ASCO Education

Dr. Christopher Booth joins guest host Dr. Gerald Hsu to discuss his ASCO Educational Book article, "Innovation, Evidence, Compassion, and Hope: Delivering Outcomes That Matter," exploring how modern trial metrics and regulatory pathways frequently prioritize surrogate endpoints over meaningful survival and quality-of-life gains. Together, they discuss actionable strategies for clinicians and policymakers to re-center cancer care on shared decision-making, patient priorities, and global access. LINK TO FULL TRANSCRIPT

Dr. Pedro Barata and Dr. Giuseppe Curigliano discuss the rapid paradigm shift of antibody-drug conjugates into frontline advanced and curative-intent perioperative settings and the clinical challenges of optimal sequencing, target selection, and cross-resistance. LINK TO FULL TRANSCRIPT

Dr. Hope Rugo and Dr. Peter Lee discuss frailty, geriatric assessments, and personalized care for older adults with genitourinary cancer. They highlight screening guidelines, treatment considerations, multidisciplinary interventions, and the emergence of AI and digital health tools in geriatric oncology. LINK TO FULL TRANSCRIPT

Dr. Pedro Barata and Dr. Kathryn Schmitz discuss evidence-based exercise oncology programs, how to incorporate exercise into cancer care and connect the right patient to the right program, and ultimately build a culture of exercise in oncology. 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 and a clinical trialist at the University Hospital Seidman Cancer Center and an associate professor of medicine at Case Western Reserve University in Cleveland, Ohio. I'm also happy to serve as a deputy editor for the ASCO Educational Book. Today, we'll be talking about exercise. We have plenty of evidence that exercise benefits symptoms, improves the quality of life of patients, and actually has been shown to reduce risk of recurrence of cancer but also improve survival. And I think that's increasingly clear as data emerges. Today, I'm delighted to be speaking to Dr. Kathryn Schmitz. She's a leading expert on integrating exercise into cancer care. Dr. Schmitz serves as the deputy director of the University of Pittsburgh Hillman Cancer Center and also a professor of hematology-oncology at University of Pittsburgh Medical School. She's the senior author of a fantastic article in the ASCO Educational Book that's titled "Implementation Science as the Secret Sauce for Integrating Exercise Screening and Triage Pathways in Oncology." She also led a really compelling piece that just got published in JCO titled "If Exercise Were a Pill, We'd All Prescribe It to Patients With Cancer. But It's Not" So I'm thrilled to have Dr. Schmitz joining us today and helping us explore evidence-based exercise oncology programs, how to incorporate exercise into cancer care, and also how to connect the right patient to the right program. So with that, welcome, Dr. Schmitz. Thank you so much for taking the time to chat with us. Dr. Kathryn Schmitz: Thank you for the opportunity. Dr. Pedro Barata: One of the highlights of ASCO last year and practice changing, in my opinion, data out of The New England [Journal of Medicine] is called the CHALLENGE trial. It did provide high level evidence that a structured, supervised exercise program could improve both disease-free survival and overall survival. This is a study in the GI world, but I think it got a lot of attraction and attention beyond the GI world, across solid tumors, really. Could you give us a little brief recap of that trial and what have you seen as being the impact in practices around oncology? Dr. Kathryn Schmitz: So, CHALLENGE was very exciting. Prior to CHALLENGE, there were any number of observational studies that indicated that there was a relationship between being more physically active and reduced recurrence and improved overall survival for colon cancer in particular. You know, notably, in 2006, Jeff Meyerhardt published two papers in the same journal, of the same issue of JCO, showing very, very similar data from two very large studies. And those were studies number five and six in this area. You know, there's a lot of evidence observationally, but we don't generally change clinical practice on the basis of observational data. So, we were all waiting very impatiently for the results of the CHALLENGE trial. And it was very exciting to be in the front row when the results were reported out and to be part of the group with a standing ovation for the authors when it was presented. To summarize, 889 colon cancer patients, stage II and III, were randomized into either a structured exercise program or a health education control comparison group and followed for an average of 7.9 years. And the structured exercise group had a 27% reduced risk of recurrence and a 38% improvement in overall survival. One of the things that's really notable about this is that what we typically expect is that when we go from the observational literature to the clinical trial literature, that we expect effects to go down. We expect to see a larger effect in the observational than in the RCT land, and that did not happen here. We actually see an effect that matches what we've seen in observational literature, which is really, really exciting. And, you know, one of the reasons why this has been so exciting across not just GI but other cancers is the notable finding of a reduced risk of second primaries. So, they only observed two breast cancer second primaries in the treatment