Podcasts about Asco

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

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

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

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

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

Patient and Physician Perspectives on Multiple Myeloma Data Presented at ASCO and EHA 2025: A Podcast In this plain language podcast, highlights from the American Society of Clinical Oncology (ASCO) Annual Meeting 2025 are discussed, supplemented with additional reflections from the European Hematology Association (EHA) 2025 Congress. These insights come from the perspective of an expert patient and physician, both of whom have experience and expertise in the field of multiple myeloma (MM). This podcast is intended to broaden the reach of complex data on MM from these scientific meetings to a broader audience, including nonspecialists, helping enable better informed treatment decisions between patients and healthcare professionals. This podcast is published open access in Oncology and Therapy and is fully citeable. You can access the original published podcast article through the Oncology and Therapy website and by using this link: https://link.springer.com/article/10.1007/s40487-025-00389-5. All conflicts of interest can be found online. This podcast is intended for medical professionals. Open Access This podcast is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The material in this podcast is included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

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

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

Mi-saison pour le Club des Cinq 2025 ! Pour l'occasion, nous rendons visite à Rémy, assistant en oncologie thoracique à l'Institut du Cancer de Montpellier. Avec lui, nous explorons un sujet qui traverse la médecine d'aujourd'hui : la place de l'intelligence artificielle dans la pratique clinique.Comment ces outils peuvent-ils enrichir la décision médicale ?Quelles en sont les limites, les risques, mais aussi les promesses ?Comment cette évolution transforme-t-elle le lien entre le médecin et son patient ?Une réflexion sincère et ancrée dans le réel, sur ce que signifie « soigner » à l'ère de l'intelligence artificielle.Dans une seconde partie, Rémy revient plus en détail sur la variation des fréquences alléliques, le sujet qu'il avait choisi de suivre au congrès de l'ASCO 2025.À très vite pour la suite de cette quatrième saison !Hébergé par Ausha. Visitez ausha.co/politique-de-confidentialite pour plus d'informations.

En esta cápsula de ESMO 2025 EXPRESS, el Dr. Juan Manuel O'Connor, oncólogo médico, jefe de la sección de Tumores Gastrointestinales del Instituto Alexander Fleming en Buenos Aires, Argentina nos comenta brevemente sobre los avances más relevantes sobre tumores gastrointestinales.El experto comenta lo siguiente: Ya se presentaron los datos del estudio MATTERHORN con resultados maduros. Como recordatorio, este estudio marca un nuevo paradigma terapéutico al incorporar la inmunoterapia junto con el esquema FLOT en el entorno perioperatorio del cáncer gástrico o de la unión gastroesofágica. Esto significa que el tratamiento logra aumentar las tasas de curación en pacientes con adenocarcinoma gástrico o de la unión gastroesofágica localmente avanzado.Según el reporte, se observa una reducción cercana al 25% en el riesgo de muerte, y la mediana de supervivencia aún no se ha alcanzado con el seguimiento disponible. Por lo tanto, como mencionaba, este resultado representa un hallazgo relevante que confirma y fortalece los datos presentados previamente en la sesión plenaria de ASCO de este año.De cara al futuro, sería importante considerar análisis por subgrupos, especialmente en pacientes con tumores de tipo difuso o en posibles diferencias relacionadas con el género, dado que se observaron resultados algo inferiores en mujeres. Estos aspectos podrían ser criterios relevantes de estratificación en futuros estudios.En cualquier caso, se trata de un estudio positivo con hallazgos significativos. En esa misma sesión se presentó también el SKYSCRAPER-07, que se enfoca en tumores de tipo escamoso, lo que nos lleva a reflexionar y plantear nuevas preguntas sobre este campo. La pregunta es si existe alguna estrategia adicional para los pacientes que han recibido tratamiento definitivo, y en este contexto se evaluó la combinación de atezolizumab con tiragolumab, un anticuerpo anti-TIGIT, como posible alternativa terapéutica, aunque el estudio no alcanzó su objetivo principal predefinido, sí evidenció ciertas señales de actividad que sugieren un potencial beneficio de la inmunoterapia como tratamiento de consolidación en pacientes con enfermedad irresecable.Y finalmente, en el área de los tumores esofagogástricos, para comentar que me llamó la atención, en el advenimiento estos anticuerpos biespecíficos, un nuevo agente que se presentó justamente en combinación o comparando con el esquema de quimioterapia para pacientes con cáncer gástrico, HER2 positivo.Y para cerrar, en el campo de los tumores esofagogástricos, me pareció interesante destacar el avance de los anticuerpos biespecíficos, con la presentación de un nuevo agente evaluado en comparación con la quimioterapia estándar en pacientes con cáncer gástrico HER2 positivo.Entre otros temas.Fecha de grabación: 19 de octubre de 2025Material exclusivo para profesionales de la salud. Este material ha sido desarrollado únicamente con fines educativos e informativos y no tiene la intención de sustituir el juicio clínico de los profesionales de la salud. Las opiniones y declaraciones presentadas en este contenido son responsabilidad exclusiva de los ponentes y no reflejan necesariamente la postura institucional de ScienceLink ni de terceros mencionados. La información presentada se basa en el conocimiento y la experiencia profesional de los ponentes. La veracidad, exactitud y actualidad científica de los datos son de su exclusiva responsabilidad. Así mismo garantizan que el contenido utilizado no infringe derechos de autor de terceros y asumen toda responsabilidad por su uso. Se deberán de revisar las indicaciones aprobadas en el país con estricto apego al marco regulatorio aplicable para cada uno de los tratamientos y medicamentos comentados. ESMO® es una marca registrada de la European Society For Medical Oncology. Este material ha sido producido de manera independiente y no está autorizado, patrocinado ni avalado por dicha organización.

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

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Dr. Hope Rugo and Dr. Giuseppe Curigliano discuss recent developments in the field of bispecific antibodies for hematologic and solid tumors, including strategies to optimize the design and delivery of the immunotherapy. 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. I am also the editor-in-chief of the Educational Book. Bispecific antibodies represent an innovative and advanced therapeutic platform in hematologic and solid tumors. And today, I am delighted to be joined by Dr. Giuseppe Curigliano to discuss the current landscape of bispecific antibodies and their potential to reshape the future of precision oncology. Dr. Curigliano was the last author of an ASCO Educational Book piece for 2025 titled, "Bispecific Antibodies in Hematologic and Solid Tumors: Current Landscape and Therapeutic Advances." Dr. Curigliano is a breast medical oncologist and the director of the Early Drug Development Division and chair of the Experimental Therapeutics Program at the European Institute of Oncology in Milan. He is also a full professor of medical oncology at the University of Milan. You can find our disclosures in the transcript of this episode. Dr. Curigliano, Giuseppe, welcome and thanks for being here. Dr. Giuseppe Curigliano: Thanks a lot for the invitation. Dr. Hope Rugo: Giuseppe, I would like to first ask you to provide some context for our listeners on how these novel therapeutics work. And then perhaps you could tell us about recent developments in the field of bispecific antibodies for oncology. We are at a time when antibody-drug conjugates (ADCs) are all the rage and, trying to improve on the targeting of specific antigens, proteins, receptors in the field of oncology is certainly a hot and emerging topic. Dr. Giuseppe Curigliano: So, thanks a lot. I believe really it was very challenging to try to summarize all the bispecific antibodies that are under development in multiple solid tumors. So, the first thing that I would like to highlight is the context and the mechanism of action of bispecific antibodies. Bispecific antibodies represent a groundbreaking advancement in cancer immunotherapy, because these engineered molecules have the unique ability to target and simultaneously bind to two distinct antigens. That is why we call them bispecific. So typically, one antigen is expressed on the tumor cell and the other one is expressed on the immune effectors, like T-cell or natural killer cells. So this dual targeting mechanism offers several key advantages over conventional monoclonal antibodies because you can target at the same time the tumor antigen, downregulating the pathway of proliferation, and you can activate the immune system. So the primary mechanism through which bispecific antibodies exert their therapeutic effects are: First, T-cell redirecting. I mean, many bispecific antibodies are designed to engage tumor-associated antigens like epidermal growth factor receptor, HER2, on the cancer cell and a costimulatory molecule on the surface of T-cell. A typical target antigen on T-cell is CD3. So what does it mean? That you activate the immune system, immune cells will reach the tumor bed, and you have a dual effect. One is downregulating cell proliferation, the other one is activation of the immune system. This is really important in hematological malignancies, where we have a lot of bispecifics already approved, like acute lymphoblastic leukemia or non-Hodgkin lymphoma.  The second, in fact, is the engagement of the tumor microenvironment. So, if you engage immune effector cells like NK cells or macrophages, usually the bispecific antibodies can exploit the immune system's ability to recognize and kill the immune cells, even if there is a lack of optimal antigen presentation.  And finally, the last mechanism of action, this may have a role in the future, maybe in the early cancer setting, is overcoming immune evasion. So bispecific antibodies can overcome some of the immune evasion mechanisms that we see in cancer. For example, bispecific antibodies can target immune checkpoint receptors, like PD-L1 and CTLA-4. Actually, there is a bispecific under development in breast cancer that has a dual targeting on vascular endothelial growth factor receptor and on PD-L1. So you have a dual effect at the same time. So, what is really important, as a comment, is we need to focus first on the optimal format of the bispecific, the optimal half-life, the stability, because of course even if they are very efficient in inducing a response, they may give also a lot of toxicities. So in clinical trials already, we have several bispecifics approved. In solid tumors, very few, specifically amivantamab for non-small cell lung cancer, but we have a pipeline of almost 40 to 50 bispecifics under development in multiple solid tumors, and some of them are in the context of prospective randomized trials. Dr. Hope Rugo: So this is really a fascinating area and it's really exciting to see the expansion of the different targets for bispecific antibodies. One area that has intrigued me also is that some of the bispecifics actually will target different parts of the same receptor or the same protein, but presumably those will be used as a different strategy. It's interesting because we have seen that, for example, in targeting HER2. Dr. Giuseppe Curigliano: Oh, yes, of course. You may consider some bispecifics like margetuximab, I suppose, in which you can target specifically two different epitopes of the same antigen. This is really an example of how a bispecific can potentially be more active and downregulating, let us say, a pathway, by targeting two different domains of a specific target antigen. This is an important point.  Of course, not all the bispecifics work this way, because some of the target antigen may dimerize, and so you have a family of target antigen; an example is epidermal growth factor receptor, in which you have HER1, HER2, HER3, and HER4. So some of them can inhibit the dimerization between one target antigen and the other one, in order to exert a more antiproliferative effect. But to be honest, the new generation of them are more targeting two different antigens, one on the tumor and one on the microenvironment, because according to the clinical data, this is a more efficient way to reduce proliferation and to activate the immune system. Dr. Hope Rugo: Really interesting, and I think it brings us to the next topic, which is really where bispecific antibodies have already shown success, and that is in hematologic malignancies where we have seen very interesting efficacy and these are being used in the clinic already. But the expansion of bispecific antibodies into solid tumors faces some key challenges. It's interesting because the challenges come in different shapes and forms. Tell us about some of those challenges and strategies to optimize bispecific antibody design, delivery, patient selection, and how we are going to use these agents in the right kind of clinical trials. Dr. Giuseppe Curigliano: This is really an excellent question because despite bispecific antibodies having shown a remarkable efficacy in hematological malignancies, their application in solid tumors may have some challenges. The first one is tumor heterogeneity. In hematological malignancy, you have a clear oncogene addiction. Let us say that 90% of the cells may express the same antigen. In solid tumors, it is not the same. Tumor heterogeneity is a typical characteristic of solid tumors, and you have high heterogeneity at the genetic, molecular, and phenotypic levels. So tumor cells can differ significantly from one another, even if within the same tumor. And this heterogeneity sometimes makes it difficult to identify a single target antigen that is universally expressed in an hematological malignancy. So furthermore, sometimes the antigen expressed on a tumor cell can be also present on the normal tissue. And so you may have a cross-targeting. So let's say, if you have a bispecific against epidermal growth factor receptor, this will target the tumor but will target also the skin with a lot of toxicity. The second challenge is the tumor microenvironment. The solid tumor microenvironment is really complex and often immunosuppressive. It is characterized by the presence of immunosuppressor cells like the T regulators, myeloid derived suppressor cells, and of course the extracellular matrix. All these factors hinder immune cell infiltration and also may reduce dramatically the effectiveness of bispecific antibodies. And as you know, there is also an hypoxic condition in the tumor. The other challenge is related to the poor tumor penetration. As you know also with antibody-drug conjugate, only 1 to 3% of the drug will arrive in the tumor bed. Unlike hematological malignancies where tumor cells are dispersed in the blood and easily accessible, the solid tumors have a lot of barriers, and so it means that tumor penetration can be very low. Finally, the vascularity also of the tumor can be different across solid tumors. That is why some bispecifics have a vascular endothelial growth factor receptor or vascular endothelial growth factor as a target. Of course, what do we have to do to overcome these challenges? First, we have to select the optimal antigen. So knowing very well the biology of cancer and the tumor-associated antigens can really select a subgroup of epitopes that are specifically overexpressed in cancer cells. And so we need to design bispecifics according to the tumor type. Second, optimize the antibody format. So there are numerous bispecific antibody formats. We can consider the dual variable domain immunoglobulin, we specified this in our paper. The single chain variable fragments, so FC variable fragments, and the diabodies that can enhance both binding affinity and stability. And finally, the last point, combination therapies. Because bispecific antibodies targeting immune checkpoint, we have many targeting PD-1 or PD-L1 or CTLA-4, combined eventually with other immune checkpoint inhibitors. And so you may have more immunostimulating effect. Dr. Hope Rugo: This is a fascinating field and it is certainly going to go far in the treatment of solid tumors. You know, I think there is some competition with what we have now for antibody-drug conjugates. Do you see that bispecifics will eventually become bispecific ADCs? Are we going to combine these bispecific antibodies with ADCs, with chemotherapy? What is the best combination strategy do you think looking forward? Dr. Giuseppe Curigliano: So, yes, we have a bispecific ADC. We have actually some bispecifics that are conjugated with a payload of chemotherapy. Some others are conjugated with immunoactivation agents like IL-2. One of the most effective strategies for enhancing bispecific activity is the combination therapy. So which type of combination can we do? First, bispecific antibodies plus checkpoint inhibitors. If you combine a bispecific with an immune checkpoint, like anti-PD-1, anti-PD-L1, or anti-CTLA-4, you have more activity because you have activation of T-cells, reduction of immunosuppressive effect, and of course, the capability of this bispecific to potentiate the activity of the immune checkpoint inhibitor. So, in my opinion, in a non-small cell lung cancer with an expression of PD-L1 more than 50%, if you give pembrolizumab plus a bispecific targeting PD-L1, you can really improve both response rate and median progression-free survival.  Another combination is chemotherapy plus bispecific antibodies. Combining chemotherapy with bispecific can enhance the cytotoxic effect because chemotherapy induces immunogenic cell death, and then you boost with a bispecific in order to activate the immune system. Bispecific and CAR T-cells, until now, we believe that these are in competition, but this is not correct. Because CAR T-cells are designed to deliver an activation of the immune system with the same lymphocytes engineered of the patients, with a long-term effect. So I really do not believe that bispecifics are in competition with CAR T-cells because when you have a complete remission induced by CAR T-cell, the effect of this complete remission can last for years. The activity of a bispecific is a little bit different. So there are some studies actually combining CAR T-cells with bispecifics. For example, bispecific antibodies can direct CAR T-cells in the tumor microenvironment, improving their specificity and enhancing their therapeutic effect.  And finally, monoclonal antibody plus bispecific is another next generation activity. Because if you use bispecific antibodies in combination with existing monoclonal antibodies like anti-HER2, you can potentially increase the immune response and enhance tumor cell targeting. In hematological malignancies, this has been already demonstrated and this approach has been particularly effective. Dr. Hope Rugo: That's just so fascinating, the whole idea that we have these monoclonal antibodies and now we are going to add them to bispecifics that we could maybe attach on different toxins to try and improve this, or even give them with different approaches. I suppose giving an ADC with a bispecific would sort of be similar to that idea of giving a monoclonal antibody with the bispecific. So it is certainly intriguing. We also will need to understand the toxicity and cost overall and how we are going to use these, the duration of treatment, the assessment of biomarkers. There are just so many different aspects that still need to be explored.  And then with that idea, can you look ahead five or ten years from now, and tell us how you think bispecific antibodies will shape our next generation cancer therapies, how they will be incorporated into precision oncology, and the new combinations and approaches as we move forward that will help us tailor treatment for patients both with solid tumors and hematologic malignancies? Are we going to be giving these in early-stage disease in solid tumors? So far, the studies are primarily focusing on the metastatic setting, but obviously one of the goals when we have successful treatments is to move them into the early stage setting as quickly as possible. Dr. Giuseppe Curigliano: Let us try to look ahead five years rather than ten years, to be more realistic. So, personally I believe some bispecifics can potentially replace current approaches in specifically T-cell selected population. As we gather more data from ongoing clinical trials and we adopt a deeper understanding of the tumor immuno microenvironment, of course we may have potentially new achievement. A few days ago, we heard that bispecifics in triple negative breast cancer targeting VEGF and PD-L1 demonstrated an improvement in median progression-free survival.  So, how to improve and to impact on clinical practice both in the metastatic and in the early breast cancer setting or solid tumor setting? First, personalized antigen selection. So we need to have the ability to tailor bispecific antibody therapy to the unique tumor profile of individual patients. So the more we understand the biology of cancers, the more we will be able to better target. Second, bispecific antibodies should be combined. I can see in the future a potential trial in which you combine a bispecific anti-PD-L1 and VEGF with immune checkpoint inhibitor selected also to the level of expression of PD-L1, because integration of antibody bispecific with a range of immunotherapies, and this cannot be only immune checkpoint inhibitors, but can be CAR T-cells, oncolytic viruses, also targeted therapy, will likely be a dominant theme in the coming years. This combination will be based on the specific molecular and immuno feature of the cancer of the patient.  Then we need an enhanced delivery system. This is really important because you know now we have a next generation antibody. An example are the bicyclic. So you use FC fragment that are very short, with a low molecular weight, and this short fragment can be bispecific, so can target at the same time a target antigen and improving the immune system. And so the development of this novel delivery system, including also nanoparticles or engineered viral vectors, can enhance the penetration in the tumor bed and the bioavailability of bispecific antibodies. Importantly, we need to reduce toxicity. Until now, bispecifics are very toxic. So the more we are efficient in delivering in the tumor bed, the more we will reduce the risk of toxicity. So it will be mandatory to reduce off-target effects and to minimize toxicity.  And finally, the expansion in new indication. So I really believe you raised an excellent point. We need to design studies in the neoadjuvant setting in order to better understand with multiple biopsies which is the effect on the tumor microenvironment and the tumor itself, and to generate hypotheses for potential trials or in the neoadjuvant setting or in those patients with residual disease.  So, in my opinion, as we refine design, optimize patient selection, and explore new combination, in the future we will have more opportunity to integrate bispecifics in the standard of care. Dr. Hope Rugo: I think it is particularly helpful to hear what we are going to be looking for as we move forward to try and improve efficacy and reduce toxicity. And the ability to engineer these new antibodies and to more specifically target the right proteins and immune effectors is going to be critical, of course, moving forward, as well as individualizing therapy based on a specific tumor biology.  Hearing your insights has been great, and it really has opened up a whole area of insight into the field of bispecifics, together with your excellent contribution to the ASCO Educational Book. Thank you so much for sharing your thoughts and background, as well as what we might see in the future on this podcast today. Dr. Giuseppe Curigliano: Thank you very much for the invitation and for this excellent interview. Dr. Hope Rugo: And thanks to our listeners for joining us today. You will find a link to the Ed Book article we discussed today in the transcript of this episode. It is also, of course, on the ASCO website, as well as on PubMed. Please join us again next month on By the Book for more insightful views on the key issues and innovations 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. Giuseppe Curigliano @curijoey 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. Giuseppe Curigliano: Leadership: European Society for Medical Oncology, European Society of Breast Cancer Specialists, ESMO Open, European Society for Medical Oncology Honoraria: Ellipses Pharma Consulting or Advisory Role: Roche/Genentech, Pfizer, Novartis, Lilly, Foundation Medicine, Bristol-Myers Squibb, Samsung, AstraZeneca, Daiichi-Sankyo, Boerigher, GSK, Seattle Genetics, Guardant Health, Veracyte, Celcuity, Hengrui Therapeutics, Menarini, Merck, Exact Sciences, Blueprint Medicines, Gilead Sciences Speakers' Bureau: Roche/Genentech, Novartis, Pfizer, Lilly, Foundation Medicine, Samsung, Daiichi Sankyo, Seagen, Menarini, Gilead Sciences, Exact Sciences Research Funding: Merck Travel, Accommodations, Expenses: Roche/Genentech, Pfizer, Daiichi Sankyo, AstraZeneca      

JCO PO author Dr. Asaf Maoz at Dana-Farber Cancer Institute shares insights into article, “Causes of Death Among Individuals with Lynch Syndrome in the Immunotherapy Era.” Host Dr. Rafeh Naqash and Dr. Maoz discuss the causes of death in individuals with LS and the evolving role of immunotherapy. TRANSCRIPT Dr. Rafeh Naqash: Hello, and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Associate Professor Medicine, at the OU Health Stephenson Cancer Center. Today, I'm super thrilled to be joined by Dr. Asaf Maoz, Medical Oncologist at Dana-Farber Cancer Institute, Brigham and Women's Hospital, and faculty at the Harvard Medical School, and also lead author on the JCO Precision Oncology article entitled "Causes of Death Among Individuals with Lynch Syndrome in the Immunotherapy Era." This publication will be a concurrent publication with an oral presentation at the annual CGA meeting. At the time of this recording, our guest's disclosures will be linked in the transcript. Asaf, I'm excited to welcome you on this podcast. Thank you for joining us today. Dr. Asaf Maoz: Thank you so much for highlighting our paper. Dr. Rafeh Naqash: Absolutely. And I was just talking to you that we met several years back when you were a trainee, and it looks like you've worked a lot in this field now, and it's very exciting to see that you consider JCOPO as a relevant home for some of your work. And the topic that you have published on is of significant interest to trainees from a precision medicine standpoint, to oncologists in general, covers a lot of aspects of immunotherapy. So, I'm really excited to talk to you about all of this. Dr. Asaf Maoz: Me too, me too. And yeah, I think JCOPO has great content in the area of cancer genetics and has done a lot to disseminate the knowledge in that area. Dr. Rafeh Naqash: Wonderful. So, let's get started and start off, given that we have hosts of different kinds of individuals who listen to this podcast, especially when driving from home to work or back, for the sake of making everything simple, can we start by asking you what is Lynch syndrome? How is it diagnosed? What are some of the main things to consider when you're trying to talk an individual where you suspect Lynch syndrome? Dr. Asaf Maoz: Lynch syndrome is an inherited predisposition to cancer, and it is common. So, we used to think that, or there's a general notion in the medical community that it is a rare condition, but we actually know now from multiple studies, including studies that look at the general population and do genetic testing regardless of any clinical phenotype, that Lynch syndrome is found in about 1 in 300 people in the general population. If you think about it in the United States, that means that there are over a million people living with Lynch syndrome in the United States. Unfortunately, most individuals with Lynch syndrome don't know they have Lynch syndrome at the current time, and that's where a lot of the efforts in the community are being made to help detect more individuals who have Lynch syndrome. Lynch syndrome is caused by pathogenic germline variants in mismatch repair genes, MLH1, MSH2, MSH6, or PMS2, or as a result of pathogenic variants in EPCAM that cause silencing of the MSH2 gene. Dr. Rafeh Naqash: Excellent. Thank you for that explanation. Now, one of the other things I also realized, similar to BRCA germline mutations, where you require a second hit for individuals with Lynch syndrome to have mismatch repair deficient cancers, you also require a second hit to have that second hit result in an MSI-high cancer. Could you help us understand the difference of these two concepts where generally Lynch syndrome is thought of to be cancers that are mismatch repair deficient, but that's not necessarily true for all cases as we see in your paper. Can you tease this out for us a little bit more? Dr. Asaf Maoz: Of course, of course. So, the germline defect is in one of the mismatch repair genes, and these genes are responsible for DNA mismatch repair, as their name implies. Now, in a normal cell, we think that one working copy is generally enough to maintain the mismatch repair machinery intact. What happens in tumors, as you alluded to, is that there is a second hit in the same mismatch repair gene that has the pathogenic germline variant, and that causes the mismatch repair machinery not to work anymore. And so what happens is that there is formation of mutations in the cancer cell that are not present in other cells in the body. And we know that there are specific types of mutations that are associated with defects in mismatch repair mechanisms, and those are associated a lot of times with frameshift mutations. And we have termed them ‘microsatellites'. So there are areas in the genome that have repeats, for example, you know, if you have AAAA or GAGA, and those areas are particularly susceptible to mutations when the mismatch repair machinery is not working. And so we can measure that with DNA microsatellite instability testing. But we can also get a sense of whether the mismatch repair machinery is functioning by looking at protein expression on the surface of cancer cells and by doing immunohistochemistry. More recently, we're also able to infer whether the mismatch repair machinery is working by doing next-generation sequencing and looking at many, many microsatellites and whether they have this DNA instability in the microsatellites. Dr. Rafeh Naqash: Excellent explanation. As a segue to what you just mentioned, and this reminds me of some work that one of my good friends, collaborators, Amin Nassar, whom you also know, I believe, had done a year and a half back, was published in Cancer Cell as a brief report, I believe, where the concept was that when you look at these mismatch repair deficient cancers, there is a difference between NGS testing, IHC testing, and maybe to some extent, PCR testing, where you can have discordances. Have you seen that in your clinical experience? What are some of your thoughts there? And if a trainee were to ask, what would be the gold standard to test individuals where you suspect mismatch repair deficient-related Lynch syndrome cancers? How would you test those individuals? Dr. Asaf Maoz: We do sometimes see discordance, you know, from large series, the concordance rate is very high, and in most series it's over 95%. And so from a practical perspective, if we're thinking about the recommendation to screen all colorectal cancer and all endometrial cancer for mismatch repair deficiency, I think either PCR-based testing or immunohistochemistry is acceptable because the concordance rate is very high. There are rare cases where it is not concordant, doing multiple of the tests makes sense at that time. If you think about the difference between the tests, the immunohistochemistry looks at protein expression, which is a surrogate for whether there is mismatch repair deficiency or not, right? Because ultimately, the mismatch repair deficiency is manifested in the mutations. So if the PCR does not show microsatellite instability and now NGS does not show microsatellite instability, the IHC may be a false positive. At the end of the day, the functional analysis of whether there are actually unstable microsatellites either by PCR or by NGS is what I would consider more informative. But IHC again is an excellent test and concordant with those results in over 95% of cases. Now there is also an issue of sampling. It's possible that there's heterogeneity within the tumor. We published a case in JCOPO about heterogeneity of the mismatch repair status, and that was both by immunohistochemistry, but also by PCR. So there are some caveats and interpreting these tests does require some expertise, and I'm always happy to chat with trainees or whoever has an interesting or challenging case. Dr. Rafeh Naqash: Thanks again for that very easy to understand explanation. Now going to management strategies, could you elaborate a little bit upon the neo-adjuvant data currently, or the metastatic data which I think more people are familiar with for immunotherapy in individuals with MSI-high cancers? Dr. Asaf Maoz: Yeah, that's an excellent question and obviously a very broad topic. Individuals with Lynch syndrome typically develop tumors that are mismatch repair deficient or microsatellite unstable. And we have seen over the last 15 years or so that these tumors, because they have a lot of mutations and because these mutations are very immunogenic, we have seen that they respond very well to immunotherapy. And this has been shown across disease sites and has been shown across disease settings. And for that reason, immunotherapy was approved for MSI-high or mismatch repair deficient cancer regardless of the anatomic site. It was the first tissue-agnostic approval by the FDA in 2017. And so there are exciting studies both in the metastatic setting where we see individuals who respond to immunotherapy for many years, and one could wonder whether their cancer is going to come back or not. And also in the earlier setting, for example, the Cercek et al. study in the New England Journal from Sloan Kettering, where they showed that neoadjuvant immunotherapy can cause durable responses for rectal cancer that is mismatch repair deficient. And in that series, the patients did not require surgery or radiation, which is standard of care for rectal cancer otherwise. And there's also exciting data in the adjuvant space, as was presented in ASCO by Dr. Sinicrope, the ATOMIC study, and many more efforts to bring immunotherapy into the treatment landscape for individuals with MSI-high cancer, including individuals with Lynch syndrome. Dr. Rafeh Naqash: A lot of activity, especially in the neo-adjuvant and adjuvant space over the last two years or so. Now going to the actual reason why we are here is your study. Could you tell us why you looked at this idea of patients who had Lynch syndrome and died, and the reasons for their death? What was the thought that triggered this project? Dr. Asaf Maoz: As we were talking about, we now know that immunotherapy really has changed the treatment landscape for individuals with Lynch syndrome, and that most cancers that individuals with Lynch syndrome do have this mismatch repair deficiency. But we also know that individuals with Lynch syndrome can develop tumors that do not have mismatch repair deficiency, and we call them mismatch repair proficient or microsatellite stable. And there was a series from Memorial Sloan Kettering showing that in colorectal cancer, about 10% of the tumors that individuals with Lynch syndrome developed did not have mismatch repair deficiency. In addition to that, we anecdotally saw that some of our patients with Lynch syndrome died of causes that were not mismatch repair deficient tumors. We wanted to see how that has changed since immunotherapy was approved in a tissue-agnostic manner, meaning that we could look at this regardless of where the cancer started, because we would anticipate that if the tumor was mismatch repair deficient, the patient would be able to access immunotherapy as standard of care. Dr. Rafeh Naqash: Thank you. And then you looked at different aspects of correlations with regards to individuals that had an MSI-high cancer with Lynch syndrome or an MSS cancer with Lynch syndrome. Could you elaborate on some of the important findings that you identified as well as some of the unusual findings that perhaps we did not know about, even though the sample size is limited, but what were some of the unique things that you did identify through this project? Dr. Asaf Maoz: The first question was what cause is leading to death in individuals with Lynch syndrome? And we had 54 patients that we identified that had died since the approval of immunotherapy in 2017, 44 of which died of cancer-related causes. And when we looked at cancer-related causes of death, we wanted to know how many of those were due to mismatch repair deficient tumors versus mismatch repair proficient tumors or MS-stable tumors. And we found, somewhat surprisingly, that 43% of patients in our cohort actually died of tumors that were microsatellite stable or mismatch repair proficient, meaning of tumors that are not typically associated with Lynch syndrome. This is not entirely surprising as a cause of death because we know that immunotherapy does not typically work for tumors that are microsatellite stable. And so in the metastatic setting, there are much less cases of durable remissions with treatment. But it was helpful to have that figure as an important benchmark. There are previous studies about causes of death in Lynch syndrome, and particularly from the Prospective Lynch Syndrome Database in Europe. Those have provided really important information about cause of death by cancer site, but they typically don't have mismatch repair status and are more difficult to interpret in that regard. They also don't include a large number of individuals who have PMS2 Lynch syndrome, which is the most common, but least penetrant form of Lynch syndrome. Dr. Rafeh Naqash: As far as the subtype of pathogenic germline variants is concerned, did you notice anything unusual? And I've always had this question, and you may know more about this data, is: In the bigger context of immunotherapy, does the type of the pathogenic germline variant for Lynch syndrome associated MSI-high cancers, does that impact or have an association with the kind of outcomes, how soon a cancer progresses or how many exceptional responders perhaps with MSI-high cancers actually have a certain specific pathogenic germline variant? Dr. Asaf Maoz: That's an excellent question, and certainly we need more data in that space. We know that the type of germline mutation, or the gene in which there is a germline pathogenic variant, determines to a large degree the cancer risk, right? So we know that individuals who have germline pathogenic variants in MLH1 or MSH2 have a much higher colorectal cancer risk than, for example, PMS2. We know that for PMS2, the risks are more limited to colorectal and endometrial, and may be lower risk of other cancers. We also know that, you know, the spectrum of disease may change based on the pathogenic germline variants. For example, individuals who have MSH2 associated Lynch syndrome have more risk of additional cancers in other organs like the urinary tract and other less common Lynch-associated tumors. The question about response to therapy is one where we have much less information. There are studies that are trying to assess this, but I don't think the answer is there yet. Some of the non-clinical data looks at how many mutations there are based on the pathogenic variant and what the nature of those mutations are, whether they're more frameshift or others. But I think we still need more clinical data to understand whether the response to immunotherapy differs. It's also complicated by the fact that the immunotherapy landscape is changing, especially in the metastatic setting, now with the approval of combination ipilimumab and nivolumab for first-line treatment of colorectal cancer that is microsatellite unstable. But in our study, we did find that, as you would expect, there is an enrichment in MS-stable cancers among those with PMS2 Lynch syndrome. Again, our denominator is those who died, right? So this is not the best way to look at the question whether this is overall true, that is more addressed by the study that Sloan Kettering published. But we do see, as we would anticipate, that there are more microsatellite stable cancers among those with PMS2 Lynch syndrome that died. Dr. Rafeh Naqash: A lot to uncover there for sure. This study and perhaps some of the other work that you're doing is slowly advancing our understanding of some of these concepts. So I'd like to shift gears to a couple of provocative questions that I generally like to ask. The first is, in your opinion, and you may or may not have data to back this up, which is okay, and that's why we're having a conversation about it. In your opinion, do you think the type or the quality of the neoantigen is different based on the pathogenic germline variant and a Lynch syndrome associated MSI-high cancer? Dr. Asaf Maoz: I think there are some data out there that, you know, I can't cite off the top of my mind, but there are some data out there that suggest that that may be the case. I think the key question is the quality, right? I think that whether these differences that are found on a molecular level also translate to a clinical difference in response is something that is unknown at this moment. Some people hypothesize that if the tumor has less neoantigens, there's less of a response to immunotherapy. But I think we really need to be careful before making those assertions on a clinical level. I do think it's a really important question that needs to be answered, among others because, you know, in the colorectal space, for example, where we have both the option of doing ipilimumab with nivolumab and the option of doing pembrolizumab, we don't really know which patients need the CTLA-4 blockade versus which patients can receive PD-1 blockade alone and avoid the potential excess toxicity of the CTLA-4 blockade. There are a lot of interesting questions there that still need to be answered. And of course, individuals with Lynch syndrome are just a fraction of those individuals who have MSI-high cancer. So there's also the question about whether non-Lynch syndrome associated MSI-high cancer responds differently to immunotherapy than Lynch syndrome associated MSI-high cancer. A lot of very interesting questions in the field for sure. Dr. Rafeh Naqash: Absolutely. My second question is more about trying to understand the role of ctDNA, MRD monitoring in individuals with Lynch syndrome. If somebody has a germline, you know, Lynch syndrome MSI-high cancer, when you do a tumor-informed ctDNA assessment, what do you capture generally there? Because, and this question stems from a discussion I've had with somebody regarding EGFR lung cancer, since I treat individuals with lung cancer, and the concept generally is that even if the tissue showed EGFR, but for MRD monitoring, when you do a barcoded sequence of different tumor specific mutations, it's not actually the EGFR that they track in the blood when they do ctDNA assessment. But from a Lynch syndrome standpoint, if you have a germline, right, which is the first hit, and then you have the somatic in the tumor, which is the second hit, are you aware or have you tried to look into this where what is exactly being followed if one had to follow MRD in a Lynch syndrome MSI-high colorectal cancer? Dr. Asaf Maoz: I think a lot of the MRD assays are proprietary, and so we don't receive information about what the mutations that are being tracked are. In general, the idea is to track mutations that we would not expect to disappear as part of resistant mechanisms. We want these to be truncal mutations. We want these to be mutations in which resistance is not expected to result in reversion mutations. But what specifically is being tracked is something that I don't know because these assays, the tumor-informed ones, are proprietary, and we don't get the results regarding specific mutations. When it's circulating tumor DNA that is not necessarily tumor-informed, we do get those results, but that is less so about the specific selection of mutations. Dr. Rafeh Naqash: Thank you for clarifying that question to some extent, of course, as you said, we don't know a lot, and we don't know what we don't know. That's the most important thing that I've learned in the process of understanding precision medicine and genomics, and it's a very fast-paced evolving field. Last question related to your project, what is the next step? Are you planning any next steps as a bigger multicenter study or validation of some sort? Dr. Asaf Maoz: There are two big questions that this study raises. One, is this true across multiple other sites, right? Because this is a single center study, and we really need additional centers to look at their data and validate whether they are also seeing that a substantial portion of deaths in individuals with Lynch syndrome are attributable to mismatch repair proficient cancer. The other question is whether we can look at specifically MSI-high cancer versus MS-stable cancer and understand what the mortality rate for each of those are. From a clinical perspective, it's important to counsel individuals with Lynch syndrome about general cancer screening outside of mismatch repair deficient tumors and to understand that there is also a risk of mismatch repair proficient tumors and that treatment for those tumors would be different. There's a lot of work to be done in the future. Another major area of need is to see whether tumors that are microsatellite stable can be sensitized to immunotherapy, and that is beyond the Lynch syndrome field, but that is something that certainly would benefit these individuals with Lynch syndrome who develop mismatch repair proficient cancer. Dr. Rafeh Naqash: That's very interesting to hear, and we'll look forward to seeing some of those developments shape in the next few years. Now, I'd like to spend a minute, minute and a half on you specifically as a researcher, clinician, scientist. Could you briefly highlight - because I remember meeting you several years back as a trainee, with your interest in genomics, computational research - could you briefly tell us what led you to hereditary cancer syndromes based on your research and work? What are some of the things that you learned along the way that other early career investigators can perhaps take lessons from? Dr. Asaf Maoz: Big questions there, thanks for asking. I got interested in the field of hereditary cancer syndromes when I came to the United States and started doing lab research in Stephen Gruber's lab at the time at USC. He's now at City of Hope. And my interest was originally looking at immunotherapy and immunology, but I went to the case conferences where we were learning about individuals with hereditary cancer, and those were kind of earlier days where we were still trying to figure out how to test and what the implications for these individuals would be. And through fellowship, I was also very interested in that, and I did my senior fellowship years with Dr. Yurgelun here at Dana-Farber, who is the director of the Lynch Syndrome Center. And I I think it's the combination between being able to treat individuals based on precision medicine and what the germline mutation is, but also the ability to prevent cancer and to develop strategies to intercept cancer early that is really appealing to me in this field. It's also a great field to be in because it's a small field. If you come to the CGA-IGC meeting, you'll be able to interact with everyone. Everyone is super collaborative, super nice, and I really recommend it to trainees. The CGA-IGC annual meeting is really a great opportunity to learn more and experience some of the advancement specifically in the GI hereditary space. Lessons for trainees. I think there are a lot of lessons that I could think about, but I think finding strong and supportive mentors is one of the things that has helped me most. I think that just having close relationship with your mentor, having frequent discussions and honest discussions about what is feasible, what is going to make a difference for your patients and your research and what you want to focus on is really important. And so I think if I had to choose one thing, I would say choose a mentor that you trust, that you feel you have a good relationship with, and that has the availability to support you. Dr. Rafeh Naqash: Thank you so much for those insightful comments, and thank you for sharing with us your journey, your project, and some of your interesting thoughts on this concept of hereditary cancers. Hopefully, we'll see more of this work being published in JCOPO through your lab or work from others. Dr. Asaf Maoz: Thank you so much. I appreciate the opportunity to be here. Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ASCO.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

