasingly confused, right? And not mentally engaging the way they did previously. Those markers have been shown in numerous publications by a colleague of mine, David Hui and others, to really be pretty strong predictors, and they resonate with clinicians more than a machine learning score might. You know, I think when clinicians do not understand what the elements in a machine learning tool are, they are less likely to trust it and more likely to say, "Oh, it is a false positive or a false negative." But very few clinicians can argue against the fact that the patient who hasn't gotten out of bed in two weeks is somebody who is less likely to benefit. Dr. Davide Soldato: Dr. Adelson, I would like to close this podcast and I would like to thank you again for joining us today. Dr. Maureen Canavan: Thank you so much. Dr. Kerin Adelson: Thank you so much for having us. Dr. Davide Soldato: Dr. Canavan, Dr. Adelson, we appreciate you sharing more on your JCO article titled "Association Between Systemic Anticancer Therapy Administration Near the End of Life With Health Care and Hospice Utilization in Older Adults: A SEER-Medicare Analysis of End-of-Life Care Quality." If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can f ind 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 Kerin AdelsonStock and Other Ownership Interests: Carrum Health Consulting or Advisory Role: Abbvie, Quantum Health, Gilead SciencesPatents, Royalties, Other Intellectual Property: Genentech Other Relationship: Genentech/Roche Employment: Emilio Health/Brightline Health(An Immediate Family Member) Stock and Other Ownership Interests: Emilio Health/Brightline Health, Lyra Health (An Immediate Family Member)