group and 12 in the comparison group. And overall, they reduced the second primaries occurrence, hazard ratio was 0.5, a 50% reduction of second primaries, which is just remarkable. It really got everybody very, very excited. And now the big question, of course, is, all right, how do I do this? How do I make this happen? The thing to note is that what they did in CHALLENGE is probably not doable in your clinic tomorrow. It's a heavy intervention. The number of touchpoints from staff is extensive, and the amount of time needed from staff for the coaching and supervised exercise is extensive as well. The criteria for getting people into the program required that people go through a series of blood tests and imaging tests that would just simply not be possible for the average community oncologist. So I'm guessing that you're going to ask me some questions about how we do this. Dr. Pedro Barata: Right. That's a fantastic segue. That's exactly right. Walk us through maybe starting by, what does that mean? Dr. Kathryn Schmitz: The first thing to say is I have to go back to the observational literature. And the observational literature shows really compellingly that we have a strong reduction of breast cancer recurrence and mortality from being more physically active, prostate cancer recurrence and mortality, and colon cancer recurrence and mortality. I find it very difficult to believe in this day and age, in our current environment, if you will, that we are ever going to have the equivalent of CHALLENGE for prostate or for breast cancer. There is an ongoing study in prostate that's led by some Australian researchers, but I just don't think that it's likely that we're going to mount something similar for another tumor site. We have tremendous correlative data that indicates that there are a number of biomarkers and biological pathways through which breast, colon, and prostate cancer would be reduced in recurrence if people were more physically active. And so, there is really, from my thinking, very little to state that it would be just a colon cancer effect. And so this is something we probably can enact in more than just the colon cancer community, overall, which is great news, and it makes it easier for us to be able to enact this type of programming. Dr. Pedro Barata: One of the things that comes up perhaps often is, if I were the leader of the cancer center and were to incentivize the different care teams to implement an exercise program at each level: GI team, GU, breast, thoracic, etc. How do we do that? Dr. Kathryn Schmitz: So, I want to give you an analogy. You're a medical oncologist, and you prescribe your patients chemotherapy. Now, just imagine, if you will, what would happen and how likely it would be for your patients to get chemotherapy if there was no chemoinfusion suite. If the chemoinfusion suite disappeared tomorrow and you were to tell your patients, "Go get some chemotherapy," what proportion of those patients do you think would go find all of the equipment necessary and all of the drugs necessary and understand how to dose the chemotherapy for themselves and get that all done? Very few people would do it. So with exercise, why would we be surprised then that our patients don't actually do a whole lot if we just simply tell them to go get some exercise? Exercise is a medicine. It is effective like a medicine. We've shown this through the CHALLENGE trial and many other correlative studies and an ocean of observational data as well. So the question is, how do we build the infrastructure that is necessary in order for your patients to do this? So the very first thing that has to happen is that somebody has to tell the patient to exercise. We currently do not have a culture of exercise in oncology. We do in heart disease. If you ask the average person on the street, "Is exercise good for your heart?" Anybody with an eighth-grade education is going to say, "Yes, of course," because the American Heart Association has done an amazing job telling everybody that exercise is good for your heart. But what has ASCO done, frankly? Can I be that bold? What has ASCO done to tell patients that they should be exercising during and after their cancer treatment? I'm not sure that I know more than a guideline. There is a guideline, and that's great. And the guideline is very helpful, but I'm not sure that patients know that there's a guideline. In fact, I can tell you that patients don't know that there is a guideline. So, you know, making sure that there's a paradigm shift in the country that says exercise is good for patients during and after their cancer treatment is the first step. The second step is getting a medical professional to say something to the patient about the exercise. And I'm very careful with the two words that I just chose: medical professional. I do understand medical oncologists are very busy. I understand that there's a whole lot to say in that 15 minutes when you're with the patient. And so maybe it isn't the medical oncologist. Ideally, it would be, but I get it that there's limited time. So it could be a nurse practitioner, it could be a nurse, there could be a social worker, it could be somebody else on the team that says, "Hey, you know, we want you to do an exercise program. We want to connect you to an exercise program." And then there's what is the program itself? You know, I'm very interested in this happening across the entire country. And so I've been working with the leadership of the