JCO PO author Dr. Bryson Katona at the University of Pennsylvania Perelman School of Medicine shares insights into his article, “Areas of Uncertainty in Pancreatic Cancer Surveillance: A Survey Across the International Pancreatic Cancer Early Detection (PRECEDE) Consortium” Host Dr. Rafeh Naqash and Dr. Katona discuss how, given differing guidelines as well as lack of detail about how PC surveillance should be performed, approaches to PC surveillance across centers often differs. TRANSCRIPT Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I am your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Associate Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, I am thrilled to be joined by Dr. Bryson Katona, Director of the Gastrointestinal Cancer Genetics Program and Director of the Lynch Syndrome Program at the Penn Medicine's Abramson Cancer Center, and also lead author of the JCO PO article entitled "Areas of Uncertainty in Pancreatic Cancer Surveillance: A Survey Across the International Pancreatic Cancer Early Detection or PRECEDE Consortium." Bryson, thanks for joining us again. Dr. Bryson Katona: Well, thank you so much for having me. I appreciate the opportunity. Dr. Rafeh Naqash: It is exciting to see that this work will be presented concurrently with the upcoming CGA meeting. Dr. Bryson Katona: Yes, it has been a fantastic partnership between JCO PO and the CGA-IGC and their annual meeting. And for those who may not be familiar, the CGA-IGC is the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer. It is basically a professional organization dedicated to individuals who have hereditary GI cancer risk and focusing on providing education, promoting research, and really bringing together providers in this space from not just throughout the US but from across the globe as well. Dr. Rafeh Naqash: That is exciting to hear the kind of work you guys are doing. These are definitely interesting, exciting things. Now, going to what you have published, it is an area that is very evolving in the space of cancer screening, cancer surveillance, especially for a very aggressive cancer such as pancreatic cancer. Could you tell us currently, what are the general consensus? I know there are a lot of differences between different guidelines or societies, but what are the some of the commonalities if we were to start there first for pancreas cancer screening? If you are not a GI oncologist, you may not be aware that there is something with regards to pancreas cancer screening. Could you give us an overview and a background on that? Dr. Bryson Katona: Yeah, I think that pancreatic cancer screening really is one of the most controversial areas of all cancer screening. Part of that controversy is just because all the guidelines, the many different guidelines that are out there, do not always match up with one another, which I think leads to a lot of confusion, not just for providers but for patients who are trying to go through this, and then also the insurance companies in trying to get these screening tests covered. You know, when we think about who is eligible for pancreatic cancer screening, you know, it is important that these are not average-risk individuals. So really, we are only offering screening to high-risk individuals. And those can include people that have a strong family history of pancreatic cancer without a germline genetic susceptibility that has been identified. And those individuals we refer to as having familial pancreatic cancer. And the other big cohort is those individuals that carry hereditary pancreatic cancer predisposition. These are due to cancer risk mutations in many different genes, including many of the breast cancer risk genes like BRCA1 and BRCA2, as well as ATM and PALB2, but then other genes such as the Lynch syndrome genes, and then some of the higher risk genes such as those leading to Peutz-Jeghers syndrome as well as FAM, which is due to CDKN2A mutations. Dr. Rafeh Naqash: Thank you for that. Again, another practical question, and this may or may not be exactly related to your specific topic here, but perhaps to some extent there might be an overlap. If I get a patient from a colleague, and I see people in the early-phase clinical trial setting, so many different tumors for novel drugs, and I find an individual with, let us say, lung cancer who has a pathogenic BRCA2, which is somatic, should I be worried about pancreas cancer screening in that individual? Or have we not met that threshold yet in that circumstance? Dr. Bryson Katona: A lot of times these variants or these genes that are associated with pancreatic cancer risk get picked up on the somatic tumor profiles. Now, you know, whether or not those are truly germline variants typically requires the next step of referring the patient for germline genetic testing. So you know, I would not screen or make any kind of screening choices based on a somatic variant alone, but nowadays germline testing is so easy, so efficient, and relatively cheap that it is easy enough to confirm whether or not these somatic hits are in fact just somatic or may confer some germline risk in addition. Dr. Rafeh Naqash: So from what I understand from what you have said, there is debate about it, but it is something that should be done or is important enough that you need to figure out a path moving forward. Was that one of the reasons why you performed this project through this very interesting consortium called the PRECEDE Consortium? Dr. Bryson Katona: Yeah, that was one of our main reasons for doing this. And for those who do not know about the PRECEDE Consortium, this is a very large international, multi-institutional organization really focused on reducing death and improving survival from pancreatic cancer, primarily through increased and more effective use of screening and early detection strategies. This is an international consortium. There are over 50 sites now with nearly 10,000 patients who are enrolled in the consortium. So it really is at this point the largest prospective study of individuals who are at high risk for pancreatic cancer who are undergoing screening. And you know, I think amongst all of us in the consortium, just amongst discussions between colleagues and then, you know, often times when I see patients that are transferring their care to Penn who maybe had their screening done in another center before, what we were realizing is that, you know, although we all do a lot of screening, it seems that people are doing it slightly differently. And it does not seem that there is a real consensus approach across all centers about how pancreatic cancer screening should really be done. And it is one thing if you are thinking comparing, okay, well, maybe in the US we do it differently than, you know, in Europe or in other locations, but even among centers within the United States, we were still seeing very large differences in how pancreatic cancer screening in high-risk individuals were done. And so that led us to really pursue this survey of pancreatic cancer screening practices across the PRECEDE Consortium. So for this survey, we actually have 57 centers who the survey was sent out to. As you know, surveys are oftentimes very difficult to get good response rates back on, but we were fortunate to have 54 of the 57, or 95% of the centers, actually get back to us about their screening practices for this particular project. Dr. Rafeh Naqash: That is good to know. I hope you did not have to use any kind of gift cards for people to respond to the survey. But nevertheless, you got the information that you needed. Could you tell us what are some of the common denominators that you did identify and some of the differences that you identified? From your perspective, it sounds like there is no established consensus guidelines. There are different societies that have different perspectives on it. So I am sure some of what you found will probably have implications in maybe creating some guidelines. Is that a fair statement? Dr. Bryson Katona: Definitely a fair statement, and we found some very interesting results. I think one important result is really just the heterogeneity in the consortium. And so even before we got into pancreatic cancer screening practices, we also, we were asking consortium sites, “At your particular site, who is the individual that is leading these in-depth discussions about pancreatic cancer screening?” And while about 50% of the sites had a gastroenterologist leading it, about a quarter of the sites had a medical oncologist, a quarter had a surgeon leading these discussions as well. And we also found heterogeneity in who is the physician or the provider actually ordering these screening tests, again, with multiple different specialties across the different sites. But really one of the main areas that we wanted to hone in and focus on was how the different pancreatic cancer screening guidelines were actually utilized in each of the particular centers. The biggest controversial area in the field is for the gene mutation carriers, whether or not we should be requiring that a family history of pancreatic cancer be present in order for those individuals to qualify for pancreatic cancer screening. And the reason that is so controversial, let us take an example of BRCA1 and BRCA2 carriers. Currently, if you look through the guidelines, NCCN and the ASGE guidelines recommend that really all BRCA2 carriers undergo pancreatic cancer screening regardless of whether or not there is a family history, starting at age 50. However, other guidelines such as the AGA guidelines, or the AGA Clinical Practice Statement, as well as guidelines from the CAPS consortium, do recommend that a family history of pancreatic cancer be present in order to qualify for screening. But then we have different things for other genes. So for BRCA1 carriers, in fact, it is the ASGE guidelines that recommend all BRCA1 and 2 carriers undergo screening, whereas NCCN and the other guidelines that are out there do not recommend those individuals undergo screening. Again, this huge heterogeneity in guidelines is quite striking. And so when we assessed all the sites in the PRECEDE Consortium, we found some really interesting results with respect to these particular genes. For BRCA2 carriers specifically, we found that about half of the sites required a family history for recommending pancreatic cancer screening, but about half of the sites would offer it to all BRCA2 carriers regardless of if there was a family history of pancreatic cancer screening. Rates for BRCA1, PALB2, and ATM carriers were a little bit lower, where about a third of sites would offer screening really regardless of whether or not there is a family history of pancreatic cancer. And for Lynch syndrome, those rates were very, very low, with only about 13% of sites offering screening to Lynch patients in the absence of a family history. But I think, you know, we are all in the same consortium, but there is still just a lot of heterogeneity in how our own individual practices are run. Dr. Rafeh Naqash: Definitely different thoughts, different practices. But from what you saw, did it matter as far as outcomes are concerned whether it was a gastroenterologist doing the screening, or it was a medical oncologist, or a geneticist? Or is it a combination of all of these that actually makes the most difference? Dr. Bryson Katona: So I think we do need to get some more information about specialty-specific screening preferences. We just had one response per site in this particular survey, and so I think we are going to need a larger sample size in order to get that data. But I think that is certainly possible that, you know, certain subspecialties may prefer, you know, screening more aggressively or not including family history. That is definitely a question that we will be asking in future studies. Dr. Rafeh Naqash: Definitely more gift cards that will be needed as well. Moving on to another aspect of the implications for early detection, from a breast cancer, colon cancer standpoint, there is health economics research that shows it saves cost in the bigger picture. Has there been anything for pancreas cancer where early detection, early identification, early treatment actually ends up saving a lot more versus detecting metastatic pancreas cancer later? Dr. Bryson Katona: It is a great question. And of course, for any screening modality, you know, we would ultimately want it to be a cost-effective measure. In pancreas cancer screening, the jury is still a little bit out about whether or not pancreas cancer screening is truly cost-effective or not. There have been several different studies that have assessed this. And I think in general, the thought is that it is a cost-effective endeavor. But I think most of these cost-effectiveness estimates are actually related to what is the risk of pancreatic cancer in the population you are studying. And so when you have very, very high-risk individuals that have over a 10% lifetime risk of pancreatic cancer, it is almost a certainty that pancreatic cancer screening is going to be cost-effective. However, you know, if you have, say for example, BRCA1 carriers where lifetime risk of pancreatic cancer may be less than 5%, likely around like 3%, those individuals, I think it is going to be a tougher sell to say that it is cost-effective. But as we get more data on pancreatic cancer screening, that will be a very important question to ask. And you know, when you mentioned how does it save money, our goal at least in pancreatic cancer screening is to really downstage pancreatic cancer at the time of diagnosis and allow someone to undergo, you know, ideally a curative-intent surgery. There is data out there showing that we can downstage the cancers, that survival after the time of diagnosis is substantially increased after detection in a pancreatic cancer screening program. But again, these are studies that are based on fairly small numbers of converters. And so I think we need more data in that space as well, which is one of the main questions that the PRECEDE Consortium is trying to answer with all of our prospective data. Dr. Rafeh Naqash: Excellent. Well, I hope we see more interesting, exciting work from the PRECEDE Consortium at meetings as well as as a publication in JCO PO. I would like to shift gears briefly for a minute or two, Bryson, to you as an individual, your career. How have you evolved over the last 5, 7 years? How did you end up doing cancer genetics? What were some of the lessons that you learned along the way and some of those that you would want to share with our listeners, especially trainees and early-career faculty? Dr. Bryson Katona: Just to give you and others listening a little bit of background, but I am a physician-scientist, gastroenterologist, but a physician-scientist. And so my clinical practice is exclusively focused on individuals with hereditary GI cancer risk. I run a basic science lab where we do a lot of studies in organoids and mouse models of these hereditary GI cancer risk syndromes. And then I also have a clinical research group where we do early-phase clinical trials and screening and early detection trials, again in these same individuals with hereditary GI cancer risk. I think probably the most important thing that kind of allowed me to get to this stage in my career where I am trying to, you know, essentially try to juggle all three of these balls at the same time is that I absolutely love what I do. And I am so incredibly interested in what I do. And I think for young individuals that are coming through the pipeline and going through training, you know, I mean, finding a specialty and a clinical niche where you truly just enjoy the work and you enjoy the patients and you enjoy your colleagues is by far the most important thing. I ended up getting into the hereditary GI cancer space because a lot of my work earlier on in my career during my PhD and then in my postdoc work in the lab really focused on colorectal cancer. And I thought that focusing on cancer genetics could allow me to really continue to think from the molecular side of things while simultaneously being a gastroenterologist and taking care of patients with hereditary cancer risk. Dr. Rafeh Naqash: Well, thank you so much for giving us a sneak peek of your journey and insights on what perhaps works best, especially when you love what you do. I think that is one of the most important reasons a work tries to keep you going and keep you interested, keep you passionate. So thank you again. Thank you for listening to JCO Precision Oncology Conversations. Do not forget to give us a rating or a review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Listen to JCO Global Oncology's Art of Global Oncology article, "Whispers After the Cure: Reflections on Marriage and Malignancy in India” by Dr. Vangipuram Harshil Sai, who is a fourth semester medical student at All India Institute of Medical Sciences. The article is followed by an interview with Harshil Sai and host Dr. Mikkael Sekeres. Sai shares his personal reflection of a visit which transformed into an education in silence, stigma, and the unseen aftermath of survivorship for young women in India. TRANSCRIPT Narrator: Whispers After the Cure: Reflections on Marriage and Malignancy in India, Vangipuram, Harshil Sai   A Summer Afternoon and A Story That Stayed The summer break of my fourth semester of medical school offered a fleeting reprieve from the relentless immersion in textbooks and caffeine-fueled study sessions. I had envisioned a few weeks of rest—a pause from the algorithms of diagnosis and the grind of multiple-choice questions that had become my daily rhythm. But one humid afternoon altered that plan. I accompanied my mother—a senior medical oncologist—to her clinic in a Tier 2 city in Southern India. Over the years, I had seen her not just as a clinician but as a quiet force of empathy. She was one of those remarkable physicians who listened not just to symptoms but also to stories. Her practice was rooted in presence, and her calm resilience often made my academic anxieties seem trivial. I settled into a corner chair in the waiting area, where the air was tinged with antiseptic and that uncomfortable waiting room stillness—an alert hush between uncertainty and news. Patients waited in quiet constellations: a man turning the same page of a newspaper, a teenage girl watching her intravenous drip as if it held answers, and a couple clasping hands without meeting eyes. It was in this atmosphere of suspended quiet that Aarthi entered. She was a young woman whose presence was composed yet tentative. Her story would become a quiet inflection point in my understanding of medicine. She was 24 years old, embodying the aspirations tied to a recent engagement. A postgraduate in English literature and a practicing psychologist; she carried herself with a rare blend of intellect, poise, and cultural grace that, in the eyes of many families, made her a deeply desirable bride. Her sari was immaculately draped, her posture measured and calm, yet in the way her fingers intertwined and her eyes briefly lowered, there was a trace of vulnerability—a shadow of the turmoil she carried within. She came alone that day, stepping into the waiting room with a composed demeanor that only hinted at the weight she bore in silence. What began as a day to observe became the beginning of something far more enduring: a glimpse into how healing extends beyond treatment—and how survival, though silent, often speaks the loudest. The Diagnosis That Changed the Wedding The consultation was precipitated by a clinical presentation of persistent neck fullness, low-grade fevers, and drenching night sweats, which had prompted a fine-needle aspiration before her visit. The atmosphere in the room held an implicit gravity, suggesting a moment of significant change. My mother, with her characteristic composure, initiated a diagnostic process with a positron emission tomography-computed tomography and biopsy. As usual, her steady presence provided reassurance amid the uncertainty. A week later, the diagnosis of classic Hodgkin lymphoma, stage IIB, was confirmed. Rapid initiation of ABVD chemotherapy would provide an almost certain pathway to remission and an excellent prognosis. Yet, this clinical assurance did not extend to personal tranquility. Aarthi made a deliberate choice to share the diagnosis with her fiancé—a considerate and empathetic individual from a well-regarded family. Their wedding preparations were already underway with gold reserves secured and a vibrant WhatsApp group of 83 members chronicling the countdown to their big day. Shortly thereafter, a prolonged silence settled, eventually broken by a call from a family member—not the fiancé—indicating that the family had decided to terminate the engagement because of apprehensions about future stability. The union dissolved without public discord, leaving Aarthi to navigate the subsequent journey independently. As expected, 6 months of chemotherapy culminated in a clean scan. Her physical health was restored, but an emotional chasm remained, unrecorded by clinical metrics. Yet beneath that silence was a quiet resilience—a strength that carried her through each cycle of treatment with a resolve as steady as any celebrated elsewhere. The regrowth of her hair prompted a conscious decision to trim it shorter, seemingly an assertion of autonomy. Her discourse on the illness shifted to the third person, suggesting a psychological distancing. Her reactions to inquiries about the terminated engagement were guarded. She would yield only a restrained smile, which intimated a multifaceted emotional response. Her remission was certain, yet the world she stepped back into was layered with quiet hurdles—social, cultural, and unseen—barriers far more intricate than the disease itself. Survivorship Without A Map In the weeks that followed Aarthi's diagnosis, I began to notice a quiet but consistent pattern in the oncology clinic—one that extended beyond medical recovery into the unspoken social aftermath. Among young, unmarried women in India, survivorship often came with a parallel challenge of navigating shifts in how they were perceived, particularly as marriage prospects. In Indian families where marital status is closely tied to stability and future security, a woman with a cancer history, even after complete remission, somehow came to be quietly perceived as less suitable. Proposals that had once moved forward with confidence were paused or reconsidered after disclosure. In some cases, financial discussions came with requests for additional support framed as reassurance rather than rejection. These changes were seldom explicit. Yet, across time, they pointed to a deeper uncertainty—about how survivorship fits into the expectations of traditional life scripts. For women like Aarthi, the narrative shifted toward caution. There were subtle inquiries about reproductive potential or disease recurrence and private deliberations over disclosure during matrimonial discussions, even within educated circles. Meanwhile, my observation of the disparity in how survivorship was interpreted across genders in our country left a profound mark on me. A 31-year-old male investment banker who had recovered from testicular cancer was hailed in local media as a testament to fortitude. Male patients seemed to gain social capital from their cancer journeys. This suggested a cultural framework where female value was quietly reassessed, influencing their post-treatment identity through unstated societal perceptions. Digital Ghosting and the New Untouchability Within the digital landscape of curated profiles and algorithmic matchmaking, the reassessment of female survivorship acquired a new dimension. In one instance, a sustained exchange of text messages ended abruptly following the mention of cancer remission. The final message remained unanswered. This form of silent disengagement—subtle, unspoken, and devoid of confrontation—highlighted how virtual spaces can compound post-treatment vulnerability. Designed to foster connection, these platforms sometimes amplified social distance, introducing a modern form of invisibility. Similar to employment status or religion, a cancer history has become another addition to a checklist used to evaluate compatibility. When Medicine Ends, but Society Does Not Begin As a medical student, I felt a growing discomfort. Our curriculum equips us to manage treatment protocols and survival metrics but rarely prepares us for the intangible burdens that persist after cure. What captures the weight of a canceled engagement? What framework supports the quiet reconstruction of identity after remission? Aarthi's path, echoed by many others, revealed a dissonance that medicine alone could not resolve. The challenge was not solely the illness but the reality that she was now unqualified to return to her normal life. Medicine delivers clean scans and structured follow-up, but social reintegration is less defined. In that space between biological recovery and social acceptance, cancer survivors often stand at the edge of wholeness—clinically well but navigating a quieter uncertainty. A Different Ending Two years later, Aarthi's journey took a quiet turn. At a spiritual retreat in Bengaluru, she met an ear, nose, and throat resident who had lost his father to lung cancer. Their connection, shaped by shared experiences, evolved into a partnership grounded in empathy and mutual respect. They married the following year. Their invitation carried a brief but powerful line: “Cancer Survivor. Love Thriver. Come celebrate both.” Today, they comanage a private hospital in Hyderabad. Aarthi leads psycho-oncology services, whereas her partner performs surgeries. He often notes that her presence brings a calm to the clinic that no medication can replicate. Aarthi's journey continues to guide me as I progress through my medical training, reminding me that cure and closure often follow separate paths. Healing, I have come to understand, extends beyond the clinic. It often unfolds in quieter spaces where scans no longer guide us. The real curriculum in oncology lies not only in staging and response rates but in recognizing the many transitions—social, emotional, and cultural—that survivors must navigate long after treatment has concluded. Social stigma is often a second metastasis—undetectable by imaging but present in tone, hesitation, and traditions that quietly redefine survivorship. For many women of marriageable age, treatment marks not the end of struggle but the start of another kind of uncertainty. These survivors carry wounds that do not bleed. Yet, they persist, navigate, and redefine strength on their own terms. Aarthi's quiet resilience became a point of reckoning for me, not as a medical case, but as a guide. Her story is not one of illness alone, but of dignity quietly reclaimed. “Out of suffering have emerged the strongest souls; the most massive characters are seared with scars.”—Khalil Gibran.   Mikkael Sekeres: Welcome back to JCO's Cancer Stories: The Art of Oncology. This ASCO podcast features intimate narratives and perspectives from authors exploring their experiences in oncology. I'm your host, Mikkael Sekeres. I'm professor of medicine and chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. In oncology, we often focus on treatment and a way to find a cure. But what about the expectations and challenges a patient may face from their diagnosis, and even discrimination, especially in different cultures? Today, we're going to examine that space with Harshil Vangipuram, a medical student from India whose JCO Global Oncology article, "Whispers After the Cure: Reflections on Marriage and Malignancy in India," touches on this complexity after treatment. Harshil, thank you for contributing to JCO Global Oncology and for joining us to discuss your article. Harshil Vangipuram: Thank you for having me, Dr. Sekeres. I was raised by a family of oncologists, my mother being a senior medical oncologist and father a senior radiation oncologist. I had exposure to contrasting worlds, which were resource constrained and a cutting edge technology world. And I have unfulfilled curiosity, and I'm still learning, forming ideals. I also see patients as my teachers, so I think that might be helpful. Mikkael Sekeres: Thank you so much for a little bit of that background. So, tell us a little bit about your journey through life so far. Where were you born and where did you do your education? Harshil Vangipuram: I was born in a state called Gujarat in the western part of India. My father got transferred to the southern part of India, so I did my education there. That's it, yeah. Mikkael Sekeres: Okay. That's enough. You're not that old. You haven't had the sort of training and final job that a lot of us have gone through. So, what about your story as a writer? How did you first get interested in writing, and how long have you been writing reflective or narrative pieces? Harshil Vangipuram: I read some books from Indian authors and from foreign, too. And they actually inspired me how patient care was being seen around globally. I always used to carry a hand note. I used to write what I used to see in the clinical postings here at AIIMS. And actually, journaling started as a stress relief for me, and slowly, after hearing patients' stories, it almost became an obligation to write about them. Mikkael Sekeres: Obligation, you use that word, which is such an interesting one. How did writing become an obligation? What did you feel obliged to do when writing about some of the patients you were seeing for the first time? Harshil Vangipuram: Many of them were having struggles which were not seen by everybody. And I got astonished by their confidence and resilience in those situations. So, I thought that I should write about them so that everybody knows about it. And these social stigmas were never talked by anyone around them. So, I felt that if I could voice them, others might eventually know about them. So, that's pretty much the reason I wrote. Mikkael Sekeres: It's so interesting. The people we meet every single day, particularly in hematology oncology, bring such fascinating backgrounds to us, and they're backgrounds that may be unfamiliar to us. And I think that as doctors and writers, we do often feel obliged to tell their stories from the mountaintops, to let other people in on some of the aspects of life and medical care that they're going through and just how inspiring some of these patients can be. Harshil Vangipuram: Yeah, yeah, very true. Very true. Mikkael Sekeres: You mentioned that your mom is a medical oncologist. What kind of influence did she have on your decision to enter medicine and perhaps your own specialty one day? Harshil Vangipuram: Observing my mother practice influenced a lot, and she taught me that medicine is not only about treating a patient, but also listening to their problems. It may be more present in the room. The textbooks I read didn't capture live experiences. I always thought that stories will stay with people longer than actual survival curves. Writing filled that gap between what I studied and what I felt in the OPD. Mikkael Sekeres: It's a great phrase you just whipped out. Patients' stories will stay with us longer than survival curves. Can you tell us a little bit about where her clinic is located? You said in southern India. Can you describe the types of patients she sees? Harshil Vangipuram: It's a small town called Nellore in Andhra Pradesh state. The patients are, most of the time, from a rural population where decisions are mostly family-driven and there's a tight community surveillance and the stigmas are more overt, too. A few of them can be from urban population also, but they have subtler discriminations towards stigmas. Mikkael Sekeres: Can you explain a little further what you mean by decisions are often family-driven? Harshil Vangipuram: If we take marriage, it is often seen as an alliance between two families that are trying to increase their social value, their economic status, and respect in the society. In arranged marriages, for suppose, it's basically driven between these concepts. Mikkael Sekeres: I don't know if it's too personal to ask, but are your parents in an arranged marriage? Harshil Vangipuram: No, not at all. Mikkael Sekeres: So not all the marriages in the clinic are arranged marriages. Harshil Vangipuram: Yeah. Mikkael Sekeres: You know, when you said that decisions are family-driven, you mentioned that people are in arranged marriages. And I wanted to talk a little bit about the stigma you highlight in your essay. I'll talk about that in a second. I thought you were going to go down a route about medical decisions being family-driven, meaning people have to support their families, and getting medical care is costly and takes time away from work, and that sometimes influences decisions about treating cancer. What examples have you seen of that in shadowing your mom? Harshil Vangipuram: I have seen patients who have Hodgkin's lymphoma, breast cancer, and ovarian cancer, who were in the age of 25 to 35, who were getting married. Many of them actually got their engagements broken. And many of them got rejected at matrimonial apps. Many of them also had been told to increase the dowry that is given actually in the form of financial security. Mikkael Sekeres: In your essay, you describe a woman who is engaged and who has a new diagnosis of Hodgkin lymphoma. Can you talk a little bit about the process of getting engaged and marrying in southern India? Harshil Vangipuram: We have the arranged marriage, love marriage, and hybrid, which is kind of arranged and kind of in love. Mostly, these problems really occur in arranged marriages. In love marriages, we don't see that that often because both are understanding about themselves and their families. And both families actually accept them both. Mikkael Sekeres: What's the process of going through an arranged marriage? What happens? Harshil Vangipuram: It can be through parents, relatives, or any known ones or through peers. We just find a man or woman who has a similar caste, who has a good financial income, and people who are respected by the society. And obviously, both the families should have aligned interests for them to accept the marriage. Mikkael Sekeres: About how often are marriages arranged and how often are they love marriages in southern India where you live? Harshil Vangipuram: Almost 90% of the marriages are arranged here. Mikkael Sekeres: Wow. So, your parents were unusual then for having a love marriage. Harshil Vangipuram: Yeah. Mikkael Sekeres: In your essay, you write, and I'm going to quote you now, "Among young, unmarried women in India, survivorship often came with a parallel challenge of navigating shifts in how they were perceived, particularly as marriage prospects. In Indian families where marital status is closely tied to stability and future security, a woman with a cancer history, even after complete remission, somehow came to be quietly perceived as less suitable." Wow, that's a really moving statement. I'm curious, what stories have you seen where, in your words, women became less suitable as a marriage prospect? Harshil Vangipuram: For women, the most important thing in a marriage is, what do you call, a family honor, fertility, and economic status in the community. So, after a long dose of chemo, many people think that people become infertile. In India, basically, we have many misconceptions and stigmas. So, people obviously think that people who have got cancer can spread it to their children or are infertile and are often excluded out of the society as a marriage prospect. Mikkael Sekeres: Gosh, that must be devastating. Harshil Vangipuram: Yeah. Mikkael Sekeres: Does the same occur for men? So, is it also true that if a man has cancer, that he is perceived as less fertile, or it may be perceived that he can pass the cancer on to children? Harshil Vangipuram: Here, after a man beats cancer, they start to celebrate it, like they have achieved something, and it's not like that for a woman. Mikkael Sekeres: In your essay, you do write about a happy ending for one woman. Can you tell us about that? Harshil Vangipuram: Yeah, a cancer survivor obviously met her true love of life in Bengaluru, who was an ENT resident then. And his father died from lung cancer. So obviously, he knew what it felt to beat cancer. Mikkael Sekeres: Yeah, he'd been through it himself. And the irony, of course, is that most cancer treatments that we give do not lead to infertility, so it's a complete misperception. Harshil Vangipuram: Yeah. Mikkael Sekeres: Tell us about your future. What are the next steps for you in your training and what do you hope to specialize in and practice? Harshil Vangipuram: Actually, I'm working on another paper which involves financial toxicity after treatment and post treatment depression. I think it would be completed in another year. And after that, after my med school is completed, I think I'm going to pursue oncology or hematology as my branch of interest. Mikkael Sekeres: Wonderful. It's thrilling to hear that somebody who is as sensitive to his patients and both their medical needs and their needs outside of medicine will be entering our field. It'll be great to know that you'll be taking care of our future patients. Harshil Vangipuram: The pleasure is all mine, sir. Mikkael Sekeres: Harshil Vangipuram, I want to thank you for choosing JCO Cancer Stories: The Art of Oncology and for submitting your great piece, "Whispers After the Cure: Reflections on Marriage and Malignancy in India" to JCO Global Oncology. To our listeners, if you've enjoyed this episode, consider sharing it with a friend or colleague or leave us a review. Your feedback and support helps us continue to have these important conversations. If you're looking for more episodes, follow our show on Apple, Spotify, or wherever you listen, and explore more from ASCO at asco.org/podcasts. Until next time, this has been Mikkael Sekeres from the Sylvester Cancer Center, University of Miami. Have a good day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Show notes:Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bio:Dr Vangipuram Harshil Sai is a fourth semester medical student at All India Institute of Medical Sciences. Additional Reading Impact of Gender of the Child on Health Care–Seeking Behavior of Caregivers of Childhood Patients With Cancer: A Mixed-Methods Study | JCO Global Oncology