In this JCO Precision Oncology Article Insights episode, host Dr. Harold Nathan Tan summarizes "Palbociclib in Patients With Head and Neck Cancer and Other Tumors With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study" by Worden et al.  TRANSCRIPT Harold Nathan Tan: Welcome to JCO Precision Oncology Article Insights, where we explore research that is reshaping our understanding of cancer therapeutics. I'm your host, Harold Nathan Tan, and today's episode centers on the TAPUR study, an analysis that confronts a long-standing assumption in molecular oncology: namely, whether CDKN2A alterations create a therapeutic vulnerability that can be exploited by CDK4/6 inhibition with palbociclib. CDKN2A is one of the most frequently altered tumor suppressors across solid tumors. Its importance lies in its production of two proteins, p16 and p14, which serve as guardians of cell cycle progression. p16 directly inhibits CDK4 and CDK6, preventing phosphorylation of the RB protein and therefore blocking entry into S phase, whereas p14 stabilizes p53 by counteracting MDM2, enabling cells to pause or die in response to oncogenic stress. When CDKN2A is lost or mutated, these dual checkpoints collapse. CDK4/6 activity becomes unchecked, RB remains phosphorylated and inactive, and p53-mediated surveillance is blunted from a mechanistic standpoint. This creates a possible dependency on CDK4/6 signaling that could, in principle, be therapeutically reversed by palbociclib. The TAPUR study is a prospective phase 2 basket study designed to evaluate whether FDA-approved targeted agents can meaningfully benefit patients with advanced treatment-refractory cancers harboring specific genomic alterations. In this analysis, patients were eligible for palbociclib if their tumors carried CDKN2A loss or mutation and retained RB activity. Two cohorts were examined: one consisting of head and neck cancers, and another composed of a broad spectrum of tumor types that collectively shared the CDK2 alteration. The results from the head and neck cancer cohort are particularly intriguing. Among the 28 available patients, the study observed a disease control rate of 40%, surpassing the predefined threshold for a positive signal. Although the objective response rate was low at only 4% with one partial response, the durability of disease stabilization was clinically meaningful. However, the most important insight comes from examining which head and neck tumors benefited. The strongest and most durable disease control occurred in non-squamous malignancies, particularly salivary gland tumors such as adenocarcinoma, adenoid cystic carcinoma, and poorly differentiated parotid tumors, as well as in esthesioneuroblastoma. In contrast, classic head and neck squamous cell carcinoma rarely demonstrated sustained benefit. When progression-free survival was analyzed, non-squamous tumors achieved a median PFS of approximately 20 weeks compared to just eight weeks in squamous tumors. This divergence reflects deep biological differences. Many non-squamous head and neck cancers preserve an intact RB axis and rely on CDK4/6-driven cell cycle control as a core proliferative mechanism. By contrast, squamous tumors tend to accumulate a dense array of co-alterations that weaken or circumvent CDK4/6 dependency. Many squamous tumors also harbor disruptive TP53 mutations, removing essential checkpoint control and allowing the cell to bypass the growth-arresting effects of palbociclib. In other words, even though CDKN2A loss is present, CDK4/6 is no longer the dominant node controlling proliferation in these cancers, and the tumor simply finds other ways to drive cell cycle entry. One of the most thought-provoking findings from the TAPUR study involves esthesioneuroblastoma. Three patients with this rare tumor achieved durable disease control despite the lack of standardized systemic treatment options for this malignancy. Genomic analyses have shown that while esthesioneuroblastoma often carries TP53 or IDH2 mutations, a meaningful subset exhibits alterations in CDKN2A or related cell cycle regulators. The consistency of this disease stabilization observed in TAPUR may reflect a lineage-specific reliance on CDK4/6 signaling, opening the door for future exploration of CDK4/6 inhibitors in this orphan disease. In the histology-pooled cohort, which included 40 available patients across 18 tumor types, palbociclib did not achieve the disease control threshold required to declare activity, with only a disease control rate of 13% and an ORR of 5%. While a few isolated responses occurred, for instance in thymic carcinoma and B-cell lymphoma, the overall disease control rate was 13%, which failed to rise above what might be expected from the natural history of advanced refractory cancers. This outcome reinforces the principle that CDKN2A loss is not a universal predictor of CDK4/6 dependency. Many of the tumors represented in this cohort, such as pancreatic cancer, melanoma, and gastrointestinal malignancies, are well known to evolve multiple compensatory mechanisms that circumvent CDK4/6 as a critical proliferative node. The safety profile of palbociclib was consistent with its known hematologic toxicities. High rates of neutropenia, leukopenia, and thrombocytopenia were observed, along with one treatment-related death due to respiratory failure. In a setting where activity is limited to specific subgroups, these toxicities underscore the importance of careful patient selection and raise the bar for demonstrating clinically meaningful benefit, particularly in heavily pretreated populations. So what do these findings tell us about the broader landscape of precision oncology? First, they remind us that a mutation's functional role is dependent on the cellular and lineage context in which it occurs. CDKN2A loss may accelerate proliferation in many tumors, but the mechanism of that acceleration varies widely, and the degree to which a tumor relies on CDK4/6 signaling is anything but uniform. Second, the findings suggest that palbociclib monotherapy may hold meaningful and durable benefit in the subset of non-squamous head and neck cancers, particularly salivary gland malignancies and esthesioneuroblastoma. Third and perhaps most importantly, the results reinforce a growing consensus that the future of CDK4/6 inhibition in solid tumors lies not in monotherapy, but in rational combination strategies. CDK4/6 inhibitors have been shown to synergize with EGFR inhibitors, PIK3CA, and mTOR inhibitors, MEK inhibition, and even immune checkpoint blockade. These combinations aim to dismantle the compensatory pathways that allow tumors to escape CDK4/6 blockade and may unlock therapeutic potential in tumors that show limited sensitivity to monotherapy. Ultimately, the TAPUR findings challenge the notion that CDKN2A is a straightforward predictive biomarker. Instead, the study reveals CDKN2A as a biomarker whose meaning is modulated by tumor lineage, co-mutation status, and the broader regulatory circuit governing proliferation. Precision oncology must therefore move beyond single-gene interpretation towards integrated frameworks that situate genomic alterations within their biologic ecosystems. In some head and neck cancer subtypes, particularly non-squamous malignancies, that ecosystem appears amenable to CDK4/6 inhibition, and that insight, not the simplistic gene-to-drug match, represents the true value of the TAPUR analysis. Thank you for joining me for this episode of JCO Precision Oncology Article Insights. I'm Harold Nathan Tan, and I look forward to exploring more research that continues to refine how we understand and strategically exploit the vulnerabilities of cancer. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. 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.

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. 

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.