Commission on Cancer on the question of, well, how would you do this in community oncology? You know, it's not enough to do it in academic medicine, but how do you do this in community oncology? And you can't expect that every community hospital is going to build a gym for their cancer patients. That is just not reasonable to do. So, we start to try to figure out some phone counseling. Could we give people Fitbits and follow them? Could we use technology to help us? Are there telehealth opportunities for us to do? Are there apps that have been built? In fact, there is a [free] app called Cancer Exercise that's on, you know, all of the platforms and available to patients. So there are programs. I've developed a directory of over 2,000 programs that exist across the country for exercise oncology that patients can find, medical oncologists can find. So there are a lot of people trying to figure out how best to get the information to medical oncologists and other medical professionals so that they can have an 'easy button' to be able to connect their patients to existing programming so that you don't feel like you have to build a whole new program. Dr. Pedro Barata: If I don't have the resources around me, what would be your advice for the care team or for the providers that might not have that available at their site? Where do they start? Who do they reach out to? Who should they be looking at to get more information on how to set it up? Dr. Kathryn Schmitz: I lead an international consortium called Moving Through Cancer. You can find us at movingthroughcancer.org. That's where you'll find the map of all of the programs across the country and the directory. We actually have a triage tool that sits at the front of the directory that allows people to discern what type of exercise they're safe to do. We do recognize that, you know, the 80-year-old that fell last week doesn't need the same program as the 35-year-old that was playing pickleball the day before diagnosis. So, you know, there are different kinds of programs for people at different levels of acuity. We're happy to be helpful to folks to help them set up programs. But the number one thing is to really be very aware of the power of saying something about doing exercise, just simply the power of saying, "I want you to be moving." Because frankly, I don't think anybody listening to this would disagree, no one benefits from sitting on the couch all day, no one. No one, no one. It doesn't matter how acute their medical issues are. We get people out of bed. We try to move people even when they're in the hospital. So I think saying something is huge. And then, if you can, applying a triage tool, if you can get something embedded within your clinical flow so that you can understand who it is that needs to go to physical therapy as opposed to who's ready for an exercise program. Those are the two things. So triage and referral is kind of step one. And if you can get that done, the rest will fall into place. Dr. Pedro Barata: This is really powerful message, where one, awareness of the care teams. Number two, bring it up to the patient. And then working on the referral, triage and referral process. That's fantastic. Another aspect that comes up quite a bit is like, "Look, this is great, but we have a system that relies on payers to make things happen, or at least to get them approved." And that can be very different or heterogeneous. The coverage can be different. Sometimes already going through a system programs for interventions, therapeutic interventions, let alone probably the insurance is not going to cover that. Is that true? Is it not true? How do you walk through the different insurance supports, perhaps, depending on where you're practicing? Dr. Kathryn Schmitz: You've just hit on the hot button. I've been working on this issue for about nine years now, trying to figure out using efforts to talk to CMS and see if we can get third party payer coverage going. We were making good progress there, and there was a change of administration and a new focus on "Make America Healthy Again," the MAHA movement. And, you know, CMS is really no longer interested in one-off national coverage determination. They instead, they want to know, "How do we make exercise happen for every American over 65?" And my question is, "Well, wait a minute, cancer patients are not just older patients. There's a lot going on there. They need something special." So I've been working on that. It's been working with accrediting bodies for policy with a little p. Very proud of the work that I've done in collaboration with the National Accreditation Program for Breast Centers, trying to get standards to get exercise referrals for breast patients. And I'm currently holding my breath to see whether the CoC is going to try to make some forward motion in this area as well, crossing all period appendages, waiting for news there. So it's not paid for unless it's done by a physical therapist. And, you know, there's published evidence and I have plenty of evidence from UPMC as well, that people don't really want to go to the physical therapist for this. I'm not saying physical therapists aren't great. Physical therapists are great, and there are people who really need to go to physical therapy, and we try hard to get those patients connected. But for the patients that are ready for something more than physical therapy, we really have an uphill battle to try to figure out what insurers are willing to pay for and what