Listen to JCO's Art of Oncology article, "A Fight Bigger Than Myeloma” by Dr. Adeel Khan, an Assistant Professor of Medicine and Public Health at UT Southwestern. The article is followed by an interview with Dr. Adeel Khan and host Dr. Mikkael Sekeres. Dr. Khan shares the story of a patient whose multiple myeloma diagnosis and treatment serves as a reminder of the civil liberties progress we've made and that we have more to go. TRANSCRIPT Narrator: A Fighter Bigger Than Myeloma, by Adeel M. Khan, MD, MPH, MS  I met her during the early part of my clinical training in hematology/oncology. She was in her late 70s, dressed in a rust-colored cardigan and a headwrap with patterns that reminded me of Ghanaian kente cloth. Her eyes were sharp, her tone polite but direct. You could tell from the moment she spoke that she had lived a life where she had to advocate—for herself, for her family, for her place in rooms that were not always welcoming.  Her chart said “multiple myeloma, R-ISS II,” but it did not say that she had first come to an emergency room at least a year earlier complaining of back pain and fatigue and had been told it was probably arthritis or old age. It did not mention that she had seen three different doctors before someone ordered the laboratory tests that finally began to work up her anemia and increasingly compromised kidney function. It would take another trio of doctors to eventually order a magnetic resonance imaging whose ghostly lytic lesions led down the path to a bone marrow biopsy and her cancer diagnosis. When I brought this up gently during one of our early appointments, she looked at me and said, “They don't hear pain the same when it comes from someone like me.” As a Black woman from the Deep South, she had grown up learning how to navigate a health care system that did not always believe her. She told me stories about being dismissed, misdiagnosed, and interrupted. She was born into an era of structural violence where she would be ignored at best and mistreated at worst. She carried the weight of those moments, but she also carried strength, and clarity, and the kind of dignity that made people sit up straighter in their leather chairs when she entered the room. She was one of the most quietly revolutionary people I have ever known, having grown up during a time of civil rights activism. She had even taken part in bending Dr King's long arc of the moral universe toward justice and could share story upon story from her glory days. Her myeloma treatments were not easy. Chemotherapy rarely is. She shared that there were days when her body was tired of fighting, when her bones ached, her blood counts dropped, and her neuropathic pain throbbed. In the back of my mind, I thought how tragic it was that her delayed diagnosis added unnecessary complications and whether she too thought of that. She was fully mindful of the issues people with her skin color faced in our American healthcare system and society as a whole and revealed how that motivated her to carry forward. “If I don't take up space here,” she told me once, “then someone else like me won't either.” Over the course of our visits, I came to understand that she did not see her myeloma as the hardest fight of her life. Not by a long shot. Her primary struggle was centered on life in Birmingham in the 1950s where separate but equal was still the law of the land; her mother cleaned houses, her father worked odd jobs, and her own prospects were uncertain. She admired the writings of Richard Wright and Jean Toomer and was not shy in sharing her passions. One day, during a particularly tough visit—her disease had progressed and we were down to limited options—I found myself meandering. We went through the usual workup and discussions: laboratory test results, symptoms, and treatment options. I offered the prospect of clinical trials, but she shook her head gently and said, “I've done my time in experiments—I can't give myself to a system that gave my people so little.” I paused. It was the first hint of what would become a larger conversation—not just about medicine, but about history. She was well aware of the atrocities of the Tuskegee syphilis trials in her home state, the Kligman experiments on incarcerated Black men, and the forced sterilization of women of color. As dependent upon medicine as she was in her old age, it carried a bloody stain of dehumanizing racism that soured her against it. Outwardly, I had little in common with her. As a young South Asian man growing up in times more conscious of racial injustice, I was far removed from these historical crimes. Although I learned of them during my education, I did not internalize their impact on the patients in front of me in clinic. But through her I came to comprehend just how scarring and enduring these events can be and how they can rob someone of trust. And the truth is the health care system had not treated her well. She had personal stories of doctors who did not believe her pain, nurses who assumed she was uneducated,  and being passed over for better options, better care, and better answers. “But I kept showing up,” she said. “Because that's what we do. We show up even when we're not wanted.” Her stories to me were revelations. In her younger years, she had helped organize teachers at her school when they tried to fire a fellow Black teacher who seemingly spoke too loud in a meeting. She had lived through redlining, through the crack epidemic, through watching young Black men vanish into prisons, and still she rose every day and worked as a public school teacher for decades. She worked for a system that largely did not work for her. I came to admire that about her—that in simply living day-to-day life with plain dignity and acute awareness of society's issues, she promoted change by living it. “You want to talk about cancer?” she once said, half laughing. “Try walking into a bank in 1972 with a good credit score and a Black face. That's a disease this country still hasn't cured.” Curiously, she did not say these things with bitterness. Not even anger, really. Just clarity. Like someone who had long ago made peace with the truth, even if it was sharp. In clinic, she challenged my every assumption—about treatment tolerance, about compliance, about who is difficult, and who is “advocating.” And she taught me to look differently at the ways bias lingers in medicine. Not just in data or policies, but in subtle moments: the tone we use when explaining options, the hesitations in our tests and referrals, and the assumptions we may not even realize we are making. And she did not just expect good care—she demanded it. She told me early on, “Don't you treat me like I'm anything other than your mother.” That landed. And in seeing patients before me now, I remind myself to wonder who they were in their past lives, what baggage burdens them, and how it all shapes their perspectives. So from my view, she fought multiple myeloma with everything she had, but from hers, she fought something bigger: an entire system shaped by inequality. And ultimately, she made me better to realize that, not just as a doctor, but as a human being. In my years since knowing her, completing my training, and beginning my practice, I reflect on her grace. I think not just about her life, but what it means to practice medicine in a world that often forgets what patients carry with them into the clinic—generations of weight, of injustice, of strength. Mikkael Sekeres: Welcome back to JCO's Cancer Stories, The Art of Oncology. This ASCO podcast features intimate narratives and perspectives from authors exploring their experiences in oncology. I'm your host, Mikkael Sekeres. I'm Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. I am so happy that today we are joined by Adeel Khan, who's Assistant Professor of Medicine and Public Health at UT Southwestern in Dallas to talk about his Journal of Clinical Oncology article, “A Fight Bigger than Myeloma.” Our guest's disclosures will be linked in the transcript. Adeel, thank you so much for contributing to JCO and for joining us to discuss your article. Adeel Khan: Thank you so much for having me. It's a pleasure to be here. Mikkael Sekeres: Adeel, I don't want to be disingenuous to our readers by acting as if we've just met. You and I have known each other for a decade since you were still in your training. I wonder if for our listeners you can tell us a little bit about yourself, where are you from and and walk us through your career so far. Adeel Khan: More than happy to. So, I grew up mostly in Oklahoma, but I've sort of lived around in the Northeast and here in the Southwest where I am currently. I did college at the University of Oklahoma. I did medical school at the University of Michigan. I did residency with good fortune at the Cleveland Clinic where I happened to get to know you and have continued to know you since. I did my fellowship then in hematology oncology at Beth Israel Deaconess in the Harvard system and along the way of all that I did a Masters of Public Health at Harvard and a Masters of Science and Epidemiology at Columbia, and that pinball finally settled here to UT Southwestern here in Dallas which I am very happy to make my second home. Mikkael Sekeres: That's great. I will say just for our listeners you've been a superstar since the moment you were a resident. It's been a real treat for me to get to know you over the years. Adeel Khan: Thank you so much. Mikkael Sekeres: Can you tell us a little bit about your own story as a writer? You're a good writer. We get submissions from some really good writers every single week. It's a real privilege to be an editor for the Art of Oncology section and it's always reinvigorating to me to see how many good writers there are in medicine. How did you start your journey as a writer and how long have you been writing reflective narrative pieces? Adeel Khan: I would say if I went back to let's say high school, you know, people tend to be divided into kind of like the sciency types versus the literary arts types and you're kind of an either/or, you know, you didn't really have as much crossover then. But you know, I actually didn't mind when we had an essay due and I liked writing back then, and when I entered college I did a minor in English because I actually did enjoy that and I just liked the idea of being able to put your thoughts on paper in a way immortalizing them. Adeel Khan: And then as I sort of pursuing medicine more and more, publishing is really- it has all kinds of flavors to it and scientific publishing is obviously what has been emphasized, but you know, there's so many things to talk about within medicine. There's the science and the art of the field, and as I've moved along, I've written different pieces focusing really on patient stories and interactions. And I think my motivation has always been that as I have gotten particularly nowadays increasingly busy, I've had the fortune and misfortune of becoming more and more busy, it's easy to lose the opportunity to really connect with people that makes what we do meaningful. And so in those times when you know, and they can be rare, but when you really get to connect with someone in front of you who you're helping to care for, it's really refreshing and it's rejuvenating and I've tried to keep that with me as long as I can as I've gone through my journey. Mikkael Sekeres: There's a lot of jumping off points from what you just said, Adeel. I wonder if I can start with do you consider yourself an English major who's good at science or do you consider yourself a scientist who's a good writer? Adeel Khan: I think I'm too humble to say either. I think I was really a science major who just happened to like writing and reading and kept that as a part of myself. Mikkael Sekeres: Because I think there are a cadre of doctors who are actually English majors and have learned to turn science into storytelling and that's their entrée into science and medicine. I remember I talked for a while with David Scadden about this. He's a brilliant translational scientist who's based at Mass General who also teaches a writing course to the Harvard undergrads and who was an English major when he was an undergrad at Case Western. We've talked about this, about how there are people, I'll include myself in this, who just think different, who probably have these liberal arts brains and they figured out a way to convert science into a way a liberal arts person can understand it. Adeel Khan: Yeah, I mean narrative medicine has been I think around all along and it has only kind of been recently named as a field, but I mean it very much speaks to that that there's so much more than just G proteins in medicine. Mikkael Sekeres: I'm thrilled to hear that by the way. You mentioned you were an English minor. Are there particular writers who are an influence on you or can you talk about what's the most recent book or article you've read? Adeel Khan: Oh, that is a great question. Paulo Coelho is someone I've liked for a long time, The Alchemist. I really liked it because I read it after I had lived in Egypt. I lived in Egypt between college and med school as a study abroad program, and I had actually been to the Faiyum Oasis where the protagonist in that story ends up. And so it was just a fascinating story to me that I could trace some of the steps that are discussed in the book and it's so much- it's a story about self discovery which at that phase of life that I was in was you know, very much a theme of my own life. And so that's one that definitely stands out in my head. Mikkael Sekeres: Do you think reading pieces outside of medicine makes you a better scientist? Adeel Khan: I think absolutely. I think it makes you a better human being. In some ways I lament that so much of what I do reading now is so much just about what's in the field, what's new in myeloma, what's new in hematology oncology and I sort of miss the escape to reading other things and being able to pursue it. And even broader than just what a novel really offers. I mean, I grew up reading comic books too and I've always loved superheroes and fiction whether it's Star Wars and other things. And really they're just stories and the medium- there might be connotations whether it's a comic book or a or a novel, but they're just different mediums, but the fact that they're just stories is fundamental. I actually think to myself that it's so fascinating that the earliest piece of writing that we've really retained as human beings is we believe, the Epic of Gilgamesh, which is really a story of a superhero when you think about it, you know, and it's it's fiction, it's phantasmic in so many ways. But it speaks to how stories are just vital as people. Mikkael Sekeres: And what is it about graphic novels or my kids now of course call them graphic novels. We're not allowed to call them comic books. Adeel Khan: As they've been renamed, yeah. Mikkael Sekeres: What is it about graphic novels or comic books or the story of a hero that appeals to us in medicine? Adeel Khan: I think it's in some ways a parable of what we're doing. There's something so powerful and fundamental about this idea of good-evil and we can rename it in different ways, but that you're trying to overcome something that's an issue, an obstacle. And when you think about what we do in- particularly in oncology, that's very much what we're trying to do. We're trying to overcome an illness, a disease, to try to help the person in front of us. And it has different aspects to it. It could be someone pursuing something in a lab, it can be treating someone in front of you in clinic, but that simple dichotomy of there's something good about what you're doing because there's something bad in front of you is just the fundamental that runs through it all. Mikkael Sekeres: It's fascinating. I wonder if 30, 40, 50 years ago people would have said, “Oh, it's because the doctor is the hero,” but we don't view ourselves that way anymore. The patient is the hero. I love how you posit this as a good versus evil, the evil of course being cancer and the good everything that our patients do and that we try to to help to do to overcome that. Adeel Khan: For sure. Mikkael Sekeres: You wrote a really great essay about a woman who was a patient of yours. Can you tell me a little bit about what inspired you this time to make this connection and to write about this woman? Adeel Khan: Within the past year or so as I had been just really- the fortune and misfortune of getting busier, I lamented that I just wasn't able to spend as much time with patients in the way that I used to. One of the beauties of medical school and you know, to some degree residency and certainly fellowship is that you just have a little bit more time as a trainee, student and trainee where you can really bond with your patients I think a little bit more. And so in trying to kind of refresh my motivation, I was thinking about just kind of randomly some stories that I've kept in the back of my mind and this patient's story is one that stood out to me as I was recalling things. It was so fascinating to me because she had the disease which I now focus on. And the way that she viewed it and the way that she viewed it as a part of her life was just so different than what I think most people think of. And in that way it was very revitalizing that her focus in her life was part of a broader theme of the way that I think she viewed society. And this was just one piece of her own part of that much, much larger puzzle. Mikkael Sekeres: You really write lovingly about her and about how meaningful her context was in how you cared for her and what her experience was in the medical system. I wonder if I can read a little bit of what you wrote because it really did grab me as well. I'm going to start out by quoting you where you say, “Outwardly, I had little in common with her. As a young South Asian man growing up in times more conscious of racial injustice, I was far removed from these historical crimes. Though I learned of them during my education, I did not internalize their impact on the patients in front of me in clinic. But through her, I came to comprehend just how scarring and enduring these events can be and how they can rob someone of trust.” Wow, there's a lot there. Could you start with what was your perspective as a young South Asian man growing up in Oklahoma and what your view was of racial injustice compared to what her experience was of racial injustice? Adeel Khan: Yeah, I have to admit I don't know that I thought that much of it back then and I think that that's part of what it is. You know, being someone who was South Asian, I'm Pakistani, I have Indian roots, and coming into American history and as we learned about it there's so much about slavery and the theme of slavery unfortunately and and the struggles that enslaved peoples have. And you know, as a relatively recent immigrant, I didn't see myself in that narrative. I didn't see myself in that historical reality. But I knew about it intellectually, you know, I knew about the Tuskegee Syphilis Experiments, you know, I learned about all these things and and you learned about how atrocious so much of it is. But again, not being so directly connected, I did not put myself in that same role as someone to view it so close to myself. I will say it hit a little bit more after 9/11 when you know, I was randomly stopped at airport security a little bit more often in those days and again, I think that speaks to racial injustices, you know, I was certainly profiled looking back then, I've been held by TSA in the past, but even that is very minor compared to what African Americans have dealt with here. And this patient in just kind of sharing her tidbits during our time together, I was not directly asking her so much of this. She was really offering a lot of it to me as we would talk and she would be very generous in sharing parts of her story. And over time I kind of understood the broader narrative of her life. You know, it was clear how much of all that was actually in the forefront of her head. Adeel Khan: And I think she might have been a little bit more unique in the way that she kept it there, but she was hyper vigilant of issues of society and the roots that brought a given society to where it is here. I kind of got to know her, this is during the COVID pandemic and this was after the injustice of what happened to George Floyd and so it was a theme that I think people were talking about more and so I think she felt comfortable in saying really what was quite a bit that was stewing in the back of her head seemingly at all times. Mikkael Sekeres: It's so interesting you talk about what you endured after 9/11 as being, I'm going to quote you now, “minor” compared to what she's been through, but even a minor affront like that can really compromise your trust. You write about her, “As a Black woman from the deep South, she had grown up learning how to navigate a healthcare system that did not always believe her.” Can you expand on that a little bit? How is it that the healthcare system didn't believe her and what can we do going into interactions with patients from different backgrounds where we're incorporating that there's a compromise of trust and we have to make up for that? Adeel Khan: Yeah, and I think you know, it's so unfortunate that so many people have stories like this where, in her case really it was back pain that was her presenting symptom. This is long before she knew me. And she'd had the back pain for quite some time, but being an older woman, she was in her 70s at that time, she was not in phenomenal health for other reasons. It sounds like she was just kind of ignored, told that it was old age, tendon changes, she did not have meaningful imaging for some time. When she finally did after seeing a slew of different providers, that's when it was revealed like there's something more significant here. And then when you kind of piece that a little bit retrospectively and I think she certainly sensed this and I did when I- hindsight's always 20/20, when I looked through things, it's like, well, this probably could have been caught much earlier. It's just that no one really I think listened to what she was speaking to with her pain and the gravity that was actually behind it. And it just speaks to the fact that I think we have to be more thoughtful in what we take away from patients and not to ignore even small comments because they might be revealing of something much bigger behind them. Mikkael Sekeres: You quote her, you have some really great quotes in your essay where you just listen to what she says and transcribe it because what she says is very meaningful. And one of the quotes you provide from her is, “They don't hear pain the same when it comes from someone like me.” Wow. “When it comes from someone like me,” someone like her, how was it that people weren't hearing her description of pain, something that was different that was going on in her body and how can we be more attentive to people when they complain about things like pain? Adeel Khan: It's unfortunate that there's even known data to show how depending upon a patient's melanin content in their skin, how likely they are to get pain medications and what happens to them is different and this is an unfortunate example of that where I think she just wasn't heard properly. And so it wasn't addressed properly and she was not shy about saying that. I mean I think she sensed that. She was very clear in feeling that herself and in wanting to have better care, she was still prevented and hence why she had to go from provider to provider. Mikkael Sekeres: You've lived in a bunch of different places in the country. I mean, following your path, you've been in Oklahoma, you've been in Michigan, Ohio, Massachusetts, and now Texas. Do you think that we as providers have to have different levels of sensitivity depending on where in the country we're practicing and how some of our patients' trust in healthcare may have been compromised in those different parts of the country? Adeel Khan: I think absolutely. I mean this particular patient was from Alabama which has a heavy history that she was again very aware of and for those of us reading history books are also very aware of too. And it's interesting how, while the U.S. is in some ways- has some aspects that are monolithic, but it's very much not so. It's very patchy and people are different, you know, if I take one theme that we're talking about here is obviously racial injustice, but if you take something like obesity, you know, prevalence rates are very different throughout the country and attitudes surrounding it are also very different. And I think we do- ought to be mindful that in treating the patient in front of us, it's not done without context. And so how they view their illness and their situation is going to be different depending upon the state, depending upon the city, depending upon actually even the era that they grew up in. So I would say now, if you took actually a similar patient, but you put her in a very modern context post-year 2000, she's likely to have different feelings of the situation around her than someone who was born in this case in the 1940s. And that just speaks to the fact that circumstances change and we should be recognizing that as providers, even though it's not always easy to. Mikkael Sekeres: Well, it just emphasizes how very important it is to know the history of the place where we practice and how it's affected our patients' perceptions of healthcare and trust and being cared for, particularly now as there's such a movement to whitewash that history and eliminate it from major institutions like the Smithsonian. It has been such a pleasure to have Adeel Khan here. He is Assistant Professor of Medicine, Public Health at UT Southwestern in Dallas and wrote just a great JCO article called “A Fight Bigger Than Myeloma.” Adeel, thank you so much for submitting your article and for joining us today. Dr. Adeel Khan: Thank you so much for having me. It's been a pleasure. Mikkael Sekeres: If you've enjoyed this episode, consider sharing it with a friend or colleague or leave us a review. Your feedback and support helps us continue to have these important conversations. If you're looking for more episodes and context, follow our show on Apple, Spotify, or wherever you listen and explore more from ASCO at ASCO.org/podcasts. Until next time, this has been Mikkael Sekeres for JCO Cancer Stories: The Art of Oncology. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Show Notes Like, share and subscribe so you never miss an episode and leave a rating or review.  Guest Bio: Dr Adeel Khan is an Assistant Professor of Medicine and Public Health at UT Southwestern.

Host Dr. Shannon Westin and guest Dr. Giancarlo Di Guiseppe discuss the JCO article "Long-Term Dynamic Financial Impacts Among Adolescents and Young Adults With Cancer: A Longitudinal Matched-Cohort Study" TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hi everybody and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts that are published in the Journal of Clinical Oncology. I'm your host, Dr. Shannon Westin, social media editor of JCO and gynecologic oncologist extraordinaire. I'm so very excited to talk to you today. We're going to speak about "Long-Term Dynamic Financial Impacts Among Adolescents and Young Adults With Cancer: A Longitudinal Matched-Cohort Study." And I'm joined today by Dr. Giancarlo Di Giuseppe. He has a PhD in epidemiology that he actually just defended with this very work you're going to hear about today at the Dalla Lana School of Public Health at the University of Toronto. He is now a research fellow at the Hospital for Sick Children.  Welcome, Dr. Di Giuseppe. It's so exciting to have you. Dr. Di Giuseppe: Thank you so much for having me. Dr. Shannon Westin: So we'll get right to it. Let's level set. Can you talk a little bit about the financial impact of cancer on survivors in general? I think this has been a growing area of interest and research, certainly. Dr. Di Giuseppe: Yeah, and I think that's a very important question, and I'm so happy that this research is now becoming more popular in the research world because it really addresses a critical issue that cancer survivors and their families must face. You know, you're diagnosed with cancer, and now you need to take time off work because you're hospitalized for chemotherapy. You're going back and forth to the hospital, and that all requires time away from your employment, and as a result of that, that has a significant financial strain, both on you and your family. And that's during therapy. Now, in survivorship, in the years after you've survived your cancer, you still need to deal with all the late effects associated with your treatment and your disease, and that can be psychological, physical, and that impacts your workability as well. So, it's not just exclusive to individuals undergoing treatment but also in survivorship afterwards. It really gets the financial strait that you face as a cancer survivor because you're time away from work and your lost productivity. Dr. Shannon Westin: Yeah, that makes sense. Then I think it would be great to talk a little bit specifically about the patient population that you studied in this particular manuscript. Can you talk a little bit about the adolescent young adult cohort, you know, why you singled out this particular group of people? Dr. Di Giuseppe: Absolutely. Adolescents and young adults, or AYAs, which I'll now refer to them as - I'm one of them - we're at a unique crossroads of our life and in our developmental stage of life. We are finishing our post-secondary education. We're entering the workforce. We're forming romantic relationships, and we're really achieving financial autonomy. It's because of this unique developmental stage in life where we've become quite susceptible to health shocks such as cancer. Really, does a cancer and the associated negative financial impacts affect our long term trajectory? So, I'm just finishing my PhD. If I was diagnosed with cancer, I would require a year or two away from my studies. I may or may not finish my education that could then impact my employment and then my financial outcomes later on in life. So it's really this unique population who are going through so many transitions and changes in their lives. How does that cancer really impact that life course trajectory? I think it's unique from an adult who might have, you know, large savings where they can bear the brunt of their cancer financial impacts, whereas AYAs may not have that same financial stability, provide a safety net for the financial impact resulting from their disease. Dr. Shannon Westin: You broke my heart a little bit. I realized I'm no longer in that group, so I guess it's time to move on. Okay. So, let's talk a little bit about the overall design of the study. Can you just kind of walk us through how you set everything up? Dr. Di Giuseppe: Yeah, absolutely. So it's a matched cohort study at the population level here in Canada. We have large national administrative databases, and we have this really unique set of data at the national level through Statistics Canada that we can link our cancer registry to tax records. It really provides this unique opportunity to longitudinally follow individuals from their disease forward in time. The main overall design is the matched cohort study. At the time of diagnosis of a cancer case, they're matched to someone from the population on certain characteristics. I follow these individuals from the index date of their cancer case forward in time. The crux of the study itself is a quasi-experimental two-group pre-post study design where I have information before the cancer diagnosis, I have information from their income after their cancer diagnosis, and it's really quantifying how much does that total income change from before the cancer to the after-cancer period. Dr. Shannon Westin: I'm always intrigued about hearing more about financial toxicity in general, certainly very multi-dimensional. Can you speak a little bit about the different ways that you can assess this and measure this and kind of what you chose? Dr. Di Giuseppe: Yeah, so financial toxicity really has two main spheres of measurement. There's a direct and the indirect measurements of financial toxicity. So your direct financial toxicities could be related to actually paying for medical treatment and any sort of financial burden as a direct consequence of your disease. Fortunately here in Canada, we have a universal health care system, so patients don't have to pay directly for most of their treatment. There's also indirect financial toxicities, which are not a direct result of the disease. So in this study here, one of the, or the indirect financial toxicity that I measured was the financial impact to income. That's not the only indirect financial toxicity. There could be out-of-pocket expenses for drugs that may not be covered in the universal health care system here. It could be lost productivity at work. There's really this direct and indirect financial toxicities that together result in a significant financial burden and hardships for cancer patients and survivors. Dr. Shannon Westin: Okay, so you guys did a lot of matching. It was extensive. Can you speak a little bit about the factors you used to match your patients and your controls and kind of why you chose them? Dr. Di Giuseppe: Yeah, absolutely. The matching I think is a really critical aspect of the study, and it really establishes this baseline period of individuals who are cancer-free, who look as similar as possible to the individuals who would eventually develop cancer. So I matched on birth year, sex, marital status, whether or not they had children, if they were born here in Canada or not, as well as a geographic measurement of census division. So it's really in the city or in a rural town. Then I also matched on a 5% buffer of their total income in the year prior to the cancer diagnosis. All this matching was really done in the year before they were diagnosed, and it's to establish this comparator cohort of individuals from the general population who looked as similar as possible to the individuals, or the AYAs, who would develop cancer. It's again to establish this baseline period of a control cohort who looks as similar as possible. So any differences that we might see after the cancer can be attributed to the effects of the AYA who would develop cancer. It's quite powerful, I think, from a study design perspective because it establishes causal inference methods through the study design and through the matching itself. Fortunately, I was able to match on an extensive list of covariates given the large population-based data that I used, particularly the tax records. Tax records contain a whole wealth of information, your marital status, your sex, your income, where you live. So it really provided this rich opportunity to match as closely as possible the AYAs who would develop cancer to someone from the population who wouldn't. Dr. Shannon Westin: Yeah, and I mean I think that's the only way to do this type of research and really make it generalizable and actually, you know, know that you can trust the results that you've got. So I just want to again congratulate you because I think this was just- when I read the design, I was so impressed. So now that we know the design and we understand everything, let's talk a little bit about the characteristics of the actual patient population that you studied. Dr. Di Giuseppe: Yeah, for sure. So average age of diagnosis was in their early 30s, so around 32 years old. The breakdown of the population was mostly females, so I think two-thirds of the cohort were actually females who were diagnosed with cancer. Really, a lot of the cancers were thyroid and the breast cancers. These cancers are more common in women than they are in men. So it's really reflective of the different distribution of cancer in AYAs compared to other populations like in children or in older adults. Dr. Shannon Westin: All right, bottom line. What did your primary analysis demonstrate and how was the income different based on the types of cancer that people might have been diagnosed with? Dr. Di Giuseppe: Yeah, the bottom line is actually quite a disturbing message, I would say, and it's really that cancer causes this long, prolonged financial hardship in survivors. That's, I think, a very important result from the study, and I think it has far-reaching implications. This study demonstrates that these individuals who were diagnosed with this disease that is unforeseen also pay a financial price, and that sustains for many years after their diagnosis. That's overall on average. Once I dove deeper, actually looking at the different cancer types, the message actually gets even more disturbing, I would say, particularly in some disease subgroups. So the central nervous system cancer survivors really have a large reduction in their income, which sustains over 25%, 10 years after their diagnosis, and they never really recover financially from their disease. There are some groups of cancer survivors who really pay a large financial price for their disease. Dr. Shannon Westin: I don't know if you're able to tease this out. This is just me thinking off the top of my head. Do you think it's the long-lasting side effects? Dr. Di Giuseppe: I think you hit the nail on the head there, absolutely. I think what we're seeing here is a direct result of the late effects that cancer survivors experience. CNS cancer survivors, whether that is a surgical resection, radiation to the head for their tumor, the late effects really impact these individuals in the post-cancer survivorship period. So I think what we're really seeing are these late effects here. Dr. Shannon Westin: The other thing I was kind of struck by is the differential and income loss over time. Can you speak a little bit about that in your work? Dr. Di Giuseppe: Yeah, absolutely. There really is this period of financial vulnerability in the first couple years of diagnosis. So that's year zero, one, two, and three, these first couple years when these individuals are diagnosed with cancer, they are significantly impacted by their disease financially. Some of these reductions in their income is 15%, 20% in the year of diagnosis and the year afterwards. It's unsurprising because this is when these individuals typically are undergoing their treatment. They're not working. They may have even lost their job or quit their job. So it's really reflective in the results in that first few years of their diagnoses where these financial impacts are the largest. I think it provides an opportunity where certain interventions might alleviate some of these large reductions in their income. Dr. Shannon Westin: Well, I really was disturbed by your work, and I hate to kind of say it that way because it's such important work. So I'm really- congratulations on everything that you're able to achieve and especially your PhD. But I think shining a light on these types of things is always pretty rough when you really look at the nitty-gritty details. So any thoughts about where we go from here, how do we support these people? Dr. Di Giuseppe: I think we can support them at multiple different levels. So at the individual level, I think within the clinic setting, financial screening for financial toxicity, financial literacy, I think all these things can be incorporated into cancer care continuum to kind of educate AYAs with cancer about the financial implications of their disease, both in the short and the long term. So I think educating these cancer patients is important. I think at the employer level, really working at the institutional level to incorporate workplace accommodations that might facilitate the return to work process for cancer survivors after their treatment or during, I think would also make the financial burden slightly less if cancer survivors are able to return to work or not have to quit their job because of their disease. And then return to work easier, I think might alleviate some of the employment consequences that these individuals face, which then lead to their adverse financial effects. Then I think also at the policy level, at the governmental level, whether that's incorporating any sort of fiscal stimulus for cancer survivors, whether they're under treatment or in survivorship, any sort of tax breaks that they might be available to them to kind of alleviate some of that financial stress. The reality of it is being diagnosed with cancer and having your income reduced by even 5% - cost of living is expensive, especially now - so I can't even imagine what cancer survivors who are in this economy are facing with rising inflation and cost of living going up. So I think really having tax breaks as well as financial aid for these cancer survivors could really support them both in their cancer journey while they're undergoing treatment as well as some of the sustained effects that they experience afterwards. It's particularly important, as we touched on earlier, for CNS cancer survivors, right? These individuals have this sustained effect that never really returns back to normal, and I think having  sort of disability pension or kind of financial aid for these individuals to support them, I think is important. Dr. Shannon Westin: We see this all the time in gynecologic cancers, these young women that support their families, young children, and then lose their ability to do so due to their diagnosis and the treatment they have to receive. So I can't say this enough how important this work was and how honored I am to get to speak with you today. I learned a ton. And thank you to all of you listeners. We're just so excited to have you. This has been long term dynamic financial impacts among adolescents and young adults with cancer: a longitudinal matched cohort study. Thanks again for listening to JCO After Hours, and please do check out our other offerings wherever you get your podcasts. Have an awesome day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

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

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

Dr Sara A Hurvitz and Dr Sara M Tolaney summarize the treatment landscape for breast cancer and discuss the implications of clinical findings recently presented at the 2025 ASCO Annual Meeting. CME information and select publications here.