the return on investment is. One of the challenges with the return on investment is that the timeline, time course for return on investment for American insurers is about one year. And I'll remind you that the time course for return on investment for CHALLENGE was 7.9 years. So we have a mismatch there. So we're trying to figure out if we can produce the evidence to show that there is an improvement in unplanned health care utilization. We have documented that for breast cancer. We're working on it for other cancers. If we can document that it is worthwhile to the insurer to pay for these programs, then I believe that they will pay for them. You know, my conversations are very positive with UPMC, which is a very large insurer and a large health plan. We're slowly working our way towards the middle, where there's a program that they can pay for and a program that is efficacious. That's the puzzle we're trying to solve for right now. Dr. Pedro Barata: This has been wonderful and super helpful. Before we wrap it up, is there anything else you would like to share with our listeners? Dr. Kathryn Schmitz: I want to make sure that your audience is aware that there are a variety of ways that exercise oncology is practiced. The program that most oncologists will be familiar with is LIVESTRONG, which is a program at the YMCA. It's a free program. At one point, there were over 800 locations across the U.S. They have contracted since COVID, probably because of COVID. So they still do exist but imagine, if you will, telling your patients that chemo is only available Tuesdays and Thursdays at 7:00 p.m. It would be difficult for patients to get there and get the chemotherapy. The same thing is true for the LIVESTRONG program. It's a fantastic, fantastic program for people who are able to get there, but that's one option. Another option for patients is there are a variety of online opportunities. I'll call out 2Unstoppable for women's cancers. It's literally the number 2Unstoppable.org. It's a free program available to women with cancer to have live, small group training programs. And they're based in Virginia, but they have programs all over the country. And then finally, I just want to overemphasize the app, the Cancer Exercise app. It's literally called Cancer Exercise in the app store. And that is a super duper easy button, very comprehensive, developed by a nurse scientist, Anna Schwartz. And then there are a variety of books. I wrote a book called Moving Through Cancer. There's a new book out [MyExerciseMedicine for Cancer] by Dr. Rob Newton as well, who's an Australian author. And there are certifications for exercise professionals that folks can look into as well through the American College of Sports Medicine. Dr. Pedro Barata: Dr. Schmitz, this is fantastic. Thank you for sharing those great insights with us. Super, super helpful. Thank you for taking the time. Dr. Kathryn Schmitz: Thank you so much. Dr. Pedro Barata: Thank you to our listeners for your time today. Remember, you'll find links to Dr. Schmitz's fantastic Educational Book as well as the JCO articles in the transcript of this episode. I'll invite all of you to go and read. And we'll also include a link to Dr. Schmitz's book titled Moving Through Cancer: An Exercise and Strength Program for the Fight of Your Life, which empowers patients and caregivers in simple five steps. So with that, please join us again next month on By the Book for more insights on key advances and innovations that are shaping modern oncology. Thank you very much for your attention. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers: Dr. Pedro Barata @PBarataMD Dr. Kathryn Schmitz @fitaftercancer 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. Kathryn Schmitz: Patents, Royalties, Other Intellectual Property: Fees from the educational program developed by Dr. Schmitz that is now offered through Klose Training and Consulting.

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

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

Dr. Pedro Barata and Dr. Rana McKay discuss the integration of innovative advances in molecular imaging and therapeutics to personalize treatment for patients with renal cell and urothelial carcinomas. TRANSCRIPT Dr. Pedro Barata: Hello, I'm Dr. Pedro Barata, your guest host of By the Book, a podcast series featuring insightful conversations between authors and editors of the ASCO Educational Book. 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 an associate editor of the ASCO Educational Book. Now, we all know the field of genitourinary cancers (GU) is evolving quite rapidly, and we have new innovations in molecular imaging as well as targeted therapeutics. Today's episode will be exploring novel approaches that are transforming the management of renal cell and urothelial carcinomas and also their potential to offer a more personalized treatment to patients. For that, joining for today's discussion is Dr. Rana McKay, a GU medical oncologist and professor at University of California San Diego. Dr. McKay will discuss her recently published article titled, "Emerging Paradigms in Genitourinary Cancers: Integrating Molecular Imaging, Hypoxia-Inducible Factor-Targeted Therapies, and Antibody-Drug Conjugates in Renal Cell and Urothelial Carcinomas." Our full disclosures are available in the transcript of this episode. And with that, Rana McKay, great to have you on the podcast today. Dr. Rana McKay: Oh, thank you so much, Dr. Barata. It's really wonderful to be here with you. So, thanks for hosting. Dr. Pedro Barata: No, thanks for taking the time, and I'm looking forward to this conversation. And by the way, let me start by saying congrats on a great article in the Educational Book. Really super helpful paper. I'm recommending it to a lot of the residents and fellows at my own institution. I would like to first ask you to kind of give our listeners some context of how novel approaches in the molecular imaging as well as targeted therapeutics are actually changing the way we're managing patients with GU, but specifically with renal cell carcinoma and urothelial carcinoma. So, what are the areas you would call out as like being big areas for innovation in this context, and why are they important? Dr. Rana McKay: Very good question. And I think this is really what this article highlights. It highlights where are we going from an imaging diagnostics standpoint? Where are we going from a therapeutic standpoint? And I think if we have to step back, from the standpoint of diagnostics, we've seen PET imaging really transform diagnostics in prostate cancer with the advent of PSMA PET imaging, and now PSMA PET imaging is used as a biomarker for selection for theranostics therapy. And so, we're starting to see that enter into the RCC landscape, enter into the urothelial cancer landscape to a lesser extent. And I think it's going to potentially be transformative as these tools get more refined. I think when we think about therapeutics, what's been transformative most recently in the renal cell carcinoma landscape has been the advent of HIF2α inhibition to improve outcomes for patients. And we have seen the approval of belzutifan most recently that has reshaped the landscape. And now there's other HIF2α inhibitors that are being developed that are going to be further important as they get refined. And lastly, I think when we think about urothelial carcinoma, the greatest transformation to treatment in that context has been the displacement of cisplatin and platinum-based chemotherapy as a frontline standard with the combination of enfortumab vedotin plus pembrolizumab. And we've seen antibody-drug conjugates really reshape treatment and tremendously improve outcomes for patients. So, I think those are the three key areas of interest. Dr. Pedro Barata: So with that, let's focus first on the imaging and then we'll get to the therapeutic area. So, we know there's been a paradigm shift, really, when prostate-specific targets emerged as tracers for PET scanning. And so, we now commonly use prostate-specific membrane antigen, or PSMA-based PET scanning, and really transform how we manage prostate cancer. Now, it appears that we're kind of seeing a similar wave in renal cell carcinoma with the new radiotracer against the target carbonic anhydrase IX. What can you tell us about this? And is this going to be available to us anytime soon? And how do you think that might potentially change the way we're managing patients with RCC today? Dr. Rana McKay: First, I'll step back and say that in the context of PSMA PET imaging, we have actually been able to better understand RCC as well. So, we know that PSMA is expressed in the neovasculature of tumors, and it can actually be used to detect renal cell carcinoma tumors. It has a detection rate of about 84% when used for detection. And so, you know, I don't think it's just restricted to carbonic anhydrase IX, but we will talk about that. So, PSMA expressed in the neovasculature has a detection rate of around 84%, particularly if we're looking at clear cell RCC. CAlX is overexpressed in clear cell RCC, and it's actually used in diagnosing renal cell carcinoma when we think of CAlX IHC for diagnosing clear cell RCC. And now there are CAlX PET tracers. The first foray was with the ZIRCON study that was actually an interestingly designed study because it was designed to detect the likelihood of PET imaging to identify clear cell RCC. So, it was actually used in the early diagnostics setting when somebody presents with a renal mass to discriminate that renal mass from a clear cell versus a non-clear cell, and it was a positive study. But when I think about the potential application for these agents, you know, I think about the entire landscape of renal cell carcinoma. This is a disease that we do treat with metastasis-directed therapy. We have certainly seen patients who've undergone metastasectomy have long, durable remissions from such an approach. And I think if we can detect very early onset oligometastatic disease where a metastasis-directed therapy or SABR could be introduced - obviously tested in a trial to demonstrate its efficacy - I think it could potentially be transformative. Dr. Pedro Barata: Wonderful. It's a great summary, and I should highlight you are involved in some of those ongoing studies testing the performance of this specific PET scanning for RCC against conventional imaging, right? And to remind the listeners, thus far, for the most part, we don't really do FDG-PET for RCC. There are some specific cases we do, but in general, they're not a standard scanning. But maybe that will change in the future. Maybe RCC will have their own PSMA-PET. And to your point, there's also emerging data about the role of PSMA-PET scanning in RCC as well, as you very elegantly summarized. Wonderful. So, let me shift gears a little bit because you did, in your introduction, you did highlight a novel MOA that we have in renal cell carcinoma, approved