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

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

Dr. Monty Pal and Dr. Matteo Lambertini discuss a compelling global study on the clinical behavior of breast cancer in young BRCA1 and BRCA2 carriers, the association of pre-diagnostic awareness of BRCA status with prognosis, and the importance of identifying healthy people who are at risk of carrying the BRCA1/2 pathogenic variants. TRANSCRIPT Dr. Monty Pal: Well, hello everyone, and welcome to the ASCO Daily News Podcast. I'm your host, Dr. Monty Pal. I'm a medical oncologist, professor, and vice chair of medical oncology at the City of Hope Comprehensive Cancer Center in Los Angeles. Now, when we think about genetic testing, whether for patients diagnosed with breast cancer or for other family members of them, it seems to be widely underutilized. Today, we're going to be discussing a recently published study in the Journal of Clinical Oncology that reported on the clinical behavior of breast cancer and specifically young BRCA1 and BRCA2 carriers, and the association of pre-diagnostic awareness of BRCA status with prognosis. I thought this was just a fascinating piece, and I honestly couldn't wait to have this conversation. It's a really compelling paper that highlights the importance of identifying healthy people who are at risk of carrying the BRCA1/2 pathogenic variants, and really the need for genetic counseling and testing to inform people about early detection that could lead to a better prognosis. I'm really delighted to welcome the study's lead author, Dr. Matteo Lambertini. He really needs no introduction. He's very well known in the breast cancer world for his amazing contributions to fertility in the context of breast cancer, to pregnancy in the context of breast cancer, and genetic testing. He's an associate professor at the University of Genova, and a breast cancer medical oncologist at the San Martino Polyclinic Hospital in Genova, Italy.  Dr. Lambertini, thank you so much for joining us today. Dr. Matteo Lambertini: Thank you very much, Dr. Pal. It's a great pleasure. Dr. Monty Pal: Oh, thanks. And just FYI, if you're listening in and you want to hear our disclosures, they're all listed at the transcript of this podcast.  So, I poured through this paper [Clinical Behavior of Breast Cancer in Young BRCA Carriers and Prediagnostic Awareness of Germline BRCA Status] yesterday, Dr. Lambertini, and first of all, congratulations on this study. This was a huge international multicenter effort, 4,752 patients. How did you pool all these patients with young breast cancer? Dr. Matteo Lambertini: Thanks a lot for the question. Yes, this was an effort made by several centers all over the world. The main idea behind the creation of this network that we have named as BRCA BCY Collaboration, was to get as many data as possible in a sort of niche patient population in the breast cancer field, meaning women diagnosed with breast cancer at the age of 40 years or younger, and all of them being BRCA carriers. We know that around, in the Western world, around 5% of breast cancer cases are being diagnosed under the age of 40 years, and among them around 10-15% are BRCA carriers. So, I would say it's a relatively rare patient population where we did not have a lot of evidence to support our choices in terms of counseling on treatment, prevention, and oncofertility as well. That was the idea behind the creation of this network that includes many centers. Dr. Monty Pal: Yeah. You know, what's so interesting about this is that you sort of draw this line between patients who have BRCA testing at the time of diagnosis and then BRCA testing earlier in their course and then leading to a diagnosis perhaps. And I think that's where really sort of the dichotomy in outcome sits. Can you maybe elaborate on this and tell us about timing of genetic testing in this study and what that meant ultimately in terms of prognosis? Dr. Matteo Lambertini: In this specific analysis from this large network, including almost 5,000 women with breast cancer diagnosed at the age of 40 years or younger and being a BRCA carrier, we looked specifically into the timing of genetic testing because this is a retrospective study and the criteria for inclusion are those that I have just mentioned, so diagnosis at a young age plus carrying germline BRCA pathogenic or likely pathogenic variant. In this analysis, we have looked into the time the patient has got the genetic testing and particular we focused on two populations: those that were diagnosed, knowing already to be a BRCA carrier, and those that got tested after being diagnosed with breast cancer. And the main findings from this analysis have been that knowing to be a BRCA carrier was associated with a lower stage at the time of diagnosis, meaning more T1 tumors, so a tumor less than 2 cm, more node-negative disease, and this translated into less aggressive treatment, so less often axillary dissection, less often use of chemotherapy and anthracycline-based chemotherapy. And even more importantly, we have seen a better overall survival for those patients that were diagnosed already knowing to be BRCA carriers as compared to those tested after breast cancer diagnosis. These results after adjusting for all the confounding, stage, treatment and so on, there was not significant anymore, meaning that it's not the timing of test per se that is probably leading to a better survival, but it is the fact that knowing to be a BRCA carrier would likely translate into having access to all the preventive measures that we have in this setting and this will translate into an overall survival benefit, so in terms of saving more lives in young BRCA carriers. Dr. Monty Pal: I think it's such an important point, and it's one that I think might sound implicit, right, but it needs to be proven, I think, through a study like this. You know, the fact that finding this early, identifying the mutation, doing enhanced screening, and so forth, is really going to lead to superior clinical outcomes. One of the things that I think many people puzzle over, including myself, is what to do? I personally occasionally will see BRCA altered patients in the context of prostate cancer. But that's a very different population of individuals, right? Typically older men. In young females with BRCA mutation, I guess there's a specific set of considerations around reproductive health. You'd already highlighted preventive strategies, but what sorts of things should we be talking about in the clinics once a patient's diagnosed and once perhaps their breast cancer diagnosis is established? Dr. Matteo Lambertini: Yes, exactly. Knowing to be a BRCA carrier has a lot of implications from prevention to treatment to survivorship issues including reproductive counseling. And this is important not only for the patient that has been diagnosed with breast cancer but also for all the family members that will get tested and maybe identify with this sort of genetic alteration before diagnosis of cancer. Why this is important is because we have access to very effective preventive measures, a few examples: MRI screening, which starts at a very young age and normally young women don't have an effective screening strategy outside the BRCA field. Also, primary preventive measures, for example, risk-reducing surgery. These women are known to have a high risk of breast cancer and high risk of ovarian cancer. So the guidelines are suggesting to undergo risk-reducing salpingo-oophorectomy at a young age, so 35 to 40 years in BRCA1 carrier, 40 to 45 years in BRCA2 carrier. And also risk-reducing mastectomy should be discussed because it is a very effective way to prevent the occurrence of breast cancer. And in some situations, including the setting that we are talking about, so young women with breast cancer, BRCA carrier, also risk-reducing mastectomy has shown to improve overall survival.  On the other side, once diagnosed with breast cancer, nowadays knowing to be or not a BRCA carrier can make a difference in terms of treatment. We have PARP inhibitors in the early setting, in the adjuvant setting as well as in the metastatic setting. And in terms of survivorship implication, one of the critical aspects for young women is the oncofertility care which is even more complicated when we talk about BRCA carriers that are women candidates for gynecological surgery at a very young age. So this sort of counseling is even more complicated. Dr. Monty Pal: One of the other things, and this is subtle in your paper and I hope you don't mind me bringing it up, is the difference between BRCA1 and BRCA2. It really got me thinking about that because there are differences in phenotype and manifestation. Do you mind just expanding on that a little bit for the audience because I think that's a really important reminder that you brought up in the discussion? Dr. Matteo Lambertini: The difference between BRCA1 and BRCA2 carriers has been known that there are different phenotypes of breast cancer that are more often diagnosed in these two different populations. Normally BRCA1 carriers have a higher likelihood to develop a triple negative breast cancer as compared to BRCA2 carriers, more likely to develop a hormone receptor-positive HER2-negative disease. In this study, again, a specific population of young women with breast cancer, we have seen the same findings, mostly triple negative disease in BRCA1 carrier, mostly luminal-like disease in BRCA2 carrier. But what's novel or interesting from this study is to look also at the age at the time of diagnosis of this disease. And particularly in BRCA1 carriers, we should be sort of more careful about diagnosis of breast cancer and also other primary tumors including ovarian cancer because the risk of developing these malignancies is higher even at a younger age as compared to BRCA2 carriers. And this has implications also in the primary and secondary prevention that we were talking about earlier. Dr. Monty Pal: Oh, interesting. I guess the fundamental question then from your paper becomes, how do we get at the right patients for screening for BRCA1 and BRCA2? And I realize our audience here is largely oncologists who are going to be listening to this podcast, oncology providers, MDs, nurses, etc. But maybe speak for a moment to the general practitioner. Are there things that, for instance, a general practitioner should be looking for to say, “Wait a minute, this patient's high risk, we should consider BRCA1, BRCA2 testing or germline screening”? Dr. Matteo Lambertini: Yes, it's a very important question for the breast cancer community. After the updated ASCO guideline, the counseling is way easier because right now the age cutoff goes up to 65 years, meaning that all the patients diagnosed with breast cancer below the age of 65 years should be tested these days. And then above the age of 65, there are different criteria like triple-negative disease or family history. From a general practitioner standpoint, it's of course a bit more difficult, but knowing particularly the family history of the person that they have in front will be crucial to know if there are cases of breast cancer diagnosed at a young age, maybe triple-negative cases, knowing cases of ovarian cancer in first-degree relatives or pancreatic cancer in first-degree relatives, and of course cases of prostate cancer as well. So, I would say probably mostly the family side will be important from a general practitioner perspective.  From an oncology one, the other point that I think is important to stress also based on the data that we have shown in this publication is that having a case of breast cancer known to carry a BRCA pathogenic or likely pathogenic variant. It means that all the people around this case should get tested and if found to be BRCA carrier and healthy carrier, these people should also undergo the primary and secondary prevention strategies because this is very critical also to improve their outcomes and try to avoid the developing of breast or ovarian cancer, but also in the case of diagnosis of this disease, a diagnosis at an earlier stage, as we have seen in this paper. Dr. Monty Pal: Brilliant. I'm going to diverge from our list of questions here and close by asking a question that I have at the top of my mind. You're very young. I know our podcast listeners can't see you, but you're very, very young. Dr. Matteo Lambertini: Thank you. Thank you for that. Not so young but yeah. Dr. Monty Pal: You have nearly 300 papers. Your H-index is 67. You've already made these seminal contributions, as I outlined it from the outset, regarding fertility, regarding use of GnRH analogs, regarding pregnancy and breast cancer. What are you studying now? What are you really excited about right now that you're doing that you think might potentially be practice changing? Give us a little teaser. Dr. Matteo Lambertini: Yeah. Thanks a lot, Dr. Pal. Receiving this compliment from you is fantastic. So, thanks a lot for that. From my side, in terms of my research, I've been interested in the field of breast cancer in young women since the start of my training. I've had very good mentors from Italy, from Europe, from the U.S. I'm still interested in this field, so I think we still have a lot to learn to try to improve the care of young women with breast cancer. For example, the oncofertility care, which is something I worked a lot over the past years. Now with all the new treatment options, there's a sort of new chapter of oncofertility counseling. So, what's the impact of immunotherapy? What's the impact of the new targeted agents?  More on the genetic aspects, now we know that there's not only BRCA1 or BRCA2. There are a lot of other different genes that may increase the risk of breast cancer and other malignancies. And also for these genes, we really don't have a lot of evidence to counsel women on prognosis, treatment, prevention strategy. So we need to learn way more for this special patient population that are quite rare, and so we really need a multicenter academic effort to try to give some evidence in this field. Dr. Monty Pal: Yeah. It's tough because these are rare circumstances, but, you know, I think that you've done really well to sort of define some collective experiences that I think really define therapy. I mean, I just remember when I was in training 25 years ago, just reading through textbooks where all the experience around breast cancer and pregnancy was really just very sort of anecdotal almost, you know? And so it's great to see that the state of the science has moved forward.  Well, gosh, I really enjoyed our conversation today. I think your study really reminds us how powerful genetic information is in terms of improving outcomes. And, you know, hopefully this will lead some individuals to perhaps test more broadly in appropriate settings. So, thank you so much, Matteo, for joining us today with your fantastic insights on the ASCO Daily News Podcast. Dr. Matteo Lambertini: Thank you very much, Dr. Pal. It's a real pleasure. Dr. Monty Pal: And thanks to our listeners too. You'll find a link to Dr. Lambertini's study in the transcript of this episode. Finally, if you value the insights that you heard today on the ASCO Daily News Podcast, please rate, review, and subscribe wherever you get your podcasts. Thanks a ton. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:    Dr. Sumanta (Monty) Pal  @montypal  Dr. Matteo Lambertini @matteolambe   Follow ASCO on social media:     @ASCO on Twitter    ASCO on Bluesky   ASCO on Facebook     ASCO on LinkedIn     Disclosures:    Dr. Monty Pal:   Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview  Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical  Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis  Dr. Matteo Lambertini: Consulting or Advisory Role: Roche, Novartis, Lilly, AstraZeneca, Pfizer, MSD, Exact Sciences, Gilead Sciences, Seagen, Menarini, Nordic Pharma Speakers' Bureau: Takeda, Roche, Lilly, Novartis, Pfizer, Sandoz, Ipsen, Knight Therapeutics, Libbs, Daiichi Sankyo, Gilead Sciences, AstraZeneca, Menarini, AstraZeneca, Menarini Research Funding (Inst.): Gilead Sciences Travel, Accommodations, Expenses: Gilead Sciences, Daiichi Sankyo Europe GmbH, Roche

In this JCO Precision Oncology Article Insights episode, Dr. Jiasen He summarizes JCO PO article "Synthetic Lethal Co-Mutations in DNA Damage Response Pathways Predict Response to Immunotherapy in Pan-Cancer" by Hua Zhong et al. TRANSCRIPT Jiasen He: Hello and welcome to the JCO Precision Oncology Article Insights. I am your host, Jiasen He, and today we will be discussing the JCO Precision Oncology article, "Synthetic Lethal Co-mutations in DNA Damage Response Pathway Predict Response to Immunotherapy in Pan-Cancer" by Dr. Zhang and colleagues. Immunotherapy has emerged as a groundbreaking treatment option for many types of cancer. However, the overall response rate to immunotherapy is low, around 10% to 30%. This highlights the critical need to identify which patients are most likely to benefit from immunotherapy. Two of the most extensively studied biomarkers are PD-L1 expression and tumor mutation burden (TMB). High levels of PD-L1 and TMB have been associated with better response to immune checkpoint inhibitors, which are now widely used in clinical practice. The predictive value of these markers is inconsistent across all settings. Some tumors with high PD-L1 or TMB still respond poorly to immunotherapy. One reason is that TMB reflects new antigen production, but recent studies suggest that new antigen levels do not always correlate with tumor immunogenicity. Many new antigens are not effectively recognized by T cells, limiting the immune response. Emerging evidence indicates that mutations in the DNA damage response (DDR) pathway play a critical role in moderating tumor immune interactions. Tumors harboring DDR pathways frequently exhibit increased genome instability, which may enhance their sensitivity to immune checkpoint inhibitors. While all these pathways are under active investigation, the optimal DDR pathway biomarkers for patient selection remain unclear. Notably, tumor cells with a defect in one DDR pathway may acquire greater reliance on alternative DDR pathways. Recent studies suggest that synthetic lethal co-mutations within DDR pathways are associated with immune-inflamed or hot tumor microenvironments. Based on this rationale, Dr. Zhang is investigating if synthetic lethal co-mutations in DDR pathway response pathway can serve as a treatment biomarker for immune checkpoint inhibitors. To address this question, Dr. Zhang and colleagues first utilized SynLethDB 2.0, a comprehensive database that integrated multiple data sets. Synthetic lethal (SL) gene pairs in this resource are identified through both experimental and computational approaches, with confidence scores assigned to each pair. These SL pairs were then mapped to gene sequencing results from several clinical cohorts. SL co-mutation status was defined as positive when both genes in a synthetic lethal pair were mutated. From this, SL co-mutation pairs specifically involving DDR pathway genes were selected. Patients were classified as DDR co-mutation positive if both genes in a synthetic lethal pair, each belonging to the defined DDR pathways, were mutated. In total, 431 DDR-related SL pairs were identified and matched to sequencing data from clinical cohorts. Clinical information was extracted from the cBioPortal, while further analysis of immune infiltration was performed using DNA mutation and RNA expression data from The Cancer Genome Atlas (TCGA) pan-cancer data set. The author first examined the correlation between SL co-mutation status and response to ICI therapy. They discovered that patients with SL co-mutation showed significantly improved outcome to ICI therapy across various clinical cohorts. Notably, in patients who did not receive ICI treatment, patients with SL co-mutation showed markedly compromised overall survival. Further analysis focused on the predictive value of SL co-mutation within DDR pathway genes. The author found that patients with DDR SL co-mutation had a longer overall survival compared to those with mutations in a single DDR gene, implying that SL co-mutations may be more effective biomarkers within the DDR pathway. To explore this further, in the TMB-MSKCC cohort, the author found that patients with DDR co-mutation constituted approximately 20% of various cancer types, including non-small cell lung cancer, melanoma, and bladder cancer. These patients demonstrated significantly better survival outcomes and disease control rates when treated with ICIs compared to DDR co-mutation negative patients. Notably, the TMB level was substantially higher in patients with DDR co-mutation, a finding consistent with data from the Miao-lung cohort. Furthermore, in cohorts not treated with ICIs, patients with DDR co-mutation had a shorter overall survival compared to their counterparts. Upon stratifying by PD-L1 expression, the author observed that patients with DDR co-mutation who were also PD-L1 positive derived the greatest clinical benefit from ICI therapy. Upon analyzing the frequency of co-mutation within the DDR pathway, the authors found that patients with SL co-mutation in the CPF-CPF pathway experienced remarkable survival benefit from ICIs. Within this group, one of the most common co-mutation combinations was TP53-ATM, observed in approximately 45% of cases, which was associated with a better response to ICI therapy. Further analysis of immune cell infiltration revealed that patients with TP53-ATM co-mutation exhibited a distinct tumor immune microenvironment. As the authors stated, the study's main limitation lies in the nature of retrospective analysis, which lacked the control over confounding variables and was subject to non-random sampling. For instance, patients with both SL co-mutations and DDR SL co-mutations exhibited high TMB, and TMB was known to be associated with improved response to ICI therapy itself. So, these findings require validation through prospective studies, and immune infiltration analysis needs confirmation via laboratory experiments. In conclusion, the authors found that patients with SL co-mutations in DDR pathways showed favorable clinical response and prolonged survival following ICI therapy. They also identified TP53-ATM co-mutations as a clinically relevant biomarker for predicting ICI treatment response. Thank you for tuning in to JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

In this JCO Article Insights episode, Dr. Ece Cal interviews Dr. Martin Wermke, author of the JCO article, "Phase I Dose-Escalation Results for the Delta-Like Ligand 3/CD3 IgG-Like T-Cell Engager Obrixtamig (BI 764532) in Patients With Delta-Like Ligand 3+ Small Cell Lung Cancer or Neuroendocrine Carcinomas." TRANSCRIPT The disclosures for guests on this podcast can be found in the transcript. Dr. Ece Cali: Welcome to this episode of JCO Article Insights. This is Dr. Ece Cali, JCO editorial fellow, and today I am joined by Dr. Martin Wermke, Professor for Experimental Cancer Therapy at Dresden University of Technology, to discuss the manuscript “Phase 1 Dose-Escalation Results for the Delta-Like Ligand 3/CD3 IgG-like T-Cell Engager Obrixtamig in Patients with DLL3+ Small Cell Lung Cancer or Neuroendocrine Carcinomas.” Obrixtamig is a bispecific T-cell engager that binds to DLL3 on tumor cells and CD3 on T-cells. This manuscript presents the phase 1A dose escalation results of Obrixtamig in patients with DLL3+ small cell lung cancer and neuroendocrine carcinomas. In this study, 168 patients were treated with Obrixtamig across four different dosing regimens. 49% of the patients had small cell lung cancer, 42% had extrapulmonary neuroendocrine carcinoma, and 8% had large cell neuroendocrine carcinoma of the lung. Patients received a median of two prior lines of therapy. 33% of the patients had brain metastases at baseline. Of note, this trial did not mandate baseline brain imaging. Maximum tolerated dose was not reached. 88% of the patients experienced a treatment-related adverse event, however, only 3.6% of the patients had to discontinue treatment due to treatment-related AEs, and dose reduction due to treatment-related AEs was documented in 2.4% of the patient population. Similar to the other DLL3-targeted bi-therapies, the most common adverse events included CRS in 57%, dysgeusia in 23%, and pyrexia in 21% of the patients. CRS events were mostly mild. They occurred more frequently in the first two to three doses. 9% of the patients experienced ICANS, of which 3% were graded as Grade 3 or higher. And let's review the efficacy results. Responses were only seen in patients who received 90 microgram per kg or more once weekly or once every three weeks dosing. The objective response rate in patients who received an effective dose was 28%. If we review by tumor type, 21% of the small cell lung cancer patients, 27% of the extrapulmonary neuroendocrine carcinoma patients, and 70% of the large cell neuroendocrine carcinoma patients had objective response. Median duration of response was 8.5 months, though this data is immature due to short follow-up. Dr. Wermke, DLL3-targeted bispecific T-cell engagers are reshaping the treatment landscape of small cell lung cancer. This trial investigates Obrixtamig in other high-grade neuroendocrine tumors as well. Can you put this trial into context for us and explain why it may represent an important step forward? Dr. Martin Wermke: Yeah, thank you for providing me with the opportunity to discuss our data today. I think the data with Obrixtamig in small cell lung cancer are largely similar to what has been observed with other bispecific T-cell engagers such as tarlatamab with respect to the response rate and duration. It has, however, been to be mentioned that BI 1438001 had a bit more liberal inclusion criteria than other trials around. You already mentioned the fact that we allowed the inclusion of patients without mandatory brain imaging, which led to some patients having their brain mets been diagnosed during the treatment with obrixtamig and then adding to the progressive disease patients. That is something which was not the case with the tarlatamab trials where you really had to have a brain imaging before, and in the Phase 1 trial you were even required to treat the brain mets before you included the patient. So it is a bit different, more poorest patient population. I think the trial adds on existing data by being the first trial to also include non-SCLC neuroendocrine carcinoma of other origin, for example from the gastrointestinal tract, and also by including large cell neuroendocrine carcinoma of the lung, which is a really hard to treat pulmonary neoplasm which currently lacks any standardized treatment. So that is really a step forward which we will build on in the future. Dr. Ece Cali: And one thing I would note in this trial, only patients with tumor expressing DLL3 were enrolled. Can you tell us a little bit more about this target, DLL3 in the context of neuroendocrine tumors, and does DLL3 expression predict clinical outcomes after treatment with DLL3 BiTEs, or do we actually need other predictive biomarkers for these novel agents? Dr. Martin Wermke: Yeah, thank you. That's a pretty interesting question. First of all, DLL3 is an atypical notch ligand, which is expressed by the majority of neuroendocrine carcinomas, virtually absent on healthy adult tissues. Therefore, turning it really into a bona fide target for T-cell engaging therapies, pretty low risk for on-target off-tumor side effects. We found that in all the patients we screened, we had an expression rate of about 94% in small cell lung cancer, 80% of large cell neuroendocrine carcinoma of the lung were positive, and also about 80% of the extrapulmonary neuroendocrine carcinoma. So it's really a high prevalence. So the fact that we only included DLL3+ tumors still means we included most of the patients that presented with these diseases. I think at the moment there are no data suggesting a clear-cut association between DLL3 expression levels and outcome on DLL3 CD3 T-cell engagers. There's also not a lot published. If you want to find this out for tarlatamab, you have to look into their patent to really see the data, but it's not clear-cut and I'm sure we need other markers to complement that. And I think what probably plays a major role is intrinsic T-cell fitness. So the question how really diseased your T-cells are, how old you are, because age also correlates with the fitness of the immune system, and other patient characteristics such as tumor burden, we've seen all across the board that the higher the tumor burden, the lower the rate of prolonged response is in such trials. And I also think we need to focus on other components of the tumor microenvironment. So see how high the T-cell infiltration with obrixtamig is and how abundant suppressive elements like regulatory T-cells or myeloid-derived suppressive cells are. That is work which is currently being done. Data are emerging, but I don't think that at the moment we have any clear biomarker helping us to select who should not receive DLL3 T-cell engagers. Dr. Ece Cali: Those are great points and there is a lot we need to learn about how to use these novel agents in the future. I'd like to highlight the results in large cell neuroendocrine carcinoma of the lung. The response rate in this group was remarkably high at 70%. Though we should note the small sample size of only 14 patients in this trial. After first line chemoimmunotherapy, current approved options for this population have very modest clinical activity. Given these trial results, how do you envision the field moving forward for patients with large cell neuroendocrine carcinoma? Dr. Martin Wermke: Yeah, I think LCNEC is really an area which urgently needs further improvement of therapeutic standards. At the moment, as I said, there is no real standard. We are usually extrapolating from results we have in small cell lung cancer or non-small cell lung cancer, but I don't think we have too many prospective trials really informing this. Of course, 14 patients is a small sample size, but I think it's still fair to say that we can claim that DLL3 T-cell engagers are not doing worse in LCNEC than they do in SCLC. And that's why I think we really need to move forward clinical trials that are specifically targeting this population. Although I fear a bit that, given the rareness of this disease and the aggressiveness of its phenotype, that this is probably not the main focus of the pharmaceutical industry. So I think it's up to us academic investigators to really come up with investigator-initiated trials trying to fill the knowledge gaps we have here. Dr. Ece Cali: And one more thing that I want to talk about is the accessibility for these drugs. These novel agents are showing real promise in improving outcomes for patients with high-grade neuroendocrine tumors, an area where progress has been limited until very recently. However, as DLL3 BiTEs become more widely used, issues of logistics and access come into sharper focus. With unique toxicities and the specialized monitoring, their use is restricted to certain centers. Looking ahead, what kinds of strategies could help mitigate some of these adverse events or make these treatments more broadly available? Dr. Martin Wermke: Yeah, I think if you look at countries like the United States where tarlatamab has already been approved, we can see how the management strategies are evolving. I've heard about a colleague equipping their patients with thermometers and a pill of Dexamethasone, alongside with a temperature control protocol and clearly instructing them, "If you measure a temperature above a certain level then start taking the Dexamethasone and come back to our office and we're going to take care of you." I think that's one way to move forward. I think we are lucky in a way that CRS usually manifests within the first 24 hours. This was the same in our study, like in the tarlatamab studies. So we really know when the time of trouble is for our patients. And in this time, I think we need to instruct the patients to stay close to the hospital. I don't think we need to hospitalize all of them, but we probably need them to stay in a nearby hotel to be able to reach the emergency room if needed in a short period of time. And I think we can also learn in this strategy how to manage bispecific antibodies from the experience our colleagues in hematology had because they have been using bispecific T-cell engagers for quite some years right now and they developed strategies and networks that were able to successfully treat these patients also on an outpatient basis. And I think that is clearly an experience we need to follow, acknowledging that we are talking about diseases which are much more frequent than the standard hematology indications. Dr. Ece Cali: Thank you so much, Dr. Wermke, for this informative discussion and for sharing your perspective on this evolving field. Dr. Martin Wermke: Yeah, thank you for providing me with the opportunity to talk about data. It was really great being able to share that, and I really think that we are just at the beginning of a new exciting area for the treatment of neuroendocrine carcinomas, and I think much improvement is yet to come for our patients. Dr. Ece Cali: Yes, that's really exciting. And thank you everyone for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Martin Wermke's Disclosures Honoraria: Lilly, Boehringer Ingelheim, SYNLAB, Janssen, Merck Serono, GWT, Amgen, Novartis, Pfizer,  BMS GmbH & Co. KG, Regeneron, MJH/PER, Takeda Consulting or Advisory Role: Bristol-Myers Squib, Novartis, Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, Amgen, immatics, Bayer, ImCheck therapeutics, AstraZeneca, Tacalyx, Regeneron, Daiichi Sankyo Europe GmbH, Zymeworks, PharmaMar, Iovance Biotherapeutics, T-Knife, Genentech Research Funding: Roche Patents, Royalties, Other Intellectual Property Travel, Accommodations, Expenses: Pfizer, Bristol-Myers Squibb, AstraZeneca,  Amgen,  GEMoaB, Sanofi/Aventis, immatics,  Merck Serono, Janssen Oncology, Iovance Biotherapeutics, Daiichi Sankyo Europe GmbH"

JCO PO authors Dr. Abhishek Tripathi and Dr. Salvador Jaime-Casas at City of Hope Comprehensive Cancer Center share insights into their article, “Comparative Genomic Characterization of Small Cell Carcinoma of the Bladder Compared With Urothelial Carcinoma and Small Cell Lung Carcinoma.”  Host Dr. Rafeh Naqash and Drs. Tripathi and Jaime-Casas discuss a novel understanding of the genomic alterations underlying SCBC, revealing actionable mutations that could serve as potential targets for improved clinical outcomes. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I am your host, Dr. Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Associate Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, I am thrilled to be joined by Dr. Abhishek Tripathi, Associate Professor in the Department of Medical Oncology and Experimental Therapeutics Research at the City of Hope Comprehensive Cancer Center, as well as his mentee, Dr. Salvador Jaime-Casas, postdoctoral research fellow and first author of the JCO Precision Oncology article entitled "Comparative Genomic Characterization of Small Cell Carcinoma of the Bladder Compared with Urothelial Carcinoma and Small Cell Lung Carcinoma". At the time of this recording, our guest disclosures will be linked in the transcript. Abhishek and Salvador, welcome to our podcast and thank you for joining us today. This is a very interesting topic given that at least the landscape for neuroendocrine carcinomas, where small cell lung cancer is on one end of the spectrum, has been changing, at least on the lung cancer side, with recent approvals and some new ADCs. So, of course, understanding the genomic and transcriptomic similarities or differences between pulmonary small cell and extrapulmonary small cell is of huge interest. Could you tell us a little bit about small cell bladder cancer, current approaches to treatment of small cell bladder cancer, and then why you wanted to investigate that in this project as far as the genomic differences or similarities are concerned? Dr. Salvador Jaime-Casas: Well, first of all, thank you very much for having me. I am very excited to be here. And really what served as backbone for this research project was the notion that there is a currently evolving genomic landscape in the area of bladder cancer. We know this is a highly heterogeneous disease when it comes to molecular underpinnings and mutational profile. Specifically, we know that the most common histologic subtype is urothelial carcinoma. Small cell bladder cancer represents a histology that is found in less than 1% of all bladder cancer cases. However, it is one of the most aggressive histologies. It presents with a very poor prognosis to patients and very poor response to treatment, which is why we attempted to really elucidate what is the mutational profile behind this and provide a comparison contrast between small cell bladder cancer, small cell lung cancer, and conventional urothelial carcinoma. As your question mentioned, in terms of treatment, the conventional urothelial carcinoma and small cell bladder cancer are two distinct pathways when it comes to treatment algorithms. We know that in the current era there are newer and newer drugs being developed for conventional urothelial carcinoma. We have perioperative immunotherapy in the context of metastatic disease. We have antibody-drug conjugates such as enfortumab vedotin. But really, this amazing track record of drug development hasn't been mirrored in small cell bladder cancer. And here most of the therapy is usually extrapolated from studies from other small cell histologies like you mentioned earlier, small cell lung cancer has given some form of background in terms of what therapies are used here. Cytotoxic chemotherapy, for some patients with localized disease and small cell bladder cancer, concurrent chemotherapy and radiotherapy or perioperative cytotoxic chemotherapy have been the cornerstone of treatment for many years now. However, like I mentioned, the oncologic outcomes are very suboptimal when it comes to comparing it with other disease histologies, which is why we really wanted to describe the landscape here and provide this comparison across three different groups. For this particular study, we leveraged the Tempus dataset. So, include patients with urothelial carcinoma with small cell bladder cancer and small cell lung cancer. We included their demographic information, as well as the frequency of most common genomic alterations identified. And really, it was a very comparable Table 1. We see the demographic data across the three groups was very similar. One key thing that we identified was the female prevalence was a little bit lower in patients with small cell bladder cancer when compared to small cell lung cancer. But other than that, the age, race, ethnicity, was comparable across groups, and even the smoking history. Most of the patients in this cohort were former smokers, which we believe comes to explain that regardless of any mutational profile that we talked about in a few minutes, there are shared commonalities between these histologies and shared environmental exposures and risk factors that are going to be implicated in the disease biology for these three histologies. Dr. Rafeh Naqash: Thank you so much, Salvador, for that useful background. I would like to shift to Abhishek real quick. Abhishek, you are a practicing clinician, you have led several studies in the GU space, especially bladder. Based on what you see in the small cell lung cancer space, how drug development is shaping up, which aligns with what you are trying to evaluate in this paper as targets, how do you see some of that being implemented for small cell bladder cancer in the current era and age? Abhishek Tripathi: Thanks so much for the excellent question, Rafeh. As a GU investigator, small cell bladder cancer has always lagged behind in some regards regarding enrollment abilities for the novel clinical trials. And small cell lung cancer has paved the way and led the development of a lot of these drugs across the board. With the most recent sort of drugs targeting DLL3 already approved and several antibody-drug conjugates currently in development. That actually translates really well to how we should approach drug development in bladder cancer. What we saw in the study is that although there are overlaps and similarities between small cell lung cancer and small cell bladder cancer, there are also certain differences. So the long-term assumption that all therapies for small cell bladder cancer can be extrapolated to small cell bladder], may or may not be true, and I think it is high time that we specifically investigate these novel agents in tissue-specific small cell carcinomas. To that effect, we are excited to be participating in trials that are looking at some of the novel DLL3 targeted agents, specifically bispecific antibodies and T cell engagers so to speak, and antibody-drug conjugates that are now starting to open enrollment specifically in non-lung cancer cohorts to evaluate its efficacy. So overall, I think studies like this have the opportunity to identify more putative targets for organ-specific development of these novel agents. Dr. Rafeh Naqash: Absolutely, I could not agree more. I think tumor-agnostic therapies definitely have a place, but not all therapies work the same in different tumors with a similar histological or genomic background because there are definitely differences. So now going to the comparison that Salvador, you guys did in this project, could you help us understand what are some of the things you looked at, what were some of the commonalities and the differences, and what were some of the conceptual thoughts that come out from those results? Dr. Salvador Jaime-Casas: Of course. So, the first thing that we identified was which were the most frequent molecular alterations across these histologies. We actually provided a table showcasing how the most common mutations that we identified were TP53, TERT, RB1. However, like Dr. Tripathi mentioned, the distinction between these histologies is notable in the sense that some are more predominant in small cell-pertaining cancers such as bladder cancer and lung cancer. While some others are more common in bladder-pertaining malignancies like urothelial carcinoma and small cell bladder cancer. For instance, we saw that TP53 and RB1 were significantly more evident in small cell histologies, both small cell bladder cancer and small cell lung cancer, as opposed to conventional urothelial carcinoma, which really this mirrors what is known about these mutations and what has been published. These are markers associated with more aggressive disease with a worse prognosis and even to resistance to treatment. We also identified how TERT mutations were characteristically more prevalent in small cell bladder cancer as opposed to small cell lung cancer, as well as in urothelial carcinoma. TERT mutations were more commonly identified than in small cell lung cancer. And we give a long list of these mutations that we identified, but really what we wanted to underscore here was, A, the most common mutations across histologies; B, the most common co-occurring mutations where we saw that these are not mutually exclusive. A lot of patients had co-occurring TP53 and RB1 or RB1 and TERT or RB1 and ARID1A, really elucidating how heterogeneous this molecular landscape is across histologies. And the third one that we believe really brings down the clinical impact of this research was evidencing the idea of clinically actionable mutations. We also provided a table here showcasing how mutations like FGFR, DLL notch pathway, HER2, were evident in these histologies, and what is the current status of some clinical trials evaluating different drug designs for these mutations. Like Dr. Tripathi mentioned in the context of FGFR, approximately 6% of our cohort with small cell bladder cancer showcased mutations in FGFR3. However, up to 14% of them had mutations in any FGFR gene, which really underscores the notion that drugs like erdafitinib, which have been introduced in the market in recent years, could potentially showcase some response in the space of small cell bladder cancer. We actually provide the description of two trials, phase two, phase three trials, that are evaluating erdafitinib in the context of high-risk non-muscle invasive bladder cancer and even metastatic urothelial carcinoma. Like Dr. Tripathi mentioned as well, antibody-drug conjugates, another very interesting area of drug development targeting HER2, we included evidence on how disitamab vedotin and trastuzumab deruxtecan are currently being explored across different phase two and phase three clinical trials, both as part of basket trial designs for solid malignancies expressing HER2, but also for patients with urothelial carcinoma where there is evidence of HER2 expression. So, we believe that the landscape is shifting in the right direction in the sense that therapies are becoming much more personalized and targeted against these known molecular profiles. Dr. Rafeh Naqash: Thank you, Salvador, for summarizing some of those very interesting results and providing a very unique conceptual context to that. I would like to go to Abhishek this last portion. Of course, I am sure you guys will expand on this work and there are a lot of other interesting things that will likely come out from this work and hopefully you will publish that in JCO PO. But one of the very important things that I wanted to highlight from this podcast specifically was the science is obviously very interesting, but I feel the more important interesting aspect is giving trainees and fellows, residents, mentorship opportunities, mentoring them and giving them lead roles in projects like this, which is what Dr. Tripathi has successfully done for you in this project, Salvador. So, Abhishek, as somebody I have known for a couple of years now, more than a couple of years, as a very successful clinical translational investigator in the GU space in the early phase setting, Abhishek, really briefly, within a minute, could you tell us about your journey and what are some of the things that have worked for you as an early career investigator that you have learned from, and then your journey of mentorship, how has that been for you and what are some of the things that you take home from your mentorship role? Abhishek Tripathi: Absolutely. And as you mentioned, mentorship has been pivotal for all early career investigators for them to really succeed. So, my journey, as you know, I started off as an early career investigator at another institution, and I think I owe it to my mentors even at that time and even now who are helping me develop some of these newer translational and clinical trial ideas, creating opportunities where we could really showcase some of the interesting work that we are doing. That actually goes a long way in terms of creating independence as an established investigator. And I think the sooner we start off with mentorship prospects, I think the better it is. And paying it forward, I think I have been lucky to have mentees like Salvador who are just extremely talented, really committed, and goal-oriented. He really led the project right from the beginning in terms of initial analyses and looking up all the sort of correlative studies that we could do and the contextual data between small cell lung cancer and bladder cancer that we have delved into for the past several years. And it really showcases the ability of young mentees like Salvador to really excel given the right guidance and the support. As a mentor, it has been a really rewarding experience. It is really helpful to actually learn from some of these mentees as well as to approach the same problem from a different angle and different thought process and guide them through the study. So, it has been incredibly helpful and rewarding both being a mentee and a mentor over the past several years as I have transitioned. Dr. Rafeh Naqash: Thank you, Abhishek, for those very insightful comments on how both being a mentee and being a mentor helps shape you as an individual as well. And then you take a lot of pride in the success of your mentees. Now real quick, Salvador, could you tell us a little bit about yourself, you know, how you ended up at City of Hope under Dr. Tripathi's mentorship and what are some of the next important things that you are looking forward to doing? Dr. Salvador Jaime-Casas: So, a little bit about who I am. I did medical school in Mexico City. I was born and raised there, and towards the end of my medical training, I started to be engaged in research projects. And through one of my mentors in Mexico, I was actually introduced to the team here at City of Hope, including Dr. Tripathi. And through this, we got the opportunity to have some conversations about what I wanted to do, become a physician-researcher in the area of genitourinary oncology and hopefully my transition to residency in a few years. And that is how I came to be his mentee here at City of Hope. I think it has been a very rewarding experience, like Dr. Tripathi said, having such an incredible mentor and really being with him both in the academic setting and in the clinical setting, in patients with clinic, seeing this curiosity and all these clinical trials, all of this evidence that we have coming together to generate this insight. Dr. Rafeh Naqash: Thank you so much for both the scientific insights, as well as the journey of being a mentee for you, Salvador, and as a mentor for you, Abhishek. I really enjoyed talking to you guys about both aspects here today and hopefully we will see more of your work, Abhishek and Salvador, as far as understanding the transcriptomic heterogeneity in neuroendocrine tumors or neuroendocrine cancers of the bladder. Dr. Salvador Jaime-Casas: Thank you very much. Thank you for having us. Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Do not forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ASCO.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.   Dr. Abhishek Tripathi Disclosures Consulting or Advisory Role:  Company: Aadi biosciences, Seattle Genetics/Astellas, Exelixis, Bayer, Gilead Sciences, Pfizer, Deka biosciences Speakers' Bureau: Company: Sanofi

To date, Michael P. Link has the unique honor of being the only pediatric oncologist to have served as president of the American Society of Clinical Oncology. Link, who is the Lydia J. Lee Professor in Pediatric Oncology at Stanford University, appeared on the Cancer History Project Podcast in conversation with Paul Goldberg, co-editor of the Cancer History Project and editor and publisher of The Cancer Letter.In honor of Childhood Cancer Awareness Month, Link revisits what drew him to pediatric oncology, his auspicious mentors, his 2011-2012 ASCO Presidential term—and his concerns about what he's seeing in oncology today.Over the course of his career, Link has seen a childhood cancer cure rate increase from a mere 40% to closer to 90%. But he's concerned about how the field of oncology is being impacted today.In his 2012 Presidential address, Link said:“There is another lesson from our children—that an ounce of prevention is worth a pound of cure. This is a lesson not just from pediatric oncology, but from pediatrics in general. Prevention strategy through immunization has proven to be one of the greatest triumphs of pediatrics and of modern medicine. Rather than diagnosing and treating diphtheria, widespread immunization simply eliminated it as a health problem in North America. The near eradication of measles, polio, and serious infections from H Influenzae is a similar triumph.”He expressed shock about how things have changed in 2025. “I'm a pediatrician, so here I am and they have measles? I mean really, measles in 2025? How is that possible?” Link said. “I never thought I'd be in a position where I have to talk to people about measles and polio and chickenpox as a threat... And measles, it's a matter of how serious your illness is going to be, and if you're immunocompromised it's life threatening.”Other concerns from his time as ASCO President have reemerged—or never really gone away.In 2012, Link said, “But all this newfound insight into these diseases and their treatment is only as good as our ability to deliver what we know. The current chemotherapy shortage is emblematic of the precarious nature of the path between the discovery and the delivery of our most exciting new findings.”Speaking on the podcast, Link called this an issue of “whack-a-mole”—where new drugs go into shortage on a regular basis. “Can you believe that here we are in whatever year it is, 20-whenever the next shortage is going to come and we don't have access to this?”A transcript of this conversation, along with an archive of related content, is available on the Cancer History Project: https://cancerhistoryproject.com/article/michael-link-podcast/ 

Dr. Monty Pal and Dr. Mina Sedrak discuss the science behind cancer treatment-induced accelerated aging and the development of drug therapies and technologies aimed at helping older patients and cancer survivors. TRANSCRIPT Transcript: Cancer and Aging: Researching the Path to Longer, More Vibrant Lives Dr. Monty Pal: Hello, and welcome to the ASCO Daily News Podcast. I am Dr. Monty Pal. I am a medical oncologist and professor and vice chair of medical oncology here at the City of Hope Comprehensive Cancer Center. I am also host of this podcast. Today, we are going to be talking to somebody that I consider to be my little brother, if you will, in oncology, Mina Sedrak. Mina is an expert in the area of cancer and aging, which really includes the development of drug therapies and technologies that help enable older adults and survivors to live longer, healthier, and more vibrant lives. I am really excited to chat with him. He is an expert not just in cancer and aging but also breast cancer. He was my former colleague here at City of Hope before he moved over to the UCLA Jonsson Comprehensive Cancer Center, where he is an associate professor and director there of the Cancer and Aging Program. Dr. Sedrak's research involves mechanisms behind cancer treatment-induced accelerated aging and really aims to take this science into more of a therapeutic direction, which I am super, super excited about.  Mina, thanks so much for joining us today, and just FYI for our listeners, we have all of our disclosures in the transcript of this episode. Dr. Mina Sedrak: Thank you, Monty. Thank you, Dr. Pal, for having me. I am really excited to be here. Dr. Monty Pal: I feel like we have to go on a first-name basis here with how well we know each other. So Mina, you and I together have witnessed this evolution in cancer and aging. I mean, both of us worked together here with just a legendary figure in the field of geriatric oncology, I will call it, Dr. Arti Hurria, mentor to me, mentor to you, mentor to so many. Can you give us a sense of where cancer and aging has gone since the time that you and I started here together at City of Hope? Dr. Mina Sedrak: Dr. Hurria and her collaborators, Dr. [Willliam] Dale and Dr. [Supriya] Mohile, they were like huge pioneers in the field. They were one of the very first people to highlight the importance of looking at older adults beyond just their chronological age and their comorbidities and moving us beyond just seeing patients and making decisions using what we call the eyeball test. "Oh, this person looks fit or not fit, frail or robust," to really using objective measures to assess our patient's health status and incorporate that assessment into our evaluation of the treatment, prognostication, and discussions with our patients throughout the cancer continuum. And so that is what geriatric oncology has and continues to be, and it is a huge, important part. And their work has laid the foundation to show that when we look at our patients beyond just their chronological age and we look at their functional age, and we do these objective assessments, we can gain much more deeper information to tailor the treatment for our patient that is sitting in front of us, rather than do a prescriptive treatment or over- or undertreatment in that population. So that is sort of where the field is growing, and a lot of the work now is, how do we implement that? How do we put that into clinical practice? Dr. Monty Pal: Well, let me kind of spearhead that discussion, right? I have these moments when I go to the ASCO Annual Meeting – I remember this happened to me a while ago when Dr. Jennifer Temel presented that terrific work around early palliative care interventions, right? Or it even happened to me this year, right, when Dr. Christopher Booth presented the CHALLENGE trial around exercise and colon cancer. You know, these amazing, I am going to say simple, they are not simple, but they are simple interventions relative to, you know, some of the complex drugs and mechanisms that we are using nowadays that really help outcomes for our cancer patients. The big question becomes, how do you implement, right? But my understanding is that there are easy ways for us to take tools in cancer and aging and sort of plug them into our daily practice. Am I right about that? Dr. Mina Sedrak: Yes, and that is something that they are – the Cancer and Aging Research Group, which was founded by Dr. Hurria and now is co-led by Dr. Dale, Dr. Mohile, and Dr. [Heidi] Klepin, they have been incredible at really trying to develop practical tools, like the Practical Geriatric Assessment, which is now endorsed by the ASCO and other NCCN guidelines. And so, there are tools that are becoming more and more practical to help incorporate that into clinic.  Now, what might be practical in a resource-intensive setting may not be practical in some of the limited resources, whether it is rural and/or other countries where the resources may be more limited. So that is why Cristiane Bergerot, Enrique Soto, and others have been really working hard. There was actually a really beautiful paper that was just published in the Journal of Global Oncology, where they have shown that there are guidelines [ASCO Geriatric Assessment Global Guideline] about how to implement these tests, these tools, these assessments in clinical practice, even in different resource settings. So I think we are going to get to the future where this is much more – it is definitely important, but it is much more easily ‘incorporatable' into our practice. Dr. Monty Pal: Yeah, you know how close I am to Cris, and I was so proud when I saw that paper come out. That was really exciting. You know, I skimmed it. I have to tell you, I did not get into the weeds, but it was apparent to me that, you know, some of these geriatric oncology tools are things that, you know, I could probably plug and play into my practice where I am double- and triple-booked over, you know, most slots, right? I mean, I could still probably afford a little bit of time or maybe have, like, a nurse or an extender kind of help participate in the evaluation process. I thought that was, yeah, really, really interesting. Dr. Mina Sedrak: I will just say that at UCLA, we are working with Dr. Arash Naeim, who is a geriatric oncologist, and he has developed an AI platform where the assessments can be done by an AI computer. So it is like talking to your ChatGPT. They can talk to you, and for a few minutes, they will ask you the questions. So you do not even have to fill it out on a piece of paper. You could give the patient a little iPad, put them in a private room while they are waiting for their doctor, and get the results, and it is right there for you. And so, we have been trying to think about how can technology help with the completion of the assessment, at least doing that? And I think it is actually, it has been very cool. We did a pilot study. He is writing that up, and we are going to continue to do some of this exciting work. How do we think about AI in the context of this? And, you know, older adults, they are not like what they used to be. A lot of older adults are very familiar with and comfortable with phones and computers and iPads, much more so today than they were even at the time when Dr. Hurria was alive. Dr. Monty Pal: That is so interesting. You mentioned this, the AI approach is something I have been thinking about in this context because what if, for instance, you know, we have got video monitors all over our hospital, right? What if you are actually just taking a look at that patient as they make their way towards your clinic? Capture that video, use an AI algorithm to say, "Hey, you know, the timed get-up-and-go test in this patient is not particularly good based on what I am seeing here," right? There are so many ways that you could, you know, stir the pot and come up with creative ways to get these tests done. Dr. Mina Sedrak: That's right. And Arash is looking at also sensors. So he has some studies where he is putting sensors inside people's homes, where they would put them, like, on top of an Alexa app or the equivalent. A lot of people have these apps, and basically, they can sense how you are moving around and what you are doing, just movement-wise. And then they can collect that information to gain information about your life beyond just what we are seeing in the 20-minute visit in the clinic. Even when I do a walk test where I get gait speed or physical performance, short physical performance battery, the chair sit-up, those are oftentimes a single, cross-sectional, static measure. But what about the dynamic ability of capturing what has been happening for the last 7 days? What has been happening for the last 25 days between the visits, between the cycles of chemotherapy? And could that inform how I make decisions when I see patients and who do I need to target and identify? And so, we are very excited because really at UCLA, Arash is leading the technology efforts and thinking about implementation of these important measures and these important tools but leveraging new technology. And we do not want to be behind; we want to be ahead of the game. Dr. Monty Pal: I love that idea because there is a Hawthorne effect, isn't there, where you observe a process, and it naturally gets better. I mean, when you ask that patient to get up in the clinic and move, they are probably functioning to the best of their abilities, but we could probably learn a lot from just watching how fast that patient picks up a remote control at home. Some simple movement like that that is volitional would probably help out a ton. And I got to tell you, it is so funny when you mention Arash Naeim's name. I distinctly remember him serving as an attending on the wards when he was brand new at UCLA on faculty when I was a resident there. And his dad is a legendary hematopathologist, right? Dr. Mina Sedrak: I did not know that. Dr. Monty Pal: Yeah, yeah. Faramarz Naeim wrote the book on a lot of heme-path malignancies. Incredible guy. Very, very storied hematopathologist at UCLA.  I could probably go on this topic forever, but in the interest of time, I am going to shift to something that again, I could probably talk about forever, which is this area of senescence that you are involved in. You know, you had mentioned this to me, I am going to say during your outro from City of Hope and towards your transition to UCLA, it is such an exciting area. I mean, understanding the actual biologic process of aging and using those underpinnings to really sort of tailor therapy. So tell us where the state of the science is there with this body of work that you are doing. Dr. Mina Sedrak: As I said before, we have tools now to assess patients and to then do something about the deficits. So if a patient is falling, what we do is we refer them to physical therapy where they can do fall precautions and strength training to give them the information. But all of these supportive care interventions are very important. They are great. But they oftentimes are not targeting the root cause of why they are happening. And so that is really where I have been very interested in, how can we understand why is it that something like chemotherapy or immunotherapy is causing a decline in cognitive function or a decline in physical function? And so that has really led us to think about geriatric oncology rather than a discipline of older adults, but to think about aging as a physiologic process. We are all aging. As every day goes by, we are aging. And what that means is that our bodies are accumulating damage, the cells are being exposed to various stressors, and the repair mechanisms are declining. And as we get older, it is really more damage and less repair mechanism at the cellular molecular level. And it turns out that these processes of how our cells repair and respond to damage are fundamental processes of biological aging. And there has been a large amount of preclinical and now really exciting clinical work to show that there are hallmarks that could be used to assess the rate of which we age by looking at these processes. And that includes things like epigenetics, telomeres, inflammation, and something called ‘cellular senescence.' And we have been interested in my lab in senescence because it is a unique process that has an important role in aging, but it also has a really important role in cancer. Senescence is a cell state. Cells, when they are stressed, they respond to entering this state of senescence. The stress could come from anything. It could come from an oncogene activation. It could come from a reactive oxygen species. It could come from a direct damage to the cell. But it is a cell state, just like apoptosis, necrosis. Senescence is a state in which the cell, in response to that stressor, undergoes an arrest from the G to the S phase. And that arrest is oftentimes associated with a resistance to apoptosis. So then the cell does not die, but it is alive, and it remains metabolically active. And in fact, downstream pathways of these cell cycle inhibition of this G-to-S phase lead to the increase of these transcription factors in the chromatin and lead to the development of these pro-inflammatory factors. So these cells, which can occur in various tissues in the body, can continue to live despite having developed these changes, and then they secrete these proinflammatory molecules like cytokines, chemokines, metalloproteinases, all of these, which are called the senescence-associated secretory phenotype, or SASP. And as we age, we accumulate more and more of these cells, and our bodies are no longer able – our immune system, like macrophages and T cells – are no longer able to remove them effectively. And as we accumulate them in various organs, these organs release a lot of inflammatory cytokines, and the chronic inflammation in that tissue leads to the tissue being damaged, and it does not work as well, and then it starts to decline in function. And that is believed to be how senescence plays a role in aging. It is the accumulation of senescent cells that occurs with increased damage and then the repair mechanism of clearing these cells effectively, which then leads to build up of inflammation and chronic inflammation leads up to damage in multiple tissues. Dr. Monty Pal: This concept to me is fascinating. And I guess the big question is – senescence is bad, right – is it not reasonable to think that this body of research, I mean, if you are able to sort of have a meaningful impact on senescence, it could have implications well beyond oncology. Is that fair? You really could extend lifespan all around. Is that reasonable to think, all-cause mortality? Dr. Mina Sedrak: One hundred percent. And that is what they have been shown in animal models. And the reason senescence is exciting is because it turns out that you can target these cells and you can induce apoptosis of these cells, but it requires active targeting of various pathways, but it can occur. And when it does, and it is done either genetically or pharmacologically in mice, we see that the mice can reverse damage. So if you take an old mouse and you genetically engineer it to remove senescent cells, that mouse will go from being frail to fit. And if you take a young mouse and you induce senescent cells at a high rate and you accumulate them in that mouse, that mouse, even though it is young, will become frail.  So that has really led to this exciting opportunity of, can we translate this finding that we are seeing in animals and in in vivo cells, cell cultures, into humans? And could that have a benefit beyond just one disease? Could it have a benefit in multiple diseases? And not just really longevity, which I think it would be great, but what people are really looking for is, how do we live healthy as we get older? How do we move the curve so that people are not developing chronic diseases in their 60s, but they are developing them in their 80s towards shortening the period of their life with disability rather than what we have currently, which is people are living to 70s, the average life expectancy is in the mid-70s, but they are spending 10 or 11 years in disability of that life. And so, how could we reduce that time frame? Dr. Monty Pal: This is brilliant, Mina. And for our audience, this compelling dialogue that we have had here thankfully is translating to funding for Mina's work. He just scored in the second percentile for his NIH R01 based on this topic. We are so, so proud of you. I mean, it is just remarkable work. It is not easy in the current climate to get funding, and a second percentile score is just absolutely wonderful. You know, Mina, I could probably go on with you for a couple more hours here talking about your work in cancer and aging. I think I am going to have to have you back on the podcast here. But a million thanks for sharing your thoughts here today on the ASCO Daily News Podcast.  And thanks to our listeners too. If you value the insights that you heard today on the ASCO Daily News Podcast, please do not forget to rate, review, and subscribe wherever you get your podcasts. Thanks, Mina. Dr. Mina Sedrak: Thank you so much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:     Dr. Sumanta (Monty) Pal   @montypal  Dr. Mina Sedrak @minasedrakmd   Follow ASCO on social media:      @ASCO on Twitter     ASCO on Bluesky    ASCO on Facebook      ASCO on LinkedIn      Disclosures:     Dr. Monty Pal:    Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview   Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical   Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis   Dr. Mina Sedrak: Patents, Royalties, Other Intellectual Property: Up-to-Date

Dr. Tanya Thomas and Dr. Aparna Jotwani join the podcast to discuss the new Oncology Nursing Society and American Society of Clinical Oncology evidence-based guideline on the management of antineoplastic extravasation. They discuss recommendations from the expert panel on: management of extravasation of vesicant or irritant with vesicant properties antineoplastic agents, management of extravasation of paclitaxel or docetaxel, use & duration of thermal compress, and escalation of care. They share the importance of this comprehensive interdisciplinary guideline, highlight the algorithm as a useful tool for clinicians, and outline the outstanding questions related to the management of extravasation. Read the full guideline, “ONS/ASCO Guideline on the Management of Antineoplastic Extravasation” at www.asco.org/supportive-care-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the JCO Oncology Practice, https://ascopubs.org/doi/10.1200/OP-25-00579  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Tanya Thomas, clinical chair of the guideline and clinical nurse specialist from University of Virginia Health, and Dr. Aparna Jotwani, medical oncologist from Baylor College of Medicine, authors on "Management of Antineoplastic Extravasation: Oncology Nursing Society – American Society of Clinical Oncology Guideline." Thank you for being here today, Dr. Thomas and Dr. Jotwani. Dr. Aparna Jotwani: Thank you. Dr. Tanya Thomas: Thank you for having us. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Thomas and Dr. Jotwani, who have joined us here today, are available online with the publication of the guideline in JCO Oncology Practice, which is linked in the show notes. So then to dive into the content here, Dr. Thomas, could you start us off by providing an overview of both the scope and the objectives of this guideline? Dr. Tanya Thomas: Yes, so the objective of this guideline is to provide the evidence-based recommendations to help support our interdisciplinary teams, including the oncologist, the advanced practice providers, pharmacists, and nurses who are involved in the care and management of patients who are experiencing an extravasation of an antineoplastic agent. While rare, the antineoplastic and certain chemotherapy extravasations are oncologic emergencies. The recommendations are to minimize negative consequences and provide a standardized approach to the care when such an event occurs. Dr. Aparna Jotwani: I would add that our scope is limited to intravenous antineoplastic vesicants, irritants, and irritants with vesicant potential. The scope of the guideline applies to the care team for adult oncology patients receiving treatments through venous access. Outside the scope is management of extravasation during other routes of treatment administration, such as intraperitoneal, intravesical, and hepatic arterial infusion. Our recommendations regarding vascular access for therapy or interventions to prevent extravasations are also outside of the scope for this guideline. Brittany Harvey: Understood. I appreciate that background and understanding what's in scope and what's out of scope for this guideline. So then I'd like to pivot and talk about the key recommendations of this guideline across the clinical questions. So first, Dr. Jotwani, what does the panel recommend for patients with extravasation of vesicant or irritant with vesicant properties antineoplastic agents? Dr. Aparna Jotwani: The panel strongly recommends for all classes where an antidote exists to proceed with using the antidote. Recommendations for paclitaxel and docetaxel are specifically addressed in a recommendation. This is further detailed in Tables 1 and 4 within the guideline. Evidence on the use of antidotes for extravasation is limited to nonrandomized, uncontrolled, observational studies and case series. Placebo-controlled trials on this topic would be unethical. There is also a lack of comparative data for different antidote strategies. However, potential benefits of using the antidotes include tissue preservation and avoiding tissue necrosis. In developing the guidelines, we had an in-person roundtable discussion and weighed risks and benefits to ensure patient safety above all else. Brittany Harvey: I appreciate that description of the recommendation here. So then you just mentioned that there's a specific recommendation for paclitaxel and docetaxel. So what is recommended for those patients with extravasation of paclitaxel or docetaxel? Dr. Aparna Jotwani: So here, we conditionally recommended the specific use of hyaluronidase as the antidote. This was based on five studies that all used hyaluronidase as an antidote to lower the risk of tissue necrosis. In the studies included, with a subgroup of patients that experienced taxane-related extravasation, development of necrosis ranged from 0% to 0.83% among the patients who received an antidote. The potential harms associated with this were likely trivial. Brittany Harvey: Thank you for providing that recommendation as well. So then the next section of the guideline, Dr. Thomas, what does the expert panel recommend for use and duration of thermal compress? Dr. Tanya Thomas: So the expert panel actually recommends the use of thermal compresses, and the recommendations are based on the available literature for the various agents and the actual time frames most frequently used for the compress application. The utilization of a thermal compress is recommended for 15 to 20 minutes at a time for 3 to 4 times daily, at least for the first 48 to 72 hours after that extravasation occurs. The actual frequency and duration may vary based on the extent of the extravasation and the agent involved in that extravasation. The intent of the warm compress is to help disperse the agent and reduce the localized accumulation of the agent, whereas the cold compress, it actually helps prevent the dispersion or the spread of the agent while allowing the antidote to help neutralize that agent. Warm compresses are recommended for extravasations involving the vinca alkaloids, etoposide, oxaliplatin, and the taxanes - paclitaxel and docetaxel - only when coadministering the antidote hyaluronidase. The use of a cold compress is actually recommended for extravasations involving the anthracyclines, antimetabolites, alkylating agents, and taxanes when coadministration of the antidote hyaluronidase does not occur. Brittany Harvey: Understood. Those specific and actionable recommendations are really key for clinical practice. So then, following those recommendations, how does the guideline address escalation of care and surgical referral for patients with central line extravasation? Dr. Tanya Thomas: So this topic actually had a lot of discussion. And while there is not enough evidence to make strong recommendations, the expert panel recognized that surgical referrals should be considered in certain scenarios. Dr. Aparna Jotwani: We discussed that certain scenarios would include high-risk populations, such as patients that are receiving DNA-binding vesicants, those with high-volume estimated extravasation, and those with CTCAE grade 2, which would be erythema associated with symptoms such as edema, pain, induration, and phlebitis, or grade 3, which would be symptoms of ulceration or necrosis or concern for severe tissue damage, or grade 4, where you would have a life-threatening consequence extravasation, may have a greater likelihood of benefiting from surgical referral and/or escalation of care as deemed appropriate. Brittany Harvey: Great. And yes, it's really important to provide all of these recommendations that you've both just gone through, even when we're faced with very low evidence. So then, Dr. Thomas, in your view, what is the importance of this guideline, and how will it impact clinical practice? Dr. Tanya Thomas: So when extravasations occur in the clinical setting, members of the interdisciplinary team can be faced with barriers related to where to look for the information, how to find all the relevant information in one concise place, how to provide education to the patient about how to care for the site of extravasation in the home setting, and also when to escalate to specialized teams. This can actually cause some added stress and anxiety, and in certain circumstances, may lead to delays in efficient management. This guideline provides the resource clinicians have been looking for. It includes comprehensive recommendations for antineoplastic extravasations in one guideline while also providing a one-page algorithm with the key information regarding the management of the extravasations. This allows all levels of providers to have evidence-based recommendations regarding initial management of the extravasation, for instance, how to manage the infusion, key site assessment reminders, available antidotes, and the use of thermal compress; the required documentation, recommended follow-up scheduling, in addition to key aspects of the patient education. This type of guidance is not found in any other single document regarding antineoplastic extravasation. Having this document readily available at the point of care potentially can reduce time required for providers to search for management recommendations and also provide consistency in patient education and follow-up management scheduling. It reduces uncertainty within interdisciplinary teams and can help inform policy development for clinicians to approach extravasations with confidence. Brittany Harvey: Absolutely. I agree that this is an incredible resource for clinicians with the recommendations, the algorithm that you mentioned, and the supporting evidence that underpins these recommendations to really provide both efficient and effective care for patients. So beyond the impact for clinical practice, Dr. Jotwani, how will these guideline recommendations affect patients receiving antineoplastic treatment for cancer? Dr. Aparna Jotwani: Exactly. In addition to the clinical care team, we want to help and benefit our patients. So, oncology patients that experience extravasations are at risk for, aside of the side effects of tissue necrosis and infection, they also are at risk for delay of cancer treatment. In making these guidelines, we kept in mind the cost and the efforts for patients, additional visits that they could incur, additional time and supplies for care of the extravasation, as well as cost. Our guideline aims to provide an evidence-based approach to the care of oncology patients receiving antineoplastic intravenous therapy. While there are gaps in the data due to the nature of these events, based on careful literature review, these guidelines serve as a basis for quality, standardized oncology care during extravasation. Personally, I hope our graphics especially can be used across the systems to guide clinical care. Brittany Harvey: Definitely. We hope that these recommendations improve treatment and treatment outcomes for all patients receiving antineoplastic treatment for cancer. So then you've also just mentioned some gaps in the literature. So Dr. Thomas, I'd like to turn to you to wrap us up and ask, what are the outstanding questions for the management of antineoplastic extravasation? Dr. Tanya Thomas: Yes, that's a good question. Two of the main outstanding questions are related to the management of extravasations involving the novel agents and extravasations involving multi-agent regimens. The current literature regarding how to effectively manage the multi-agent regimens, for instance, there is no clear guidance for managing the extravasation for someone who is receiving a regimen that involves simultaneous administration of, let's say, a vinca alkaloid and an anthracycline. One of those agents requires a warm compress while the other requires a cold compress, and there are different antidotes for those two agents. Additionally, there has not been a lot of published information on the impact of extravasation of those novel agents like the antibody-drug conjugates. With the pace of the drug development, a subgroup of the guideline panelists actually are exploring case reports specific to novel agents to help inform some future work. Brittany Harvey: Yes, we'll look forward to learning more about how to address these ongoing issues and potentially impact guideline recommendations in the future as well. So I want to thank you both so much for your work to develop this incredibly important guideline, and thank you for your time today, Dr. Thomas and Dr. Jotwani. Dr. Aparna Jotwani: Thank you for the opportunity. Dr. Tanya Thomas: Yes, thank you. Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. I also encourage you to check out the companion episode on this guideline on the ONS podcast, available on Amazon Music, Apple Podcasts, Spotify, and YouTube Music. And finally, you can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