for use, initially for VHL disease, and after that for sporadic clear cell renal cell carcinoma. We're talking about hypoxia-inducible factor 2-alpha inhibitors, or HIF2α inhibitors, such as belzutifan. But there's also others coming up. So, as a way to kind of summarize that, what can you tell us about this breakthrough in terms of therapeutic class, this MOA that got to our toolbox of options for patients with advanced RCC? Tell us a little bit what is being utilized currently in the management of advanced RCC. And where do you see the future going, as far as, is it moving early on? Is it getting monotherapy versus combinations? Maybe other therapies? What are your thoughts about that? What can you tell us about it? Dr. Rana McKay: Belzutifan is a first-in-class HIF2α inhibitor that really established clinical validation for HIF2α as a therapeutic target. When we think about the activity of this agent, the pivotal LITESPARK-005 trial really led to the approval of belzutifan in patients who were really heavily pretreated. It was patients who had received prior IO therapy, patients who had received prior VEGF-targeted therapy. And in the context of this study, we saw a median PFS of 5.6 months, and there did seem to be a tail on the curve when you looked at the 12-month PFS rate with belzutifan. It was 33.7% compared to 17.6% with everolimus. And then when we look at the response rate, it was higher with belzutifan on the order of 22-23%, and very low with everolimus, as we've previously seen. I think one of the Achilles heels of this regimen is the primary PD rate, which was 34% when used in later line. There are multiple studies that are testing belzutifan in combination across the treatment landscape. So, we have LITESPARK-011, which is looking at the combination of belzutifan plus lenvatinib in the second-line setting. We've got the MK-012 [LITESPARK-012] study, which is looking at belzutifan in various combinations in the frontline setting. So there is a combination with IO plus belzutifan. And so this is also being looked at in that context. And then we also have the LITESPARK-022 study, which is looking at pembrolizumab with belzutifan in the adjuvant setting. So there's a series of studies that will be exploring belzutifan really across the treatment landscape. Many of these studies in combination. Additionally, there are other HIF2α inhibitors that are being developed. We have casdatifan, which is another very potent HIF2α inhibitor. You know, I think pharmacologically, these are different agents. There's a different half-life, different dosing. What is going to be the recommended phase 3 dose for both agents, the EPO suppression levels, the degree of EPO suppression, and sustainability of EPO suppression is very different. So, I think we've seen data from casdatifan from the ARC-20 trial from monotherapy with a respectable response rate, over 30%, primary PD rate hovering just around 10%. And then we've also seen data of the combination of casdatifan with cabozantinib as well that were recently presented this year. And that agent is also being tested across the spectrum of RCC. It's being looked at in combination with cabozantinib in the PEAK-1 study, and actually just at the KCRS (Kidney Cancer Research Summit), we saw the unveiling of the eVOLVE-RCC trial, which is going to be looking at a volrustomig, which is a PD-1/CTLA-4 inhibitor plus casdatifan compared to nivo-ipi in the frontline setting. So, we're going to see some competition in this space of the HIF2α inhibitors. I think when we think of mechanism of action in that these are very potent, not a lot of off-target activity, and they target a driver mutation in the disease. And that driver mutation happens very early in the pathogenesis. These are going to be positioned much earlier in the treatment landscape. Dr. Pedro Barata: All these studies, as you're saying, look really promising. And when we talk about them, you mentioned a lot of combinations. And to me, when I think of these agents, it makes a lot of sense to combine because there's not a lot of overlapping toxicities, if you will. But perhaps for some of our listeners, who have not used HIF2α inhibitors in practice yet, and they might be thinking about that, what can you tell us about the safety profile? How do you present it to your patients, and how do you handle things like hypoxia or anemia? How do you walk through the safety profile and tolerability profile of those agents like belzutifan? Dr. Rana McKay: I think these drugs are very different than your traditional TKIs, and they don't cause the classic symptoms that are associated with traditional TKIs that many of us are very familiar with like the rash, hand-foot syndrome, hypertension, diarrhea. And honestly, these are very nuanced symptoms that patients really struggle with the chronicity of being on a chronic daily TKI. The three key side effects that I warn patients about with HIF2α inhibitors are: (1) fatigue; (2) anemia; and (3) hypoxia and dysregulation in the ability to sense oxygen levels. And so, many of these side effects - actually, all of them - are very dose-dependent. They can be very well-managed. So, we can start off with the anemia. I think it's critically important before you even start somebody on belzutifan that you are optimizing their hemoglobin and bone marrow function. Make sure they don't have an underlying iron deficiency anemia. Make sure they don't have B12 or folate deficiency. Check for these