What if art could open the door to a new life after prison? What if creative work wasn't just healing, but a literal job offer?In a time when reentry programs are scarce and trust is hard to rebuild, this episode, the second of our two part series on the work of California Lawyers for the Arts, introduces Designing Creative Futures, a groundbreaking initiative that uses the power of the arts to help formerly incarcerated individuals reclaim their future. With stories from inside and outside the system, we explore how mentorship, hands on creativity and belief in potential can lead to lasting change.In it, we'll hear how a coalition led by California Lawyers for the arts helped over 200 individuals find not just reentry internships, but purpose.We'll learn how mentorship and woodworking in prison and Designing Creative Futures on the outside helped one man, Frank Quiros, discover his calling and build a new life.And we'll discover how storytelling, craft and persistence are reshaping re entry with dignity, creativity and impact Notable MentionsPeopleBill Cleveland – Host of Art Is Change, community arts practitioner, and long-time leader in arts and social change .Alma Robinson – Longtime Executive Director of California Lawyers for the Arts; spearheaded the Designing Creative Futures reentry initiative .Frank Quiroz – Formerly incarcerated artist who rebuilt his life through woodworking, pottery, and arts internships via Designing Creative Futures .Governor Gavin Newsom – California governor who announced early releases during COVID to mitigate prison overcrowding .Ms. Larkey – Daughter of musician Carole King, connected with the People's Pottery Project .Carole King – Iconic singer-songwriter; her daughter was involved in supporting the People's Pottery Project .Jack Reedy – Woodworking mentor and teacher at Taft Correctional Facility who profoundly influenced Frank's artistic and personal growth .Sergeant Rodriguez – Prison staff member who supported incarcerated woodworkers in shipping their creations home .Frank Hernández (Gro) – Artist associated with Self Help Graphics, part of its influential legacy .Patssi Valdez – Chicana artist and founding member of the Asco collective, connected to Self Help Graphics .Marvea – Director at Self Help Graphics who helped connect Frank to work at LACMA .EventsCOVID-19 Early Releases in California (2020) – Governor Newsom's plan to release up to 8,000 incarcerated individuals due to overcrowding and health risks .NEA Our Town Grant (2020) – $100,000 awarded to California Lawyers for the Arts to pilot Designing Creative Futures .California State Contract (2022) – $3 million contract expanding Designing Creative Futures placements to Los Angeles and the Bay Area .Geffen Galleries Opening at LACMA (2025) – $898 million expansion project at LACMA,...

Dr. Kathleen Horst, Dr. Rachel Jimenez, and Dr. Yara Abdou discuss the updated guideline from ASTRO, ASCO, and SSO on postmastectomy radiation therapy. They share new and updated recommendations on topics including PMRT after upfront surgery, PMRT after neoadjuvant systemic therapy, dose and fractionation schedules, and delivery techniques. They comment on the importance of a multidisciplinary approach and providing personalized care based on individual patient characteristics. Finally, they review ongoing research that may impact these evidence-based guidelines in the future. Read the full guideline, “Postmastectomy Radiation Therapy: An ASTRO-ASCO-SSO Clinical Practice Guideline” at www.asco.org/breast-cancer-guidelines" TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-01747  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Kathleen Horst, expert panel chair from Stanford University; Dr. Rachel Jimenez, expert panel vice chair from Massachusetts General Hospital; and Dr. Yara Abdou, ASCO representative from the University of North Carolina, authors on "Postmastectomy Radiation Therapy: An American Society for Radiation Oncology, American Society of Clinical Oncology, and Society of Surgical Oncology Clinical Practice Guideline." Thank you for being here today, Dr. Horst, Dr. Jimenez, and Dr. Abdou. Dr. Kathleen Horst: Thank you for having us. Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Horst, Dr. Jimenez, and Dr. Abdou who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. Then to dive into the content that we are here today to talk about, Dr. Horst, could you start us off by describing what prompted the update for this joint guideline between ASTRO, ASCO, and SSO, and what is the scope of this 2025 guideline on postmastectomy radiation therapy? Dr. Kathleen Horst: Thank you. This joint guideline was last updated in 2016. Over the past decade, the treatment of breast cancer has evolved substantially. Newer systemic therapy regimens have increasingly personalized treatment based on tumor biology, and local therapy management has explored both the de-escalation of axillary surgery and more abbreviated courses of radiation therapy. Given these advances, it was important to revisit the role of postmastectomy radiotherapy in this modern era of breast cancer therapy. This updated guideline addresses four key questions, including postmastectomy radiation therapy after upfront surgery as well as after neoadjuvant systemic therapy. It also reviews the evolving role of various dose and fractionation schedules and optimal treatment techniques and dose constraints. Brittany Harvey: Excellent. I appreciate that background, Dr. Horst. So then, next, Dr. Jimenez, I would like to review the recommendations of this guideline across those four key questions that Dr. Horst just mentioned. So first, what does the panel recommend for PMRT for patients who received initial treatment with mastectomy? Dr. Rachel Jimenez: The panel provided pretty strong consensus that patients with positive lymph nodes or patients with large tumors involving the skin or the chest wall should receive postmastectomy radiation. However, the panel also recognized that the omission of postmastectomy radiation may be appropriate for select patients who have positive lymph nodes and have an axillary lymph node dissection if they have a low nodal burden and other favorable clinical or pathologic features. For patients without lymph node involvement at the time of surgery and no involvement of the skin or chest wall, postmastectomy radiation was not advised by the panel. Brittany Harvey: Understood. It is helpful to understand those recommendations for that patient population. Following that, Dr. Abdou, what are the key recommendations for PMRT for patients who received neoadjuvant systemic therapy before mastectomy? Dr. Yara Abdou: When we think about PMRT after neoadjuvant treatment, the key point is that the initial stage of presentation still matters a lot. So for example, if a patient comes in with more advanced disease, say a large primary tumor, like a clinical T4, or more extensive nodal disease, like an N2 or N3 disease, those patients should get PMRT, no matter how well they respond to neoadjuvant therapy, because we know it reduces the risk of recurrence and that has been shown pretty consistently. On the other hand, if there are still positive lymph nodes after neoadjuvant treatment, basically residual nodal disease, PMRT is also strongly recommended because the risk of local-regional recurrence is much higher in that setting. The gray area is the group of patients who start with a lower burden of nodal disease, such as N1 disease, but then become node negative at surgery. For those patients, we tend to individualize the decision. So if the patient is young or has triple-negative disease, or if there is a lot of residual disease in the breast even though the nodes are cleared, then radiation is probably helpful. But if everything has melted away with pCR in both the breast and the nodes, then it may be safe to omit PMRT in those patients. For patients with smaller tumors and no nodal involvement to begin with, like a clinical T1-T2 N0, if they are still node negative after neoadjuvant treatment, then PMRT is generally not recommended because their baseline recurrence risk is low. And finally, if the margins are positive and cannot be re-excised, then PMRT is recommended after neoadjuvant therapy. Brittany Harvey: Yes, those distinctions are important for appropriate patient selection. So then, Dr. Horst, we have just reviewed the indications for PMRT, but for those patients who receive PMRT, what are the appropriate treatment volumes and dose fractionation regimens? Dr. Kathleen Horst: The guideline addresses coverage of the chest wall and regional nodes with a specific discussion of the data regarding internal mammary nodal irradiation, which has been an area of controversy over many years. The guideline also reviews the data exploring moderate hypofractionation, or shorter courses of radiation therapy. The task force recommends utilizing moderate hypofractionation for the majority of women requiring postmastectomy radiation, which is likely to have a large impact on clinical practice. This recommendation is based on the evolving data demonstrating that a 3-week course of radiotherapy after mastectomy provides similar oncologic outcomes and minimal toxicity for most patients compared to the standard 5-week treatment course. Brittany Harvey: Thank you for reviewing that set of recommendations as well. So then, Dr. Jimenez, to wrap us up on the key questions here, what delivery techniques are recommended for treating patients who receive PMRT? Dr. Rachel Jimenez: So this portion of the guideline is likely to be most helpful for radiation oncologists because it represents the most technical part of the guideline, but we do believe that it offers some important guidance that has, to this point, been lacking in the postmastectomy radiation setting. So first, the panel recommends that all patients should undergo 3-dimensional radiation planning using CAT scan based imaging, and this includes contouring. So contouring refers to the explicit identification, using a drawing interface on the CAT scan imaging, by the radiation oncologist to identify the areas that are targeted to receive radiation, as well as all of the nearby normal tissues that could receive unintended radiation exposure. And we also provide radiation oncologists in the guideline with suggestions about how much dose each target tissue should receive and what the dose limits should be for normal tissues. Additionally, we make some recommendations regarding the manner in which radiation is delivered. So for example, we advise that when conventional radiation methods are not sufficient for covering the areas of the body that are still at risk for cancer, or where too high of a dose of radiation would be anticipated to a normal part of the body, that providers employ a technique called intensity modulated radiation therapy, or IMRT. And if IMRT is going to be used, we also advise regular 3-dimensional imaging assessments of the patient's body relative to the treatment machine to ensure treatment fidelity. When the treatments are delivered, we further advise using a deep inspiration breath-hold technique, which lowers the exposure to the heart and to the lungs when there is concern for cardiopulmonary radiation exposure, and again, that image guidance be used along with real-time monitoring of the patient's anatomy when those techniques are employed. And then finally, we advise that patients receiving postmastectomy radiation utilize a bolus, or a synthetic substance placed on the patient's skin to enhance radiation dose to the superficial tissue, only when there is involvement of the skin with cancer or other high-risk features of the cancer, but not for every patient who receives postmastectomy radiation. Brittany Harvey: Understood. And then, yes, you just mentioned that section of the guideline is probably most helpful for radiation oncologists, but I think you can all comment on this next question. What should all clinicians, including radiation oncologists, surgical oncologists, medical oncologists, and other oncologic professionals, know as they implement all of these updated recommendations? Dr. Rachel Jimenez: So I think one of the things that is most important when we consider postmastectomy radiation and making recommendations is that this is a multidisciplinary panel and that we would expect and encourage our colleagues, as they interpret the guidelines, to employ a multidisciplinary approach when they are discussing each individual patient with their surgical and medical oncology colleagues, that there is no one size fits all. So these guidelines are intended to provide some general guidance around the most appropriate techniques and approaches and recommendations for the utilization of postmastectomy radiation, but that we recognize that all of these recommendations should be individualized for patients and also represent somewhat of a moving target as additional studies, both in the surgical and radiation oncology realm as well as in the systemic therapy realm, enter our milieu, we have to adjust those recommendations accordingly. Dr. Kathleen Horst: Yeah, I would agree, and I wanted to comment as a radiation oncologist, we recognize that local-regional considerations are intertwined with systemic therapy considerations. So as the data evolve, it is critical to have these ongoing updates in a cross-disciplinary manner to ensure optimal care for our patients. And as Dr. Jimenez mentioned, these multidisciplinary discussions are critical for all of us to continue to learn and understand the evolving recommendations across disciplines but also to individualize them according to individual patients. Dr. Yara Abdou: I could not agree more. I think from a medical oncology perspective, systemic therapy has gotten much better with adjuvant CDK4/6 inhibitors, T-DM1, capecitabine, and immune therapy. So these are all newer adjuvant therapies, so the baseline recurrence risks are lower than what they were in the trials that established PMRT. So the absolute benefit of radiation varies more now, so smaller for favorable biology but still relevant in aggressive subtypes or with residual disease. So it is definitely not a one-size-fits-all. Brittany Harvey: Yes, I think it is important that you have all highlighted that multidisciplinary approach and having individualized, patient-centric care. So then, expanding on that just a little bit, Dr. Abdou, how will these guideline recommendations affect patients with breast cancer? Dr. Yara Abdou: So basically, reiterating what we just talked about, these guidelines really move us towards personalized care. So for patients at higher risk, so those with larger tumors, multiple positive nodes, or residual nodal disease after neoadjuvant therapy, PMRT remains essential, consistently lowering local-regional recurrence and improving survival. But for patients at intermediate or lower risk, the recommendations support a more selective approach. So instead of a blanket rule, we now integrate tumor biology, response to systemic therapy, and individual patient factors to decide when PMRT adds meaningful benefit. So the impact for patients is really important because those at high risk continue to get the survival advantage of radiation while others can be spared the unnecessary treatment and side effects. So in short, we are aligning PMRT with modern systemic therapy and biology, making sure each patient receives the right treatment for their situation. Brittany Harvey: Absolutely. Individualizing treatment to every patient will make sure that everyone can achieve the best outcomes as possible. So then, Dr. Jimenez, to wrap us up, I believe Dr. Horst mentioned earlier that data continues to evolve in this field. So in your opinion, what are the outstanding questions regarding the use of PMRT and what are you looking to for the future of research in this space? Dr. Rachel Jimenez: So there are a number of randomized phase III clinical trials that are either in active accrual or that have reported but not yet published that are exploring further de-escalation of postmastectomy radiation and of axillary surgery. And so we do not yet have sufficient data to understand how those two pieces of information integrate with each other. So for example, if you have a patient who has a positive lymph node at the time of diagnosis and forgoes axillary surgery aside from a sentinel lymph node biopsy, we do not yet know that we can also safely forgo radiation entirely in that setting. So we expect that future studies are going to address these questions and understand when it is appropriate to simultaneously de-escalate surgery and radiation. Additionally, there is a number of trials that are looking at ways in which radiation could be omitted or shortened. So there is the RT CHARM trial, which has reported but not yet published, looking at a shorter course of radiation. And so we do make recommendations around that shorter course of radiation in this guideline, but we anticipate that the additional data from the RT CHARM study will provide further evidence in support of that. Additionally, there is a study called the TAILOR RT trial, which looks at forgoing postmastectomy radiation in patients who, to Dr. Abdou's point, have a favorable tumor biology and a low 21-gene recurrence score. And so we are going to anticipate the results from that study to help guide who can selectively forgo postmastectomy radiation when they fall into that favorable risk category. So there are a number of questions that I think will help flesh out this guideline. And as they publish, we will likely publish a focused update on that information to help provide context for our colleagues in the field and clarify some of these recommendations to suit the latest data. Brittany Harvey: Absolutely. We will look forward to those de-escalation trials and ongoing research in the field to build on the evidence and look for future updates to this guideline. So I want to thank you for your work to update these guidelines, and thank you for your time today, Dr. Horst, Dr. Jimenez, and Dr. Abdou. Dr. Rachel Jimenez: Thank you. Dr. Yara Abdou: Thank you. Dr. Kathleen Horst: Thank you. Brittany Harvey: And then finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Featuring an interview with Dr Jacob Sands, including the following topics: Management of Adverse Events of Special Interest Associated with Datopotamab Deruxtecan (Dato-DXd) (0:00) Heist RS et al. Clinical management, monitoring, and prophylaxis of adverse events of special interest associated with datopotamab deruxtecan. Cancer Treat Rev 2024;125:102720. Abstract  Sands J et al. Analysis of drug-related interstitial lung disease (ILD) in patients (pts) treated with datopotamab deruxtecan (Dato-DXd). ASCO 2024;Abstract 8623. Intracranial Efficacy of Dato-DXd for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) with Actionable Genomic Alterations in the TROPION-Lung05 Study (7:23) Lisberg A et al. Intracranial efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously treated advanced/metastatic non-small cell lung cancer (a/m NSCLC) with actionable genomic alterations (AGA): Results from TROPION-Lung05. ASCO 2024;Abstract 8593.  Clinical Evidence Supporting the Combination of Dato-DXd with Immune Checkpoint Inhibition for Advanced NSCLC (12:12) Bessede A et al. TROP2 is associated with primary resistance to immune checkpoint inhibition in patients with advanced non-small cell lung cancer. Clin Cancer Res 2024;30(4):779-85. Abstract Levy BP et al. TROPION-Lung02: Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC). ASCO 2025;Abstract 8501. Waqar SN et al. First-line (1L) datopotamab deruxtecan (Dato-DXd) + rilvegostomig in advanced or metastatic non-small cell lung cancer (a/mNSCLC): Results from TROPION-Lung04 (cohort 5). ASCO 2025;Abstract 8521. Current and Future Development of Antibody-Drug Conjugates in the Treatment of Lung Cancer (17:11) Tawfiq RK et al. Targeting lung cancer with precision: The ADC therapeutic revolution. Curr Oncol Rep 2025;27(6):669-86. Abstract CME information and select publications

Listen to ASCO's Journal of Clinical Oncology Art of Oncology article, "Brown Paper Bags” by Dr. Stephanie Graff, who is an Associate Professor of Medicine at Brown University and Director of Breast Oncology at Brown University Health in Providence Rhode Island. The article is followed by an interview with Graff and host Dr. Mikkael Sekeres. Dr Graff shares how she handled receiving a gift from a patient. TRANSCRIPT Narrator: Brown Paper Bags, by Stephanie Graff, MD, FACP, FASCO  Minor demographic features of the patients described have been altered to honor their privacy “Why are you being weird about opening the bag?” he asks.  The gift that William brought me is still sitting on the edge of the clinic examination room counter, the proverbial elephant in the room. He presented it to me the moment I entered the examination room, excited as a child giving their first Christmas gift. I have demurred, stating I will open it later. I have tried to avoid opening the bag, explaining that I do not like opening gifts in front of people. William is as tenacious about me opening this gift right now as he is about facing his disease. I treat William for male breast cancer. I have always called him William because it is what the electronic medical record says as his preferred name. It is his first name, and when I verified on our first meeting what he preferred to be called, he said “William is fine,” but just like the Sheryl Crow song says, “I'm sure it's Bill or Billy or Mack or Buddy.” 1 William is electric. He lights up the examination room, engages my staff while playfully ribbing them, and has a laugh that reverberates down the hallway. He comes to each visit with a colorful story about the events that have transpired since our last appointment, vividly painting images of his children and grandchildren and his life outside the clinic walls. He swells with pride discussing his grown children like a new mother showing off photos of her baby. “Ryan just finished the most beautiful presentation deck for work. You should see it. Those slides! I bet he would show it to you.” Ryan works in banking or finance or insurance—I cannot remember—but I confess I never took William up on the offer to see the slide deck.  Abruptly, William stands up, moving faster than an elderly patient with metastatic cancer should be able to move. In a single swift movement, he grabs the brown paper bag from where I abandoned it on the counter and drops it in my lap. “Open it!” I sigh deeply, carefully unroll the top, and peek in. “I got those for the mister!” he exclaims. Inside is a bag of Werther's hard caramels. As relief floods me, I laugh a deep, slow laugh of appreciation for this 70-something man and his ability to brighten the world around him in the most surprising ways. During our last clinic visit, he told me hard caramels take the chemotaste out of his mouth, and I had confessed that my husband is also Werther's devotee, but prefers the soft chews. William made a case then and there for the hard caramels and told me I should try to get “Mr Dr Graff” to make the change. He approached the soft caramel versus hard caramel discussion with the intensity of a high school debate champion. Needless to say, the Graff household now alternates our caramels—enjoying both hard caramels and soft chews. “Seriously. What gives with you and the bag?” he probes again. I recognize that William is not going to let this go. He is too astute and persistent. So, I decided to tell him the whole truth about gifts from patients and brown paper bagsThat first year as an oncology fellow, after months on inpatient consults, I finally started outpatient clinics just as the holidays season began. The patients, many of whom had deep and long relationships with the attending oncologists—the same relationships I was eager to build, the relationships that drove me to oncology as a profession—brought in gift after gift, homemade cookies, handmade quilts, and jars of homemade jam. It was rarely something elaborate as the patients knew the faculty could not accept anything too over the top, but it often showed the same tender thoughtfulness that you show a dear friend or favorite relative. Their favorite coffee. A T-shirt of a favorite band. Or something jovial, like a rival sports team or college's coffee mug. It was during this time of the busy holidays, maybe the second week of December, in my own fellow's clinic, that one of my patients with solid tumor arrived with a small brown paper bag. He of course had synchronous primary malignancies that in no way aligned for a simple plan of care and was experiencing dreadful side effects, which seemed to be the way of fellow's clinic. I had been seeing him quite often, pouring every ounce of my nascent skills into trying to help him through his treatment. He handed me the bag, and in my enthusiasm and naivety and holiday spirit, I bubbled with excitement thinking “oh, he brought me a little gift!” But my own thoughts were pouring over him saying “I brought this in for you because…” and as he was saying the rest, I tore open the bag, all the while with my eyes on him as he spoke, and plunged my hand into the bag, grabbing the…what exactly…cloth something…to hear him saying….  “…because I wanted you to see how bad this diarrhea is! Pure liquid. Bloody. Constant. I can't even make it to the bathroom,” he was saying. Yes. I was holding—in my bare hand—his soiled, blood-stained underwear. Merry Christmas. I have not excitedly torn open a mystery gift or plunged my hand into a bag since. This is not a lesson that took more than one time to learn. In retrospect, perhaps my patient did give me a tremendous gift that day. I was given a true under-standing of his side effects, of what it means to have grade 3 diarrhea, hemorrhoidal bleeding, and fecal incontinence. If there was any chance I did not believe patients before that day, I have always believed patients since—no need to bring me evidence in a little brown bag. Thanks. I'm good. By this point in my retelling of the story, William was nearly doubled-over in laughter, red-faced, and barely able to breathe or stay in his chair. Thus, our little ritual began. William continued to bring me gifts in brown paper bags at every visit for the rest of his time as my patient. Always small tokens. A pocket pack of Kleenex during cold season. A can ofsoup “to warm my hands,” which are perpetually cold during physical examinations. A small handmade Christmas ornament. Sometimes, he would put a bag inside a bag, inside a bag…laughing like an evil super villain, while I nervously unpacked his brown paper bags of torture. William elected to go to hospice care appropriately, living a few months with a good quality of life with home hospice. A few weeks after his passing, his son arrived at the registration desk and asked to speak with me. When I went to the front of the clinic to invite him back, to hug him, and tell him how much his father mattered to all of us at the cancer center, he handed me a brown paper bag. “He insisted” was all William's son said. I opened it, genuinely concerned what I might find this time, nervously peeking into the bag. It was a copy of William's obituary, thanking the cancer center for all the care we had shown him and for inviting him to be part of our lives as much as we were a part of his. This is the greatest gift—the gift of impact. Of knowing my care mattered, of knowing we were truly on the same care team. I carry my patients and their families with me through life, recalling their anecdotes, wisdoms, and warnings at just the right moments. I save their precious words in a box of cards I keep at my desk. I also have a collection of hilarious, insightful, peculiar, and profound assortment of little gifts that made a patient think of me—a curio of curiosities, a microcosm of my career. I think this is why patients give these small tokens in the first place—to make tangible the gratitude, the emotion, and the bond that is ex-changed between the patient and the oncologist. In giving, we are connected. Gifts speak for us when the weight of emotion and the vulnerability of truth are too much. A gift says “you matter in my life” as much as a gift says “I want you to feel how life altering the diarrhea I have been experiencing at home has been.” I have received both those gifts. They have changed me. So, I do not know—I am thinking maybe it is time I go back to plunging my hand straight in? Because in the end, somewhere down there at the bottom, that is where all the good stuff is hidden. Mikkael Sekeres: Welcome back to JCO's Cancer Stories: The Art of Oncology. This ASCO podcast features intimate narratives and perspectives from authors exploring their experiences in oncology. I am your host, Mikkael Sekeres. I am Professor of Medicine and Chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami. Today, I am so excited to be joined by Dr. Stephanie Graff, Associate Professor of Medicine at Brown University and Director of the Breast Oncology Program at Brown University Health in Providence, Rhode Island, to discuss her Journal of Clinical Oncology article, "Brown Paper Bags." Our guests' disclosures will be linked in the transcript. Stephanie, I am so excited to have you here. Welcome to our podcast, and thank you for joining us. Dr. Stephanie Graff: It is such an honor to be here and to discuss this with you. Mikkael Sekeres: Stephanie, I have to say, I feel like I know you so well because I have read your writing over years, and there is an intimacy to how you write and an honesty to it where I really feel as if we are sitting together over a table drinking an International House of Coffee mocha blend, talking about our recent trip to Paris. But I am not sure all of our listeners know you quite as well, so I am wondering if you can tell us a little bit about yourself. Dr. Stephanie Graff: Sure. So I am on the JCO Art of Oncology editorial board, and live in Providence. So you and I have many shared interests. I love to write and I love to read, and I think that how you described my writing reflects my communication. I think that I tend to be really honest and open with patients about, about everything, about both myself and their disease. And I think that that is really what you are capturing in my story writing. I am an avid reader. I read just nonstop and write a variety of different styles of writing. I have written several breast cancer related texts, obviously academic papers. I have confessed to you in the past that I write poetry, but it is for myself. It is very unlikely to end up in the pages of JCO. I like writing stories like this when I feel like a story has been percolating in my mind for a while. Mikkael Sekeres: Boy, there is a lot of jumping off points I want to take from what you just said, of course. Maybe we can start with your writing process. What triggers a story and how do you face the dreaded blank page? Dr. Stephanie Graff: I think it is different for different stories. Often, it is something that has been the struggle or the relived experience that I keep turning over. And I find that like when I am walking my dog in the morning or when I am running on the treadmill, that sometimes the same moments keep coming back up in my mind: a difficult patient encounter, a heartwarming patient encounter, a challenging conflict with a peer or colleague. Those are the things that I keep going back to. And I think that as I go back to it over time, I craft that narrative. And crafting the narrative is also what helps me work through the story and cement it as a lesson that I learned from or that becomes a memory that is important to me, and ultimately makes it easy to just sit down and write, which is often, I do just sit down and write the whole story and it comes out pretty much in the form I end up submitting. But I think that that is because I have spent so much pre-contemplative thought before I get to pen to paper. Sometimes it is, with this story, and I think I had said this in my original cover letter with "Brown Paper Bags," one of my nurses, my nurse practitioner, actually had gotten a gift from a patient that was actually wildly inappropriate for her, both as a gift from a patient and for her as an individual. And she had like brought it back to our shared workspace and was like, "Guys, like, what do I do with this?" And it prompted all of us to share our stories of like really fantastic things that patients have given us, really weird things that patients have given us, and just to end up laughing hysterically about the funny moments and getting a little teary-eyed thinking about the way that we hold on to some of those memories. Mikkael Sekeres: I love that whole description. First of all, starting with your writing process. I think we all come out of a room sometimes where we have been meeting with a person, and our stomach just turns. There is something that did not sit right with us about the interaction or there is something that was really special about the interaction. And I think if we are thoughtful people and thoughtful doctors, we ruminate over that for a while and think to ourselves, “What was it that was really special about that, that really worked that I can actually apply to other patients?” Or, “What was it that did not work, that something that went south where I probably need to change my behavior or change how I am entering an interaction so that does not happen again?” Dr. Stephanie Graff: Yeah, I think about it like those, you know, I am sure you have the same experience I do that a lot of your early childhood memories are actually photos of your early childhood that you can remember more clearly because you have the picture of them, and certainly the same is true for my own children. But I think that having that description, that powerful visual description of a photograph from a moment, helps you cement that memory and treasure it. And I think that the same is true with writing, that when we have an experience that if we are able to make it tangible, write about it, turn it into a song, turn it into a poem, turn it into a piece of art, whether that is, you know, an interpretive dance or a painting, whatever your expression is, that is going to be something that becomes a more concrete memory for you. And so regardless of whether it is a good memory or a bad memory, I think sometimes that that is how we learn and grow. Mikkael Sekeres: I think that is spot on. I believe there are some theories of memory also that talk about accessing the memory over and over again so that you do not lose it and you do not lose the connections to it. And those connections can be other memories or they can be anything that occurred with our five senses when the event actually occurred. Dr. Stephanie Graff: Yeah. That- so one of my favorite books is Audrey Niffenegger's book called The Time Traveler's Wife. Have you read that? It is- the gentleman has a, you know, genetic condition in the fictional book that makes him travel in time and he like leaves his body, his clothes are on the floor and travels back and he is drawn to moments that are important to him. So he is drawn back constantly to the moment he met his wife, he is drawn back constantly to the moment his parents died. And I think that that is true, right? Our memory takes us back to those really visceral, important moments over and over again. Mikkael Sekeres: So you mentioned before, one of the jumping off points I wanted to explore a little bit more was when someone gets an unusual gift and brings it back to the workroom and there is that moment when everyone looks at it and the person says exactly what you said, "What do I do with this?" Right? And it is interesting that it is even a question because sometimes there is a really weird gift and there are certain people who would just immediately put it in the trash, but as oncologists, we do not, do we? Dr. Stephanie Graff: No. Mikkael Sekeres: That is not an option, but we want to know what it is we can do with it. So I do not know if you can remember any particularly unusual gifts you received or your colleagues received during that conversation and then what do you do with them? Dr. Stephanie Graff: Yeah, I think that sometimes they are, I mean, honestly, like the truth is is that I have them, right? Like they are all over my life, these little trinkets and doodads, even to the point that sometimes I give gifts that are inspired by my patients, too. Like two Christmases ago, I gave all of my colleagues as their Christmas gift these blown glass octopuses because one of my patients was obsessed with octopi and it like had led to several conversations, and they have obviously eight arms, we all know that, but they have numerous hearts, they have this very complex, empathetic brain, they are thinking and feeling, very cool, cool animals if you really start to learn and read about them. And I really started to think both about how much we had all kind of rallied around this one patient and her unique love of octopi, but also like how much that animal represents what it means to practice team based care, to have this larger than life heart, to feel like you are more than one brain, like you have eight arms because you work with these really great people. So I wrote that much more eloquently than I am doing right now in a card for my team and gave them these glass octopuses for Christmas. And so, you know, I think that our patients, it is not always even a physical gift. Sometimes it is just sharing their stories that ends up staying with us. Mikkael Sekeres: And that must not have been that long after the documentary was released about the man who had this special relationship with an octopus as well. So do you save the gifts given to you by patients? Why or why not? Dr. Stephanie Graff: So, obviously we get a lot of things like food and we just eat that, right? I am sure your clinic is a collection of boxes of chocolates and, so in Rhode Island, there is a lot of Portuguese patients and so we get a lot of like Portuguese bread and things like that too, which is delicious. So we have all sorts of food all the time and that just gets eaten. I do save patients'- and I realize we are not on camera for our viewing audience, but I have bizarrely, so one patient gave me this red devil, which is amazing because Adriamycin, which is obviously a really common breast cancer drug, is called the "red devil." And this is kind of a famous folk art carving by Alexander Girard. I think the actual real one is in Philadelphia at their art museum, but she was like, "You gave me the red devil, so I am going to give you the red devil." And like, I think that is hilarious. Like, I will save that forever. But I have so many other patients that have given me like little angels because I like meant a lot to them or helped them through this difficult moment. And I have all of those things, right? And so I have this kind of funny little shelf of angels and devils in my office, which is, I think, amusing. And then, obviously I wrote about the brown paper bags. You know, that patient filled it with little things like butterscotches and a can of soup and an instant hot cocoa mix. It was stuff that like you can realistically use. It kind of comes and goes. It is not necessarily something that you have forever. I had all three of my children during my time, one in fellowship and two as a practicing oncologist, and I was practicing in the Midwest then. I have a wealth of absolutely gorgeous quilts, baby quilts, that were made by my patients for my kids. And I have saved every single one of those. I can tell you which patient made it for which child because those are just such heirlooms to me. Yeah, lots of really great things. I am curious about you. You have to have these treasures too in your life. Mikkael Sekeres: Oh, absolutely. Isn't it remarkable that people in the face of life threatening illnesses, and I probably have a patient population specializing in acute leukemia and myelodysplastic syndromes where their illness is often more acute than, than your typical patient in your patient population even, but even during those times, I am always so moved how people take the time to ask about us and want to know about our lives as physicians and take the time to give a gift. And sure, I have my own shelf of curios, I think that is how you refer to it in your essay, from patients and it is very meaningful. There was one patient I treated who was a baseball fan. We were both living in Cleveland at the time. I am a Yankees fan. Both my parents are from the Bronx, so they raised me the right way, of course, even though I was raised in Providence, Rhode Island. And she was a Red Sox fan, and every time she came to visit me, she would wear red socks. It became this ongoing joke. She would wear her red socks and I would remember to wear my Yankees socks. So when we reached the five year mark, she was cured of her leukemia, she gave me a framed box of red socks to hang up. So, yeah, we have these stories and they are immediately evocative of the person we took care of and built a relationship, hopefully a long term relationship with. Gift giving in oncology can be nuanced at times. Why do you think patients give gifts and why are they meaningful to us as caregivers? Dr. Stephanie Graff: I mean, I think that gift giving at its heart is sometimes just a more comfortable way to express emotion for so many patients, right? And humans, right? We give gifts to celebrate births, weddings, birthdays, anniversaries, major holidays, right, for our own friends and family. And so it makes sense that that cultural or social tradition exists where we give gifts to acknowledge and celebrate that someone is important and a part of our life. And so often, I think it is just a way for a patient to say, "You have been here for me, I see you, I see the work you do, I appreciate you." So it is a way to say thank you that to any individual patient feels bigger than just the words. Obviously, I want to say as- if any patient stumbles onto this podcast, just the words are more than enough and we do not even need that. Like it is my greatest honor to care for the patients that allow me to enter their lives and care for them. Like, I do not need them to tell me thank you. I certainly do not need them to give me a gift, but I think that is a big part of why patients do it. But I think another part of it is that in many ways, you know, we have all seen that when somebody is diagnosed with cancer, that they have this real reckoning with their family and friends where people that they thought were very good friends do not know how to show up for them. And so sometimes they see these shifting dynamics in their friend groups, especially maybe for our younger patients or mid aged patients that just their friends are so busy. There is lots that goes on, right, that I think that often the gift is saying, "Thank you for showing up." We were a constant in their life during that time and for many of my patients, they do not have that constancy from the other people in their life. And so again, if anyone stumbles onto this podcast and someone in your life that you love is diagnosed with cancer, the most important thing that any of us can do for someone battling a chronic illness is just show up. And I often tell people even uninvited, like, show up and offer to take their laundry back to your house, show up and drop off a meal because I think that the people saying, "Well, let me know what I can do," is not helpful because it is really awkward to tell people what to do when you are battling an illness. Mikkael Sekeres: That notion of presence is just so important and you enunciated it beautifully. When my patients say to me, "Oh, I want to get you something," I always respond the same way that you do. I always say, "Your good health is the greatest gift that I could hope for," and just the, just the words and the presence are enough. I wanted to end quoting you to yourself and asking you to reflect on it. You write, "I carry my patients and their families with me through life, recalling their anecdotes, wisdoms, and warnings at just the right moments." Stephanie, what are those moments when you lean on the anecdotes and wisdom of your patients? Dr. Stephanie Graff: Patients will say things to me about - oh gosh, I will get all teary thinking about it - you know, patients say things to me who are my, you know, stage four metastatic patients about what has mattered to them in life. And it makes it so easy for me to leave that thing undone and go home at the end of the day because none of them say, "It really mattered to me that I spent that extra hour at work or that I got that promotion or that raise." I am in the habit of, when I meet patients for the first time and they are at a visit with their husband or their wife or their partner, I will ask how long they have been together. And when patients tell me that it has been decades, 40, 50, 60 years, I will ask what the secret is, because I am at 17 years of marriage and I'd love to see 63, which is my record for a patient story. And my one patient during a visit, the wife and I were talking and I asked how long they had been married. We had already had a pretty long visit at that point when it came up, and the whole visit, the husband had just sat in the corner, very quiet, had not said a word. For all I know, he could have been nonverbal. And she said, "Oh, we have been married 60 years." And I said, "Oh my gosh, what is the secret?" And before she could even open her mouth, he goes, "Separate bathrooms." I think about it all the time. Like any time I am like annoyed with my husband getting ready in the morning, I am like, "Yep, separate bathrooms. It is the key to everything." Bringing those little moments, those little things that patients say to you that just pop back up into your mind are so wonderful. Like those rich little anecdotes that patients share with you are really things that stay with you long term. Mikkael Sekeres: So it does not surprise me, Stephanie, that you and I have settled on the same line of questioning with our patients. I wrote an Art of Oncology piece a few years ago called exactly that: "What I Learned About Love From My Patients," asking the exact same question. It was a fascinating exploration of long term marriage from people who say, "Oh, you have to have a sense of humor," which you always hear, to some things that were just brutally honest where somebody said, "Well, I could not find anybody better, so I just settled," right? Because they are in the oncologist's office and sometimes people will speak very dark truths in our clinics. But my favorites were always the people where I would ask them and the husband and wife would turn to each other and just hold hands and say, "I do not know, I just love her." And I always thought to myself, that is the marriage for me. Dr. Stephanie Graff: My husband and I trained together. He was a fellow when I was a resident. So we had one rotation together in our entire careers and it was in cardiology. Like he was like the fellow on cardiovascular ICU and I was the resident on cardiology. And the attending had been prodding this woman who had heart disease about how she needed to be more physically active and said something to the extent to the patient about how he could tell that she was more of a couch potato, that she really needed to get more active. Mind you, this is a long time ago. And her husband, I mean, they are older patients, her husband boldly interrupts the attending physician and says, "She may be a couch potato, but she is my sweet potato." And my husband and I every once in a while will quip, "Well, you are my sweet potato" to one another because we still, we both remembered that interaction all these years later. Like, that is love. I do not know what else is love if it is not fighting for your wife's honor by proclaiming her your ‘sweet potato'. Mikkael Sekeres: Well, I cannot say just how much of a treat it has been to have you here, Stephanie. This has been Stephanie Graff, Associate Professor of Medicine at Brown University and Director of the Breast Oncology Program at Brown University Health in Providence, Rhode Island, discussing her Journal of Clinical Oncology article, "Brown Paper Bags." If you have enjoyed this episode, consider sharing it with a friend or colleague or leave us a review. Your feedback and support helps us continue to have these important conversations. If you are looking for more episodes and context, follow our show on Apple, Spotify, or wherever you listen and explore more from ASCO at asco.org/podcasts. Until next time, this has been Mikkael Sekeres. Thank you for joining us. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review.    Guest Bio: Stephanie Graff, MD, FACP, FASCO is an Associate Professor of Medicine at Brown University and Director of Breast Oncology at Brown University Health in Providence Rhode Island   Additional Reading: What My Patients Taught Me About Love, by Mikkael Sekeres    

Dr. Mark Lewis visits Healthcare Unfiltered Express to provide how data presented at major scientific meetings, such as ASCO, needs to be put in context from a patient perspective.

In this episode of SurgOnc Today, we will discuss a few of the practice changing trials presented at the American Society of Clinical Oncology annual meeting this past June. The episode is moderated by Dr. Kelly Hewitt and offers insightful discussion by leaders in medical oncology, including Dr. Jo Chien, Dr. Laura Kennedy and Dr. William Gradishar.  Highlights include discussion of results from COMPASS Her2, SERENA-6 and the current state and utility of circulating tumor DNA in patients with early-stage breast cancer.

Host Dr. Shannon Westin and guest Dr. Hani Babiker discuss the JCO article "Tumor Treating Fields With Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study." TRANSCRIPT TTFields in Locally Advanced Pancreatic Adenocarcinoma Dr. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth with manuscripts that have been published in the Journal of Clinical Oncology. I am your host, gynecologic oncologist Shannon Westin, social media editor at the JCO, and just excited to be here to learn today about pancreatic cancer. None of our participants have conflicts of interest related to this podcast, and it is my honor to introduce Dr. Hani Babiker. He is an associate professor of medicine, consultant in oncology at the Mayo Clinic in Jacksonville, Florida. Welcome, Dr. Babiker. Dr. Hani Babiker: Hi, Dr. Westin. Thank you for the great opportunity to discuss our trial, and thank you for having me here. I really appreciate it, and I am excited. Dr. Shannon Westin: All right, so are we. So we are going to be talking about “Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: A Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study.” This was simultaneously published and presented in the JCO and at the annual meeting of ASCO on 5/31/2025. So, let's level set. Can you speak to us just a little bit about pancreatic cancer? What is the survival, and what is the typical treatment for locally advanced disease? This gynecologic oncologist has not kept up in this field. Dr. Hani Babiker: Absolutely, Dr. Westin, and thank you for that question. Pancreatic adenocarcinoma is a lethal cancer. When I first started my career, the 5-year survival, per the Surveillance, Epidemiology, and End Results, was at 4.5%. I always, whenever I was giving talks, say that I really hope that I will see it in the double digit. Now, the 5-year survival for all pancreatic adenocarcinoma is 13.3%. And the 5-year survival, and although it is a double digit, I still hope that I will see it in a higher double digit in the future. It is even worse in patients with metastatic cancer, about 3% 5-year survival for metastatic pancreatic cancer. It is a dismal diagnosis. I really hope in the future we will find a better therapeutic approach to this lethal cancer. Dr. Shannon Westin: Yes, I just lost a very dear friend and colleague to this disease, so I completely agree with you. Well, now that we are settled kind of with the basics here, I would love to talk a little bit about kind of the primary piece of this intervention, the Tumor Treating Fields. So, how does this work? And what diseases has it gotten indications in as yet? Dr. Hani Babiker: Absolutely. So, Tumor Treating Fields is alternating frequency electrical fields that have been studied preclinically and shown that it abrogates cancer cell proliferation. Earlier on, we knew that it inhibits polymerization of tubulin, and hence, it affects cancer cells from proliferating. Later, we are learning that there are multiple mechanisms of action. It affects permeability, allowing for better drug delivery. It also inhibits cancer cell proliferation through affecting autophagy mechanisms that pancreatic cancer cells will use for proliferating and becoming more aggressive. There is also some early data preclinically in colorectal cancer cell lines and lung cancer cell lines and in vivo models showing that it potentially could activate the microenvironment to make it more pro-immunogenic. We recently published papers showing that it could also affect the nanomechanical properties of the tumor microenvironment within pancreatic cancer, hinting towards affecting, potentially, the stroma. So, there are multiple mechanisms to Tumor Treating Electric Fields. It is a new, novel therapeutic approach. Sometimes when I speak with my trainees, I say, "Well, we have surgery, we have radiation and chemotherapy, and this is something new." Tumor Treating Fields initially was studied in refractory GBM and got an indication there. Subsequently, frontline treatment of GBM in a randomized clinical trial, and then malignant pleural mesothelioma and non-small cell lung cancer. We have studied it in pancreatic cancer. Dr. Shannon Westin: I don't think I have ever heard it described so perfectly. That was brilliant. So thank you, and I hope everyone listening knows that you just got a masterclass on this mechanism. You know, they dabbled in it a little bit in ovarian cancer and it didn't quite make the grade, so I was a little definitely disappointed. But very excited about the data we're going to talk about today. So let's get into the PANOVA-3 study. Can you highlight the overall design and also the key eligibility criteria that would be helpful for our listeners? Dr. Hani Babiker: Absolutely. So, it started off with preclinical work in pancreatic cancer showing Tumor Treating Fields with chemo abrogate cancer cell perforation. It led to a trial, the PANOVA-2 trial, that was run in Europe that showed efficacy for OS and PFS in patients with locally advanced pancreatic cancer, which included metastatic and locally advanced pancreatic cancer, more so in locally advanced that led to the PANOVA-3 trial, which was an international, global study. This was in more than 190 centers, 20 countries in Latin America, North America, Europe, and Asia. It was a randomized trial. Patients were randomized 1 to 1 to either chemotherapy with gemcitabine plus nab-paclitaxel per drug label. The other arm was with Tumor Treating Fields at 150 kHz for a recommendation for patients to wear it 18 hours per day. The primary end point of the trial was OS, overall survival. The secondary end point included other efficacy landmarks such as local PFS, pain control, quality of life, and safety. And there was a post hoc that looked at distant PFS. Dr. Shannon Westin: That's a pretty common secondary end point in pancreatic studies of looking at the pain-free interval. I thought that was really brilliant because, you know, I think in gyn cancers, we see resolution of symptoms as being a really big deal, but it's not necessarily something that we always look at. So I thought that was really nice that you included that. Okay, talk to us a little bit about the population. So, the population that actually got treated in PANOVA-3 is pretty generalizable to what people are treating in the clinic. Dr. Hani Babiker: So, in pancreatic cancer, unfortunately, most of our patients present, approximately 80%, with metastatic disease. Local is divided to resectable, borderline, and locally advanced. We studied this trial, a randomized trial, in locally advanced and unresectable, which is really an unmet need. Most of our patients with locally advanced and unresectable are grouped up with other trials in the metastatic setting without a focus on locally advanced and unresectable, save for a few trials. This year, a trial that we were looking for for a long time, the LAPLACE trial, unfortunately, that we were very excited about, this is a molecule that targeted connective tissue growth factor, that showed earlier efficacy in a randomized trial, did not meet up the median OS end point. And hence, PANOVA-3 is the first trial in locally advanced and unresectable that did meet its primary end point. So, it's a very unmet need in locally advanced and unresectable. A lot of the times, our patients in clinic are treated with frontline chemotherapy that was studied in metastatic disease and locally advanced and unresectable, which include either FOLFIRINOX, NALIRIFOX, or gemcitabine/abraxane. I do have in my clinic multiple patients that would stay on the regimen for such a long time, and then we would have to devise a mechanism of maintenance, although this is not studied really in details, either with capecitabine or dropping the oxaliplatin to continue FOLFIRI. And then we also approach chemoradiotherapy. So the trial was in a disease in pancreatic cancer that really is an unmet need. So the inclusion criteria included a patient with locally advanced and unresectable. These were done at multiple centers. Most of them academic centers were discussed at the tumor board, and if it's unresectable, they will be meeting specific metrics of appropriate liver function tests, kidney function tests, and blood counts. We excluded patients that obviously had, given that these are electric fields, patients that have, for example, stimulators or pacemakers, knowing that this could potentially affect some of these devices. But for the most part, it was locally advanced and unresectable patients with a very good performance status and good counts. Dr. Shannon Westin: That's great. I think everyone's excited to hear about the primary outcome of overall survival. What did you find, and how does it compare to some of the recent trials? Dr. Hani Babiker: We're very excited that it did meet its primary end point of median overall survival. It was very exciting knowing that a lot of us were disappointed a little bit of some of the trials that were presented at ASCO GI, such as the LAPLACE trial that I alluded to. Just before the presentation, the PRODIGE 29 trial that is in locally advanced and unresectable that randomized patients with locally advanced disease to either FOLFIRINOX or single-agent gemcitabine, allowing for a crossover, although it did meet its primary end point of PFS, there was no overall survival benefit. So that kind of got us a little bit disappointed, but having the PANOVA-3 trial being positive in median OS got us all excited. In addition, the 12-year overall survival rate was increased in both the intention-to-treat and modified intention-to-treat. The modified intention-to-treat were patients that have had at least one cycle of therapy with TTFields daily and/or one cycle with chemotherapy, which was gemcitabine plus nab-paclitaxel. There was a trend to improvement in PFS and local PFS, although that did not have statistical significance, but the 12-year PFS rate in both the intention-to-treat and modified intention-to-treat was significant. For me, as one of the investigators, that told me that there might be a specific biomarker that would tell me that patients could respond greater than others, more exceptional than others, given that 12-month PFS rate was improved. On a post hoc analysis, the distant PFS was improved with the intervention of Tumor Treating Fields with gemcitabine plus nab-paclitaxel. In addition, there was an improvement in global health status and quality of life in addition to pain-free survival, which is a strong hurdle in our patients with pancreatic adenocarcinoma that most present with significant abdominal pain. Dr. Shannon Westin: One of the other questions that I think has come up is around central review. So did you all use central review in this study? Dr. Hani Babiker: Most of the centers were academic centers. These were discussed in tumor boards, which included radiation oncologists and surgeons. I wanted to point out that it's very important to note that the primary end point was overall survival. So the primary end point was not PFS. Hence, the central review would help us, for example, with elaborating and making sure patients were actually locally advanced disease, but in a setting where the primary end point is overall survival, that was the key point of the clinical trial. This trial was discussed at academic centers, and all included tumor boards to decide if patients were locally advanced or not. In the trial, there was a good proportion of patients, or percentage, that had a CA 19-9 more than 1000. That could indicate that potentially there are a fraction of patients that actually had metastatic disease, micrometastatic disease. So that could hint towards why the median OS was slightly lower then in both arms when compared to, for example, the trial that was presented at ASCO GI, the LAPLACE trial. However, having said that, we were very excited about the trial. It was the first positive trial in locally advanced and unresectable to meet median OS survival. Dr. Shannon Westin: It's so awesome. So congratulations. Okay, so let's talk a little bit about your very detailed secondary end points because you had a lot of really prudent choices there. So anything that was interesting or informative in those end points? Dr. Hani Babiker: One major hurdle back we have for most of our patients with pancreatic adenocarcinoma, like I mentioned earlier, is pain. We try to approach it, obviously, with narcotics. If it doesn't work, we try to do celiac axis block interventionally, and that sometimes is successful and sometimes is not. So actually, to see the pain-free survival end point to be met was very exciting for us. And as for me, as a scientist that studies TTFields in clinic and lab as also to develop a mechanism and understanding really how that works. That was very important for us that in addition to chemotherapy, it improved pain-free survival or deterioration of pain. And most importantly, our patients with pancreatic cancer, this disease is very aggressive. It affects quality of life of patients. Patients feel fatigued, tired. It's a procoagulant tumor that causes clots and strokes, etcetera, marantic endocarditis. And one big problem we deal with when we're seeing patients in clinic is obviously that quality of life. Although data have shown with treatment, with frontline regimens, that quality of life improves with treatment and chemotherapy, it's actually great to see that that improvement happens early in addition to Tumor Treating Fields. The other interesting point was that it was not only pain and quality of life, but also digestive symptoms that are improved with this intervention, knowing that a lot of our patients do have pancreatic cancer, pancreatic exocrine insufficiency that affect also with digestion, and a lot of our patients have abdominal pain after eating and diarrhea. So it was interesting to see that also improved with the intervention. Dr. Shannon Westin: You have touched a little bit on some of the adverse events, kind of with the TT mechanisms, but I'd love to hear a little bit more detail around adverse events in general in this study, as well as specific AEs related to the Tumor Treating Fields. Dr. Hani Babiker: Absolutely. So when we compared both arms, there was a similar toxicity related to the regimen, mostly with chemotherapy, but in specifically to Tumor Treating Fields, there was a rash, and that included dermatitis and rash. Most of the side effects were grade 1 and grade 2. Grade 3 toxicities related to skin was less than 10%, approximately 7% to 8%, and hence did not affect many patients. But it was something to note, and it's something that in the future, when we develop a mechanism of treating patients to note early. We in our clinic have learned to treat patients in the clinical trial early with topical steroids to each patient, of shifting the arrays to mitigate some toxicity and rash. We do advise our patients in hot areas, we keep them aware that sweating, for example, can lead to higher conductivity of electrical fields with a predisposition for rash. So if there's an opportunity to stay in a little bit of a cold area, make sure that the arrays are shifted, use topical steroids early. If it's a significant rash, to hold treatment for at least 48 hours and speak to the investigators. And through these mechanisms, we have learned that we were able to mitigate the rash quite a bit. Dr. Shannon Westin: That's awesome. Thank you so much. Yeah, I'm, it's summer right now, and I think- I'm in Texas, you're in Florida, like we know. Okay, so I guess, again, you have been kind of touching on this, but I would love to know, like if in the quality-of-life assessments or if just in your discussions with patients, like how easy is this to use? How easy is the Tumor Treating Fields device to use, and what do patients really think? Dr. Hani Babiker: Absolutely. We have learned that whenever we speak with patients, it's always good to discuss with them briefly the science of it. A lot of patients would want to know if it's interventional, is that something that goes, is delivered percutaneously or not, and we explain that these are delivered through arrays that are through the skin. We always touch base with them about a lot of question I get about mechanism of action and then about compliance. So I think one important thing to note is that compliance with the use of the device is a lot of the question we'll get quite a bit. Patients know there's going to take an effort from them, and some of my patients enjoyed it because they felt like they also are fighting the disease by wearing the device. I have learned very quickly that having a team, surrounded by a team that knew how to mitigate some of the side effects and knew how to explain how to use the device helped quite a bit. And this included some of our nurses and our nurse practitioners and our clinical research coordinators who've done a wonderful job of showing these arrays actually to patients before they start on the trial, look at it, know how it works. The other point to know is that the sponsor provided Device Support Specialist, we call them DSS, they have been instrumental in helping us, helping the patients know how to use the device, how to use the generator, how to change the batteries, and that helped us conduct the trials and enroll very well. I would envision in the future with education and relying on the Device Support Specialist and having a team that knows how to use the device and mitigate some of the side effects will go a long way for patients to learn about this treatment. Many of the times our patients said while they are on the clinical trial felt like they are also being part of this team in applying the device and fighting the cancer. Dr. Shannon Westin: That's awesome. Well, I guess the bottom line. Is it ready for prime time? Is this something you are going to use for your patients in the clinic? Dr. Hani Babiker: Absolutely. In a disease that has poor prognosis, and we are trying our best to find new treatments to fight this cancer and treatment modalities, presenting patients with all the treatment options that are out there would be recommended. It's what I would do it for in my clinic. And you know, it's funny that I am mentioning that right now. I had a patient who was seen internationally asking about the trial and the device and had locally advanced and unresectable before they start frontline treatment. I do think that there is going to be an educational piece. Obviously, this is not a pill, it's not an intravenous chemotherapy that we're very well and accustomed to. And some of us in academic centers know it very well. I usually joke that whenever I am talking about it in pancreatic cancer, if there is a radiation oncologist in the room, they will be like, "Yeah, we know all about it. We have been treating patients with GBM over there." So a lot of the times, when we first went to trial, if I had any questions, I would call them and ask them. So from their perspective, they, because they use it as a standard of care in treatment of GBM, they develop significant expertise in it. I think in the GI world, specifically and with oncologists that treat pancreatic cancer and specifically oncologists in the community, learning about the device and how to use it, how to recommend it, how to mitigate side effects, will be hopefully for prime time in the future. Dr. Shannon Westin: That's great. Sounds like some real educational opportunities there. Well, this has been awesome. Thank you so much, Dr. Babiker. I mean, I learned a ton, and I wish that we could find a way to use this in gynecologic cancers, but really, really just want to commend you on the design of the trial and the success in this really devastating disease. So again, this was "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: A Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study." And as always, I am your host, Shannon Westin. Please go check out our other offerings wherever you get your podcasts and have an awesome day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Dr. Babiker Disclosures Consulting or Advisory Role: Endocyte, Celgene, Idera, Myovant Sciences, Novocure, Ipsen, Caris MPI, Incyte, Guardant Health Speakers' Bureau: Guardant Health Research Funding:  Spirita Oncology, Novocure, AstraZeneca, JSI, Incyte, Qurient, HiFiBiO Therapeutics, Revolution Health Care, Elevation Oncology, Dragonfly Therapeutics, Zelbio, BMS, Mirati Therapeutics, Strategia        

JCO fellow Dr. Ece Cali speaks with JCO Associate Editor Dr. Thomas E. Stinchcombe to discuss the JCO article "Phase 2 Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Exon 20 Insertion Mutations (WU-KONG1B)", that was simultaneously released at the IASLC 2025 World Conference on Lung Cancer. TRANSCRIPT Dr. Ece Cali: Hello, and welcome to our series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's most important oncology meetings. I am your host, Dr. Ece Cali, JCO editorial fellow, and I am joined by Dr. Tom Stinchcombe, JCO associate editor, to discuss the Journal of Clinical Oncology article and 2025 World Conference on Lung Cancer abstract presentation, “Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non–Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations.” The WU-KONG1B trial is a multinational, phase II study that investigated the efficacy and safety of different doses of sunvozertinib in patients with metastatic non-small cell lung cancer and EGFR exon 20 insertion mutations after progression on platinum based chemotherapy. Tom, before we dive into the results, could you walk us through the rationale for this study, and how does it fit into the current treatment options for patients with EGFR exon 20 insertion? Dr. Tom Stinchcombe: Thank you, Dr. Cali. I think the clinical context is always important. We have known that EGFR exon 20 insertions exist and that they are resistant to our currently available EGFR tyrosine kinase inhibitors, and I think there have been attempts in the past to develop a tyrosine kinase inhibitor, but there is a very narrow therapeutic window between the dose you need to inhibit the EGFR mutation in the cancer and the EGFR receptor on normal tissues, most notably the mucosa, the gut, and the skin. And so, our previous attempts have failed largely because the dose required was not tolerable for patients and they could not really stay on the drug for a long time or they were not very active. And so, I think there was a real desire to develop an EGFR tyrosine kinase inhibitor, and then, historically, the standard had been a platinum based doublet as the standard of care. And more recently, platinum based doublet with amivantamab has proven to be superior to platinum based chemotherapy alone. I think the context is also important that amivantamab is not necessarily available in all the countries, and so, there are patients who do not have access to amivantamab. Going to the rationale, I think that this drug had shown preliminary promise of having activity but without that being encumbered by those EGFR wild type toxicities, and, therefore, it was really explored in this larger study. Dr. Ece Cali: And what are some key findings from this trial? Dr. Tom Stinchcombe: So, I think that we should look at the study design. It is a little quirky, for lack of a better term, in that there is a randomization to 200 versus 300 mg, and then, there was a nonrandomized cohort of 300 mg. So, when you look at the study, if you are a purist, you will just look at the randomized patients. If you are sort of an aggregator, you look at all patients. So, it shows reporting on three cohorts, but I think the key findings are that the 200 mg and the 300 mg treatments had similar toxicities in terms of response rate, duration of response, and progression free survival. And as you know going through the review, there was a lot of queries from the reviewers as to which would be the preferred dose, and to me, I think this really illustrates a dose finding component to a trial design because there is a lot of debate about what the minimal effective dose is or the optimal dose. And in this case, having the two dose cohorts did provide us some valuable efficacy and toxicity information. And then, when I look at the study, I want to make sure it reflects my patient population, and about a quarter of patients had brain metastases, and about 15% had previous amivantamab, and about 5% to 10% had another EGFR tyrosine kinase inhibitor. Dr. Ece Cali: And what is the objective response rate and the duration of response? These are pretty good numbers for this patient population. Dr. Tom Stinchcombe: In the 200 mg cohort, it was about 46%. The duration of response was around 11 months, and the PFS was around 8 months. The 300 mg cohort was 46%, duration of response 9.8, and the median PFS is 6.9 months, and I think that this is greater activity than we have seen with our previous attempts at EGFR tyrosine kinase inhibitors. Dr. Ece Cali: And based on these data, FDA granted accelerated approval for sunvozertinib very recently at 200 mg once daily dosing in this setting. So, that is a major step forward for our patients. Dr. Stinchcombe, how does this impact your clinical practice, and what side effects should oncologists be watching for if they prescribe this medication? Dr. Tom Stinchcombe: So, I think it was very interesting that they chose the 200 mg dose, which I think was more tolerable, and when we kind of look at this, there still was a rate of diarrhea, all grade, rash, paronychia, which are the EGFR related toxicities. There can be some decreased appetite, stomatitis, and then, it can lead to some lab abnormalities, like increased CPK and creatinine that physicians have to be aware of. You know, how it will affect my practice is that all these patients had received a platinum based chemotherapy as the first line therapy. I think that this would become my preferred second line therapy for patients outside the context of a trial because of the activity and the tolerability. Dr. Ece Cali: And lastly, several other tyrosine kinase inhibitors are being evaluated for EGFR exon 20 insertion, including in the frontline setting. So, what are some of the outstanding questions in this space, and what data should our listeners keep an eye on moving forward? Dr. Tom Stinchcombe: I think you are right that now, there is going to be another EGFR tyrosine kinase that may become available in the next year, and there is another drug, furmonertinib, that is being investigated. I think, for the clinical question, is, well, can we move these into the first line setting? And actually, the development path has two ways of doing this. There is EGFR tyrosine kinase compared to platinum based chemotherapy, and then, platinum based chemotherapy with an EGFR tyrosine kinase versus platinum based chemotherapy, and both have their merits and strengths. And so, I think it is going to be very interesting as we see if those first line trials, one, can they be demonstrated to be superior to platinum based chemotherapy, and then by what magnitude and what the side effects are. But I think we are hoping that in the next couple of years, we will have an additional first line option for our patients. Dr. Ece Cali: Yeah, it is always great to have more options for our patients. Thank you, Dr. Stinchcombe, for speaking about the JCO article, “Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations.” Join us again for the latest JCO simultaneous publications. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of World Lung Conference. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. 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    

Dr. Halmos from Montefiore in New York shares his views on the most impactful practice changing or informing data for lung cancer from the ASCO 2025 meeting.