parameters. Many patients who have kidney cancer may have some hematuria, other things where there could be some low-level blood loss. So, make sure that those are resolved or you're at least addressing them and supplementing people appropriately. I monitor anemia very closely every 3 to 4 weeks, at least, when people start on these medications. And I do initiate EPO, erythropoietin, should the anemia start to worsen. And I typically use a threshold of around 10g/dL for implementing utilization of an EPO agent, and that's been done very safely in the context of the early studies and phase 3 studies as well. Now, with regards to the hypoxia, I think it's also important to make sure that you're selecting the appropriate individual for this treatment. People who have underlying COPD, or even those individuals who have just a very high burden of disease in their lung, lymphangitic spread, pleural effusions, maybe they're already on oxygen - that's not an ideal candidate for belzutifan. Something that very easily can be done in the clinic before you think about initiating somebody on this treatment, and has certainly been integrated into some of the trials, is just a 6-minute walk test. You know, have the patient walk around the clinic with one of the MAs, one of the nurses, put the O2 sat on [measuring oxygen saturation], make sure they're doing okay. But these side effects, like I said, are very dose-dependent. Typically, if a patient requires, if the symptoms are severe, the therapy can be discontinued and dose reduced. The standing dose is 120 mg daily, and there's two dose reductions to 80 mg and 40 mg should somebody warrant that dose modification. Dr. Pedro Barata: This is relatively new, right? Like, it was not that we're used to checking oxygen levels, right? In general, we're treating these patients, so I certainly think there's a learning curve there, and some of the points that you highlight are truly critical. And I do share many of those as well in our practice. Since I have you, I want to make sure we touch base on antibody-drug conjugates as well. It's also been a hot area, a lot of developments there. When I think of urothelial carcinoma and renal cell carcinoma, I see it a little bit different. I think perhaps in urothelial carcinoma, antibody-drug conjugates, or ADCs, are somewhat established already. You already mentioned enfortumab vedotin. I might ask you to expand a little bit on that. And then in renal cell carcinoma, we have some ADCs as well that you include in your chapter, and that I would like you to tell us what's coming from that perspective. So, tell us a little bit about how do you see ADCs in general for GU tumors, particularly UC and RCC? Tell us a little bit about the complexity or perhaps the challenges you still see. At the same time, tell us about the successes. Dr. Rana McKay: Stepping back, let's just talk about like the principles and design of ADCs. So, most ADCs have three components. There's a monoclonal antibody that typically targets a cell surface antigen, which is conjugated by a linker, which is the second component, to a payload drug. And typically, that payload drug has been chemotherapy, whether it be topoisomerase or whether it be MMAE or other chemotherapeutic. We can start in the RCC space. There's been multiple antibody-drug conjugates that have been tested. There's antibody-drug conjugates to CD70, which is expressed on clear cell RCC. There's been antibody-drug conjugates to ENPP3, which is also expressed on RCC. There's antibody-drug conjugates to CDH6. And they have different payloads, like I said, whether it be topoisomerase I or other microtubule inhibitors. Now, when we think about kidney cancer, we don't treat this disease with chemotherapy. This disease is treated with immunotherapy. It is treated with treatments that target the VEGF pathway and historically has not been sensitive to chemo. So, I think even though the targets have been very exciting, we've seen very underwhelming data regarding activity, and in some context, seen increased toxicity with the ADCs. So, I think we need to tread lightly in the context of the integration and the testing of ADCs in RCC. We just came back from the KCRS meeting, and there was some very intriguing data about a c-Kit ADC that's being developed for chromophobe RCC, which is, you know, a huge unmet need, these variant tumors that really lack appropriate therapeutics. But I just caution us to tread lightly around how can we optimize the payload to make sure that the tumor that we're treating is actually sensitive to the agent that's targeting the cell kill. So, that's a little bit on the ADCs in RCC. I still think we have a long way to go and still in early testing. Now, ADCs for UC are now the standard of care. I think the prototypical agent, enfortumab vedotin, is a nectin-4-directed ADC that's conjugated to an MMAE payload and was the first ADC approved for advanced urothelial, received accelerated approval following the EV-201 trial, which was basically a multicenter, single-arm study that was investigating EV in cisplatin-ineligible patients with advanced urothelial carcinoma, and then ultimately confirmed in the EV-301 study as well. And so, that study ended up demonstrating the support superiority of EV from an overall survival standpoint, even PFS standpoint. Building on that backbone is the EV-302 study, which tested EV in combination with pembrolizumab versus platinum-based chemotherapy in the frontline setting. And that was a pivotal, landmark study that, like I said, has displaced platinum therapy as a frontline treatment for people with advanced urothelial carcinoma. And when we think about that study and the median overall survival and just how far we've come in urothelial cancer, the median OS with EV-pembro from that trial was 31 and a half months. I mean, that's just incredible. The control arm survival was 16 and a half months. The hazard ratio for OS, 0.47. I mean this is why when this data was presented, it was literally a standing ovation that lasted for several minutes because we just haven't seen data that have looked that good. And there are other antibody-drug conjugates that are being tested. We've all been involved in the saga with sacituzumab govitecan, which is a trophoblast cell surface antigen 2 (Trop-2) targeted ADC with a topoisomerase I payload. It was the second ADC to receive approval, but then that approval was subsequently withdrawn when the confirmatory phase 3 was negative, the TROPiCS-04 trial. So, approval was granted based off of the TROPHY-U-01, single-arm, phase 2 study, demonstrating a response rate of around 28% and a PFS of, you know, about 5 and a half months. But then failure to show any benefit from an OS standpoint. And I think there's a lot of controversy in the field around whether this agent still has a role in advanced urothelial carcinoma. And I think particularly for individuals who do not have molecular targets, like they're not HER2-amplified or have HER2-positivity or FGFR or other things like that. Dr. Pedro Barata: Fantastic summary, Rana. You were talking about the EV, and it came to mind that it might not be over, right, for the number of ADCs we use in clinical practice in the near future. I mean, we've seen very promising data for ADC against the HER2, right, and over-expression. It also can create some challenges, right, in the clinics because we're asking to test for HER2 expression. It's almost like, it's not exactly the same to do it in breast cancer, but it looks one more time that we're a little bit behind the breast cancer field in a lot of angles. And also has vedotin as a payload. Of course, I'm referring to disitamab vedotin, and there's very elegant data described by you in your review chapter as well. And it's going to be very interesting to see how we sequence the different ADCs, to your point as well. So, before we wrap it up, I just want to give you the opportunity to tell us if there's any area that we have not touched, any take-home points you'd like to bring up for our listeners before we call it a day. Dr. Rana McKay: Thank you so much. I have to say, you know, I was so excited at ASCO this year looking at the GU program. It was fantastic to see the progress being made, novel therapeutics that really there's a tremendous excitement about, not just in RCC and in UC, but also in prostate cancer, thinking about the integration of therapies, not just for people with refractory disease that, even though our goal is to improve survival, our likelihood of cure is low, but also thinking about how do we integrate these therapies early in the treatment landscape to enhance cure rates for patients, which is just really spectacular. We're seeing many of these agents move into the perioperative setting or in combination with radiation for localized disease. And then the special symposium on biomarkers, I mean, we've really come a long, long way. And I think that we're going to continue to evolve over the next several years. I'm super excited about where the field is going in the treatment of genitourinary malignancies. Dr. Pedro Barata: Oh, absolutely true. And I would say within the Annual Meeting, we have outstanding Educational Sessions. And just a reminder to the listeners that actually that's where the different teams or topics for the Educational Book chapters come from, from actually the educational sessions from ASCO. And your fantastic chapter is an example of that, right, focusing on advanced GU tumors. So, thank you so much, Rana, for taking the time, sharing your insights with us today on the podcast. It was a fantastic conversation as always. Dr. Rana McKay: My pleasure. Thanks so much for having me, Dr. Barata. Dr. Pedro Barata: Of course. And thank you to our listeners for your time today. You will find the link to the article discussed today in the transcript of this episode. I also encourage you to check out the 2025 ASCO Educational Book. You'll find an incredible wealth of information there. It's free, available online, and you'll find, hopefully, super, super important information on the key science and issues that are shaping modern oncology, as we've heard from Dr. McKay and many other outstanding authors. So, thank you, everyone, and I hope to see you soon. 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. Rana McKay @DrRanaMcKay 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. Rana McKay: Consulting or Advisory Role: Janssen, Novartis, Tempus, Pfizer, Astellas Medivation, Dendreon, Bayer, Sanofi, Vividion, Calithera, Caris Life Sciences, Sorrento Therapeutics, AVEO, Seattle Genetics, Telix, Eli Lilly, Blue Earth Diagnostics, Ambrx, Sumitomo Pharma Oncology, Esiai, NeoMorph, Arcus Biosciences, Daiichi Sankyo, Exelixis, Bristol Myers Squibb, Merck, Astrazeneca, Myovant Research Funding (Inst.): Bayer, Tempus, AstraZeneca, Exelixis, Bristol Myers Squibb, Oncternal Therapeutics, Artera

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