Dr. Sumanta (Monty) Pal and Dr. Petros Grivas discuss innovative new intravesical therapies and other recent advances in the treatment of non-muscle invasive bladder cancer. TRANSCRIPT Dr. Sumanta (Monty) Pal: Hello and welcome. I'm Dr. Monty Pal here at the ASCO Daily News Podcast. I'm a medical oncologist and professor and vice chair of academic affairs at the City of Hope Comprehensive Cancer Center in Los Angeles. And I'm really delighted to be your new host here. Today's episode is going to really sort of focus on an area near and dear to my heart, something I actually see in the clinics, and that's bladder cancer. We're specifically going to be discussing non-muscle invasive bladder cancer, which actually comprises about 75% of new cases. Now, in recent years, there's been a huge shift towards personalized bladder-preserving strategies, including innovative therapies and new agents that really are reducing reliance on more primitive techniques like radical cystectomy and radiation therapy. And I'm really excited about this new trend. And really at the forefront of this is one of my dear friends and colleagues, Dr. Petros Grivas. He's a professor in the Department of Medicine and Division of Hematology Oncology at the University of Washington. It's going to take a while to get through all these titles. He's taken on a bunch of new roles. He is medical director of the International Program, medical director of the Local and Regional Outreach Program, and also professor in the Clinical Research Division at the Fred Hutch Cancer Center. Petros, welcome to the program. Dr. Petros Grivas: Thank you so much, Monty. It's exciting for me to be here. Dr. Sumanta (Monty) Pal: Just FYI for our audience, our disclosures are available in the transcript of this episode.  We're going to get right into it, Petros. Non-muscle invasive bladder cancer, this is a really, really challenging space. We see a lot of recurrence and progression of the disease over time, about 50% to 70% of patients do have some recurrence after initial treatment, and about 30% are ultimately going to progress on to muscle-invasive or metastatic disease. Now, I will say that when you and I were in training, non-muscle invasive bladder cancer was something that was almost relegated to the domain of the urologist, right? They would use treatments such as BCG (Bacillus Calmette-Guérin) in a serial fashion. It was rare, I think, for you and I to really enter into this clinical space, but that's all changing, isn't it? I mean, can you maybe tell us about some of the new therapies, two or three that you're really excited about in this space? Dr. Petros Grivas: Monty, you're correct. Traditionally and conventionally, our dear friends and colleagues in urology have been managing patients with non-muscle invasive bladder cancer. The previous term was superficial bladder cancer. Now, it has changed, to your point, to non-muscle invasive bladder cancer. And this has to do with the staging of this entity. These tumors in superficial layers of bladder cancer, not invading the muscularis propria, the muscle layer, which makes the bladder contract for urine to be expelled. As you said, these patients have been treated traditionally with intravesical BCG, one of the oldest forms of immunotherapy that was developed back in the 1970s, and this is a big milestone of immunotherapy development. However, over the years, in the last 50 years, there were not many options for patients in whom the cancers had progression or recurrence, came back after this intravesical BCG. Many of those patients were undergoing, and many of them still may be undergoing, what we call radical cystectomy, meaning removal of the bladder and the lymph nodes around the bladder. The development of newer agents over the last several years has given the patients the option of having other intravesical therapies, intravesical meaning the delivery of drugs, medications inside the bladder, aiming to preserve the bladder, keep the bladder in place. And there are many examples of those agents. Just to give you some examples, intravesical chemotherapy, chemotherapy drugs that you and me may be giving intravenously, some of them can be given inside the bladder, intravesical installation. One example of that is a combination of gemcitabine and docetaxel. These drugs are given in sequence one after the other inside the bladder, and they have seen significant efficacy, good results, again, helping patients keeping the bladder when they can for patients with what we call BCG unresponsive non-muscle invasive bladder cancer. And again, there's criteria that the International Bladder Cancer Group and the FDA developed, how to define when BCG fails, when we have BCG unresponsive non-muscle invasive bladder cancer. Dr. Sumanta (Monty) Pal: And we're actually going to get into some of the FDA requirements and development pathways and so forth. What I'm really interested in hearing, and I'm sure our audience is too, are maybe some of the new intravesical treatments that are coming around. I do think it's exciting that the gemcitabine and docetaxel go into the bladder indeed, but what are some of the top new therapies? Pick two or three that you're excited about that people should be looking out for in this intravesical space. Dr. Petros Grivas: For sure, for sure. In terms of the new up-and-coming therapies, there are a couple that come to mind. One of them is called TAR-200, T-A-R 200. This agent is actually a very interesting system. It's an intravesical delivery of a chemotherapy called gemcitabine, the one that I just mentioned a few minutes ago, that is actually being delivered through what we call a pretzel, which is like a rounded [pretzel-shaped] structure working like an osmotic pump, and that is being delivered inside the bladder intravesically by urologists. And this drug is releasing, through the osmotic release mechanism, this chemotherapeutic drug, gemcitabine, inside the bladder. And this can be replaced once every 3 weeks in the beginning. And the data so far from early-phase trials are really, really promising, showing that this agent may be potentially regulatory approved down the road. So TAR-200 is something to keep in mind. And similarly, in the same context, there is a different drug that also uses the same mechanism, and this osmotic release, this pretzel, it's just encoded with a different agent. The different agent is an FGFR inhibitor, a target therapy called erdafitinib, a drug that you and me may give in patients with metastatic urothelial carcinoma if they have an FGFR3 mutation or fusion. And that drug is called TAR-210. Dr. Sumanta (Monty) Pal: And can I ask you, in that setting, do you have to have an FGFR3 mutation to receive it? Or what is the context there? Dr. Petros Grivas: So for TAR-210, TAR-2-1-0, usually there is a checking to see if there is an FGFR3 mutation or fusion. And the big question, Monty, is do we have adequate tissue, right? From a limited tissue on what we call the TURBT, right, that urologists do. And now there is a lot of development in technology, for example, urine circulating tumor DNA to try to detect these mutations in the urine to see whether the patient may be eligible for this TAR-210. Both of those agents are not FDA approved, but there are significant promising clinical trials. Dr. Sumanta (Monty) Pal: So now let's go to a rapid-fire round. Give us two more agents that you're excited about in this intravesical space. What do you think? Dr. Petros Grivas: There is another one called cretostimogene. It's a long name. Dr. Sumanta (Monty) Pal: They really make these names very easy for us, don't they? Dr. Petros Grivas: They are not Greek names, Monty, I can tell you, you know. Even my Greek language is having trouble pronouncing them. The cretostimogene, it's actually almost what we call a growth factor, a GM-CSF. The actual name of this agent is CG0070. This is a replicating mechanism where GM-CSF is replicating in cells. And this agent has shown significant results again, like the TAR-200, in BCG unresponsive non-muscle invasive bladder cancer. I would say very quickly, two agents that actually were recently approved and they're already available in clinical practice, is nadofaragene firadenovec, another long name. That's a non-replicating vector that has the gene of interferon alfa-2b that stimulates the immune system in the bladder. It's given once every 3 months. And the last one that was, as I mentioned, already FDA approved, it's an interleukin-15 superagonist. It's another long name, which is hard to pronounce, but I will give it a try. It's a drug that was recently actually approved also in the UK. The previous name was N-803. It's given together with BCG as a combination for BCG unresponsive non-muscle invasive bladder cancer. Dr. Sumanta (Monty) Pal: This is a huge dilemma, I think, right? Because if you're a practicing, I'm going to say urologist for the moment, I guess the challenge is how do you decide between an IL-15 superagonist? How do you decide between a pretzel-eluting agent? How do you decide between that and maybe something that's ostensibly, I'm going to guess, cheaper, like gemcitabine and docetaxel? What's sort of the current thinking amongst urologists? Dr. Petros Grivas: Multiple factors play into our account when the decision is being made. I discuss with urologists all the time. It's not an easy decision because we do not have head-to-head comparisons between those agents. As you mentioned, intravesical chemotherapy with gemcitabine and docetaxel has been used over the years and this is the lowest cost, I would say, the cheapest option with good efficacy results. Obviously, the nadofaragene firadenovec every 3 months and the interleukin-15 superagonist, N-803, plus BCG have also been approved. The question is availability of those agents, are they available? Are they reimbursed? Cost of those agents can come into play. Frequency of administration, you know, once every 3 months versus more frequent. And of course, the individual efficacy and toxicity data, preference of the patients; sometimes the provider, the urologist, may have something that they may be more familiar with. But we lack this head-to-head comparison. Of course, I want to make sure I mention that radical cystectomy may still be the option for appropriate patients. So that complicates also the decision making and has to be individualized, customized, and personalized, taking into account all those factors. And there is not one size fitting all. Dr. Sumanta (Monty) Pal: So I think we discussed five intravesical therapies. As you point out, and you know, I'm going to get some calls about this: I think I referred to radical cystectomy as being a more primitive procedure. Not true at all. I think it's something that still is, you know, a mainstay of management in this disease space. But I guess it gets even more complicated, am I right, Petros? Because now we have systemic therapies that we can actually apply in this non-muscle invasive setting for at this point, refractory disease. Can you maybe just give us a quick two-minute primer on that? Dr. Petros Grivas: Absolutely, and systemic therapies now come into play, as you said. And a classical example of that, Monty, came from the KEYNOTE-057 trial that we published about 6 years ago. This is intravenous pembrolizumab, given intravascularly, intravenously, as opposed to the previously discussed intravesical administration of agents. Pembrolizumab was tested in that KEYNOTE-057 trial and showed efficacy about, I would say, one out of five patients, about 20%, had a complete response of the tumor in the bladder in a year after starting the treatment. Again, it's hard to compare across different agents, but obviously when we give something intravenously, there is a risk of toxicity, side effects systemically, what we call immune-related adverse events. And this can also play in the decision making, right? When you have intravesical agents versus intravascular agents, there is different toxicity profiles in terms of systemic toxicity. But intravenous pembrolizumab has been an option, FDA approved, since, if I remember, it was early 2020 when this became FDA approved. There are other agents being tested in this disease, but like atezolizumab through the SWOG study that Dr. Black and Dr. Singh led, but atezolizumab is not FDA approved for this indication. Again, this is for BCG unresponsive, high-risk, non-muscle invasive bladder cancer. Dr. Sumanta (Monty) Pal: So maybe teach us how it works, for instance, at an expert center like the Fred Hutch. When you see a patient with non-muscle invasive bladder cancer, there's obviously the option of surgery, there's the intravesical therapies, which I imagine the urology team is still really at the helm of. But then, I guess there has to be consideration of all options. So you've got to bring up systemic therapy with agents like pembrolizumab. In that context, are you involved that early on in the conversation? Dr. Petros Grivas: That's a great discussion, Monty. Paradigm is shifting as we mentioned together. The urologists have been treating these patients and still they are the mainstay of the treaters, the managers in this disease. But medical oncologists come to play more and more, especially with the FDA approval of intravenous pembrolizumab about 5 years ago [GC1]  [KM2] . We have the concept of multidisciplinary bladder cancer clinic here at Fred Hutch and University of Washington. This happens every Tuesday morning, and we're very excited because it's a one-stop shop for the patients. We have the urologist, a medical oncologist, radiation oncologist, and experts from radiology and pathology, and we all review cases specifically with muscle-invasive bladder cancer. But every now and then, we see patients with BCG unresponsive non-muscle invasive bladder cancer. And this is where we discuss and we talk to the patient about pros and cons of all those options. And that's a classic example where medical oncologists may start to see those patients and offer their input and expertise. In addition to that, sometimes we have clinical trials, we may see these patients because there are systemic agents that may be administered in this setting. We have the SunRISe trial program that includes also a systemically administered checkpoint inhibitor. So that's another example where we see patients either in the context of multi-clinic or in individual solo clinics to counsel the patients about the pros and cons of the systemically administered agents in the context of clinical trials. Usually checkpoint inhibitors are the class of agents that are being tested in this particular scenario. Dr. Sumanta (Monty) Pal: I can see a scenario where it's really going to require this sort of deep dive, much in the way that we do for prostate cancer, for instance, where the medical oncologist is involved very early on and planning out any sort of systemic therapy component of treatment or at the very least, at least spelling out those options. I think it's going to be really interesting to see what this space looks like 5 or 10 years down the road. In closing, I wanted to go through something that I think is so different in this space, at least for the time being, and that is the paradigm for FDA approval. When you and I have our fellows in the clinics, we always say, “Look, you know, the paradigm in this disease and that disease and the other disease needs to be phase 3 randomized trials, right? Big thousand patient experiences where you're testing clinical endpoints.” That's tough in non-muscle invasive bladder cancer, right? Because thankfully, outcomes can actually be quite good, you know, in this setting, right? It's tough to actually estimate overall survival in some of these early-stage populations. Tell me what the current regulatory bar is, and this is a tough thing to do in 2 minutes or less but tell me where you see it headed. Dr. Petros Grivas: You alluded to that before, Monty, when I was giving the background and we talked about the regulatory approval. And I have to very quickly go back in time about 10 years ago because it's important for context that can help us in other disease types too. We had workshops with the FDA and the NCI with the help of the International Bladder Cancer Group and other colleagues. And we try to define a framework, what endpoints are meaningful for those patients in this disease. It was a multidisciplinary, multiple stakeholders meeting, where we tried to define what is important for patients. What are the available agents? What are the trial designs we can accept? And what are the meaningful endpoints that the regulatory agencies can accept for regulatory approval? And that was critical in that mission because it allowed us to design clinical trials, for example, single-arm trials in a disease where there was no standard of care. There was intravesical valrubicin and chemotherapy anthracycline that was approved for many years, but was not practically used in clinical practice, despite being approved, the valrubicin. And because of that, the FDA allowed these single-arm trials to happen. And obviously the endpoint was also discussed in that meeting. For example, for carcinoma in situ, complete response, clinical complete response, because the bladder remains intact in many patients, clinical complete response was a meaningful primary endpoint, also duration of response is also very important. So what is the durable clinical complete response in 1 year or 18 months is relevant. And when you have papillary tumors like Ta or T1 with CIS, for papillary tumors, event-free survival becomes one of the key endpoints and you look at it over time, for example, at 12 or 18 months, what is the event-free survival? So clinical complete response, duration of response, event-free survival, depending on the CIS presence or papillary tumors, I think these are endpoints that have allowed us to design those trials, get those agents approved.  Now, the question going forward, Monty, and we can close with that is, since now we have the embarrassment of riches, many more options available compared to where we were 6 and 7 years ago, is now the time to do randomized trials? And if we do randomized trials, which can be the control group? Which of those agents should be allowed to be part of the control group? These are ongoing discussions right now with the NCI, with other agencies, cooperative groups, trying to design those trials and move forward from here.[GC3]  Dr. Sumanta (Monty) Pal: Well, it's awesome to have you here on the program so we can get some early looks into some of these conversations. I mean, clearly, you're at the table at a lot of these discussions, Petros. So I want to thank you for sharing your insights with us today. This was just tremendous. Dr. Petros Grivas: Thank you, Monty. You know, patients in the center, I just came back from the Bladder Cancer Advocacy Network meeting in Washington, D.C., and we discussed all those questions, the topics you very eloquently mentioned and asked me today, and patients gave us great feedback and patients guide us in that effort. Thank you so, so much for having me and congratulations for the amazing podcast you're doing. Dr. Sumanta (Monty) Pal: Oh, cheers, Petros, thanks so much.  And thank you to the listeners who joined us today. If you really like the insights that you heard on this ASCO Daily News Podcast, please rate, review, and subscribe wherever you get your podcasts. Thanks, everyone. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers:      Dr. Sumanta (Monty) Pal  @montypal  Dr. Petros Grivas @PGrivasMDPhD   Follow ASCO on social media:     @ASCO on Twitter    ASCO on Bluesky   ASCO on Facebook     ASCO on LinkedIn     Disclosures:    Dr. Sumanta (Monty) Pal:   Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview  Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical  Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis  Dr. Petros Grivas: Consulting or Advisory Role: Merck, Bristol-Myers Squibb, AstraZeneca, EMD Serono, Pfizer, Janssen, Roche, Astellas Pharma, Gilead Sciences, Strata Oncology, Abbvie, Bicycle Therapeutics Replimune, Daiichi Sankyo, Foundation Medicine, Bicycle Therapeutics, Eli Lilly, Urogen Pharma, Tyra Biosciences Research Funding (Inst.): Bristol-Myers Squibb, Merck, EMD Serono, Gilead Sciences, Acrivon Therapeutics, ALX Oncology, ALX Oncology, Genentech Travel, Accommodations, Expenses: Gilead Sciences

Featuring an interview with Dr Erika Hamilton, including the following topics: Monitoring, mitigating and managing adverse events with antibody-drug conjugates (ADCs) for breast cancer (0:00) Heist RS et al. Clinical management, monitoring, and prophylaxis of adverse events of special interest associated with datopotamab deruxtecan. Cancer Treat Rev 2024;125:102720. Abstract Management protocols for adverse events associated with sacituzumab govitecan (7:49) García JMP et al. Prevention of sacituzumab govitecan (SG)-related neutropenia and diarrhea in patients with triple-negative or HR+/HER2- advanced breast cancer (ABC; PRIMED): A phase 2 trial. ASCO 2024;Abstract 1101. Pérez-García JM et al. Prevention of sacituzumab govitecan-related neutropenia and diarrhea in patients with HER2-negative advanced breast cancer (PRIMED): An open-label, single-arm, phase 2 trial. eClinicalMedicine 2025;85:103309. Abstract Datopotamab deruxtecan for patients with breast cancer brain metastases or leptomeningeal disease (10:51) Tarantino P et al. DATO-Base: A phase II study of DATOpotamab deruxtecan for patients with breast cancer brain metastases or leptomeningeal disease. ASCO 2025;Abstract TPS1134. Sequencing ADCs in breast cancer (13:12) Pacholczak-Madej R et al. Sequencing of antibody drug conjugates in breast cancer: Evidence gap and future directions. Biochim Biophys Acta Rev Cancer 2025;[Online ahead of print]. Abstract CME information and select publications

Welcome back to the Oncology Brothers podcast! In this episode, we continue the three-part CME series on small cell lung cancer, focusing on adverse events and management strategies for extensive stage small cell lung cancer treatments. We are thrilled to have Dr. Misty Shields from the Indiana University join us to discuss the latest advancements in treatment options following the exciting data presented at ASCO 2025. We dived into the treatment algorithm for patients with good performance status, including the use of chemoimmunotherapy, lurbinectedin, and tarlatamab. Key topics covered in this episode: •⁠  ⁠Overview of the current treatment landscape and new data from ASCO 2025 •⁠  ⁠Common side effects associated with lurbinectedin and immunotherapy •⁠  ⁠Strategies for managing adverse events, including hematologic toxicities and liver function monitoring •⁠  ⁠The role of supportive care and palliative care in enhancing patient quality of life •⁠  ⁠Collaboration between community oncologists and academic centers for optimal patient care Join us as we explore the challenges and opportunities in managing extensive stage small cell lung cancer, and learn how to provide the best care for patients facing this devastating disease. Accreditation/Credit Designation Physicians' Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physicians' Education Resource®, LLC designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Acknowledgment of Commercial Support This activity is supported by an educational grant from Jazz Pharmaceuticals, Inc. Link to gain CME credits from this activity: https://www.gotoper.com/courses/practical-considerations-and-future-directions-for-new-treatment-strategies-in-sclc Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ #SCLCtoxicity #Lurbinectedin #Tarlatamab #SupportiveOncology #CMEoncology

At the latest ASCO-2025 meeting, Dr. Chris Booth shared the results of a study showing that adjuvant structured exercise improves overall survival in colon cancer. He joins Healthcare Unfiltered EXPRESS to detail the study, its findings, and what is next. Please share and join the conversation.

In this special edition episode, recorded live at the ASCO Annual Meeting, hosts Shikha Jain, MD, and Edward Kim, MD, honor Healio's 2025 Disruptive Innovators for their positive disruption in the field of hematology/oncology, and for pushing the status quo to improve clinical practice.  •    Welcome to the fourth annual Healio Disruptive Innovator Awards in hematology/oncology. 1:00 •    VK Gadi, MD PhD, presents the Health Equity Award. 3:56 •    The Health Equity Award winner, Ana Velázquez Mañana, MD, makes a speech. 6:00 •    Morgan Collier presents the Woman Disruptor of the Year Award. 7:38 •    Betty S. Pace, MD, accepts the Woman Disruptor of the Year Award. 9:19 •    The Social Media Influencer Award, presented by Eleonora Teplinsky, MD. 11:53 •    Amani Jambhekar, MD, also known as @ajvictorymd on Instagram and TikTok, accepts the Social Media Influencer Award. 13:13 •    Brenda M. Nevidjon, MSN, RN, FAAN, presents the Advanced Practice Trailblazer Award. 14:40 •    Ashley Leak Bryant, PhD, RN, OCN, FAAN, delivers her acceptance speech for the Advanced Practice Trailblazer Award. 16:19 •    Kamal Jethwani, MD, MPH, presents the Patient Voice Award. 18:44 •    Founder Kimberly Richardson, MA, accepts the Patient Voice Award for the Black Cancer Collaborative. 20:44 •    Healio's chief content officer, Joan-Marie Stiglich, ELS, presents the NextGen Disruptor Award to Nazli Dizman, MD. 22:22 •    The Clinical Innovation Award goes to UNC Lineberger Comprehensive Cancer Center for their at-home symptom reporting, led by Ethan Basch, MD, MSc. 24:18 •    Hope S. Rugo, MD, wins the Lifetime Disruptor Award. 26:48 •    The Industry Breakthrough Award goes to Breyanzi (lisocabtagene maraleucel, or liso-cel) from Bristol Myers Squibb. 30:57 •    On behalf of Bristol Myers Squibb, Amy Corrao, MSN, NP-C, accepts the Industry Breakthrough Award. 32:33 •    Thanks to all of the winners, nominees and sponsors! 35:39 •    Thanks for listening. 36:21 We'd love to hear from you! Send your comments/questions to Dr. Jain at oncologyoverdrive@healio.com. Follow Healio on X and LinkedIn: @HemOncToday and https://www.linkedin.com/company/hemonctoday/. Follow Dr. Jain on X: @ShikhaJainMD. Read the full coverage from Healio's Disruptive Innovators here.

Dr. Cris Bergerot and Dr. Enrique Soto join the podcast to discuss the new global guideline on geriatric assessment. This guideline provides evidence-based, resource-stratified recommendations across the basic, limited, and enhanced settings. Dr. Bergerot and Dr. Soto discuss who should receive a geriatric assessment, the role of geriatric assessment, which elements of geriatric assessment can help predict adverse outcomes, and how a geriatric assessment is used to guide care and make treatment decisions. They comment on the importance of this guideline worldwide, and the impact of this guideline for a wide range of clinicians, patients, researchers, policymakers, and health administrators.   Read the full guideline, “Geriatric Assessment: ASCO Global Guideline” at www.asco.org/global-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/global-guidelines. Read the full text of the guideline, view clinical tools and resources, and review authors' disclosures of potential conflicts of interest in the JCO Global Oncology,       https://ascopubs.org/doi/10.1200/GO-25-00276       Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Cris Bergerot from OncoClínicas & Co and Dr. Enrique Soto from the University of Colorado, co-chairs on “Geriatric Assessment: ASCO Global Guideline”. Thank you for being here today, Dr. Bergerot and Dr. Soto. Dr. Cris Bergerot: Thank you. Dr. Enrique Soto: Thanks for the invitation, Brittany. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bergerot and Dr. Soto who have joined us here today, are available online with the publication of the guideline in JCO Global Oncology, which is linked in the show notes. So then to jump into the guideline here, Dr. Soto, could you start by providing an overview of the scope and the purpose of this global guideline on geriatric assessment? Dr. Enrique Soto: Of course, Brittany. So, this guideline comes from a request from the global oncology community and from the geriatric oncology community, who is very interested in making sure that geriatric oncology recommendations that are used in the United States can be adopted and used globally. So, this was a very highly rated topic when we had our call for proposals for guidelines, and that's why we decided to do this. The idea of this guideline is to provide resource-stratified recommendations for the use of geriatric assessments and interventions in older adults with cancer across different settings, right? And that these guidelines can be applied by clinicians working in low- and middle-income countries, but also, in a way, by clinicians working in community settings where the availability of resources may be limited. And the idea of these recommendations is to help clinicians evaluate older people with cancer better and also understand which interventions can be implemented with the resources they have and which interventions have a bigger bang for the buck, so to speak. And as all evidence-based, stratified guidelines that ASCO conducts, we stratified resources as basic, limited, or enhanced. And that means resources that go from those that provide the greatest benefits for patients in terms of outcomes to those that are evidence-based but provide additional additive benefits. And those resource-stratified recommendations can be found in the ASCO website as to how these guidelines are developed, and that's pretty standard for most resource-stratified guidelines. Brittany Harvey: Great. I appreciate that background and the impetus for this guideline, and thank you for providing that resource-stratified framework of basic, limited, and enhanced. I think that helps provide context for the guideline recommendations here. So then, Dr. Bergerot, I'd like to next review the key recommendations of this guideline across the four clinical questions that the guideline addresses. So, across those settings, the basic, limited, and enhanced settings, what is the role of geriatric assessment in older adults with cancer to inform specific interventions? Dr. Cris Bergerot: I think this is one of the most important points, so let's break it down. First off, who should actually receive the geriatric assessment? And the recommendation is clear. All patients aged 65 and older who are being considered for systemic cancer therapy should undergo a geriatric assessment. Now, depending on the available resources, for example, in basic setting, a quick screening may be enough, but in enhanced setting, a comprehensive geriatric assessment is encouraged. And for our next question, in which elements of the geriatric assessment can help predict poor outcomes, the core domains to focus on include things like physical function, comorbidities, polypharmacy, cognition, nutrition, social support, and psychological health. And there are also validate tools like the G8, the CGA, and the CARG that can be used depending on the setting and resources available. Now, talking about how we actually use the geriatric assessment to guide care, the assessment results can guide interventions to reduce treatment-related toxicities and maintain the patient functions. So, even in basic settings, the result can help guide those adjustments or identify the need for supportive care. And in more resource settings, we can implement more tailored intervention based on those findings. And finally, for our fourth question: How can geriatric assessment help guide treatment decisions? So, GA can influence decisions about how aggressive treatment should be, help clarify goals of care, and determine whether a curative or palliative approach makes the most sense. And again, even in settings with limited resources, a simplified GA can still provide meaningful guidance. Brittany Harvey: Great. Thank you, Dr. Bergerot, for that high-level overview of the recommendations of this guideline. So then, following that, Dr. Soto, which geriatric assessment tools and elements should clinicians use to predict adverse outcomes for older patients receiving systemic therapy across the basic, limited, and enhanced settings? Dr. Enrique Soto: Yeah, so that is an excellent question because it's something that people want to know, right? When people start developing a geriatric oncology clinic, one of the first things they want to know is which tools should I use. And we hope that this guideline will provide some clarity regarding this. So, our overarching recommendation is that every patient, regardless of the level of resources, should receive some sort of geriatric assessment. And that geriatric assessment can go from a simple screening tool, such as the G8 tool, which is available online and very easy to do, and that can be done in basic settings, to a more sophisticated geriatric assessment. The important thing, and what we emphasize in the guideline, is that regardless of the tool you use, it should include those high-priority domains that are associated with outcomes in older adults with cancer. And those include an assessment of physical function, of cognition, emotional health, comorbidities, polypharmacy, nutrition, and social support. In addition to that, an important thing that the guideline does is endorse the recommendation from our parent guideline, the guideline from high-income settings, the practical geriatric assessment, which is a tool that was actually developed by the ASCO Geriatric Oncology Group, which is a self-administered tool that people can use to evaluate their patients in a prompt and fast manner. And what we actually did for this guideline is include the validation of the various tools included in the practical geriatric assessment in the five most widely spoken languages in the world, including Hindi, Chinese, Spanish, and French, and Portuguese. And so, most of these tools are validated in these languages. So, we believe that the practical geriatric assessment is a tool that can be utilized across settings and that doesn't require a lot of resources. I think an important future step is making sure that we get the practical geriatric assessment translated into various languages, and we're working with the ASCO team in getting that done. Brittany Harvey: That's an excellent point. And yes, we'll hope to have the practical geriatric assessment translated into more languages. And that tool is available linked in the guideline itself, and we'll also provide a link for listeners in the show notes of this episode (Practical Geriatric Assessment). So then, following that, Dr. Bergerot, in resource-constrained settings, what general life expectancy data should clinicians use to estimate mortality and inform treatment decision-making? Dr. Cris Bergerot: So, in basic and limited resource environments, you might not have access to every tool or specialist, but you can still make informed and thoughtful decisions. So, what the guideline recommends is to start with population-level life expectancy tables. These are available through the WHO Global Health Observatory, and they offer useful starting points. And if available, clinicians should also look for country-specific or regional survival data. That kind of local information can be even more relevant to your patient population. The clinical judgment is also key here, and it becomes even more powerful when it's guided by the patient's geriatric assessment results. And when possible, use age- and comorbidity-adjusted models, like the Lee index or tools from the ePrognosis. This can help refine estimates of mortality risk and also inform how aggressive treatment should be. Brittany Harvey: Absolutely. I appreciate you providing those specifics as well. So then, following that, Dr. Bergerot mentioned this a little bit earlier, but Dr. Soto, how should geriatric assessment be used to guide management of older patients with cancer across the basic, limited, and enhanced settings? Dr. Enrique Soto: Yeah, and again, that's another important focus, right? Because if we assess things and then don't do anything about them, then why even assess them, right? And in many settings, people say, “Well, I don't have the tools to provide the interventions that these patients actually need.” And a very significant part of building this guideline was coming up with a resource-stratified and evidence-based way in which to prioritize which interventions provide most benefits for older adults with cancer. And so, for each level and each domain, we have a series of interventions that have been stratified according to importance and evidence base, and that is actually one of the coolest features of the guideline. We included a table, and then we have for each of the domains, including falls, functional status, weight loss, et cetera, what are the interventions that oncologists can do in their clinical visit without needing a lot of resources, including providing some specific information, giving some recommendations to patients, to more high-level things that can be done when the healthcare system allows it, such as working with a nutritionist, providing supplements, testing for particular cognitive impairments, et cetera. So, I encourage people to take a look at that table. It was really a lot of work putting that table together, and that table has specific recommendations for each setting, and I think people will find it very useful. Brittany Harvey: Absolutely. That table certainly contains a lot of information that's very helpful for clinicians. I think it's important to call out those tailored interventions to improve care and quality of life for every patient. So then, we've just reviewed all of the recommendations in this guideline. So, I'd like to ask you, Dr. Bergerot, in your opinion, what should clinicians know as they implement these recommendations across resource levels? Dr. Cris Bergerot: I would say that clinicians should remember that even a brief geriatric assessment can make a meaningful difference. You don't need a full suite of tools to improve quality of care, but clinicians should tailor all the tools that are available in their local context and always keeping in mind the core geriatric domains that we have mentioned in the very beginning of our podcast. And let's be clear, the goal of the assessment isn't just to gather data, as Enrique mentioned; it's to use this information to guide treatment decision and also to improve outcomes. And whenever possible, clinicians should engage interdisciplinary teams that might include nurse, psychologist, social workers, community health workers, or anyone who can help address the patient's broader needs. And flexibility really matters. So, especially in settings with limited access to specialists or diagnostics, we should prioritize what is feasible and what will truly help our patients during their journey. And above all, we should keep this in mind that equity in care delivery is essential. Just because resources are limited doesn't mean we can't deliver age-sensitive and even patient-centered care. Brittany Harvey: Definitely. That multidisciplinary care that you mentioned is key, and also thinking about what is feasible across every resource level to provide optimal care for every single patient. So then, to expand on that just a little bit and to wrap us up, Dr. Soto, what is the impact of this guideline for older adults with cancer globally? Dr. Enrique Soto: Well, what we hope this guideline will lead to is to a boom in geriatric oncology worldwide, right? That is our final goal. And what we want is for clinicians interested in starting a geriatric oncology program or setting up a geriatric oncology clinic to use these guidelines in order to justify the interventions that they're going to do, to pick the important partners they need for their multidisciplinary team, to choose the tools that they're going to implement. And then, with that, to present this to leaders in their hospitals, leaders in their healthcare system so that they can start these clinics that will ultimately lead to better outcomes for older adults with cancer. So, I encourage people to view this as high-quality, evidence-based recommendations that are done by a group of experts and with a thorough review of the literature and also based on our parent guidelines. The fact that these guidelines are resource-stratified does not by any mean signify that they're of less quality or that the recommendations that are included in those are not proven to improve outcomes, cancer-specific and also general outcomes, in older adults with cancer. Another thing that I think these guidelines could do in the future is motivate researchers in low- and middle-income countries to fill in the gaps that we have identified in these guidelines. We've made it very clear across the guidelines where evidence is lacking. And I think that this should prompt researchers across the globe to start trying to fill in these gaps with high-quality research. And finally, I also think that this is a call for policymakers, health administrators, and people interested in public health to start scaling up resources so that places with basic resources can eventually become places with more sophisticated resources. And I think this does not only apply to low- and middle-income countries, but also to community oncologists in the US who may be facing resource constraints. And I think that these guidelines can help them stratify and understand what things should be implemented first and how to scale up. So yeah, that's the dream that with this guideline, more people will start implementing geriatric oncology around the globe and that ASCO will continue to be a leader in setting the stage for what should be done in geriatric oncology and for improving care to older adults with cancer, regardless of where they live. Brittany Harvey: Absolutely. This guideline is wide-reaching and has important impacts worldwide. So, I want to thank you both so much for the huge amount of work you took to develop this evidence-based guideline, and thank you for joining me on the podcast today, Dr. Bergerot and Dr. Soto. Dr. Cris Bergerot: Thank you so much. Dr. Enrique Soto: Thank you for the invitation. It was a pleasure. Brittany Harvey: And finally, thank you to our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/global-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

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