Podcasts about tp53

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

Dr. Jyoti Patel is back on the podcast to discuss the updates to the living guideline on therapy for stage IV NSCLC with driver alterations. She shares updated recommendations in the first- and second-line settings for patients with stage IV NSCLC and classical EGFR mutations, and the impact of these updates for clinicians and patients. We also look to the future to discuss ongoing developments in the field. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-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-24-02785     Brittany Harvey: 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. Jyoti Patel from Northwestern University, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3.” It's great to have you back on the show today, Dr. Patel. Dr. Jyoti Patel: Thanks so much. Happy to be here. 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. Patel, who has joined us here today, are available online with the publication of the guideline and in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content of this update, Dr. Patel, this clinical practice guideline for systemic therapy for patients with stage IV non small cell lung cancer with driver alterations is living, meaning that it's continuously reviewed and updated. So what data prompted this latest change to the recommendations? Dr. Jyoti Patel: Thanks so much. So it's really been an exciting time in the treatment of EGFR lung cancer, particularly this past year has required us to rethink approaches to front- and second-line therapy. In this particular update, we examined what patients in the front-line setting may be offered by their clinicians. And so we're talking about the population of classical EGFR mutations, so exon 19 and exon 21 L858R substitution. And so certainly for this population, osimertinib has a high level of evidence and should be offered to all patients at the time of diagnosis when they present with advanced disease. Our last update included a recommendation that patients could also get platinum doublet chemotherapy with osimertinib or osimertinib alone. This current recommendation also introduces another alternative therapy and that's the combination of amivantamab plus lazertinib. And so now, clinicians are faced with three really good options for their patients with EGFR exon19 deletion or L858R. Brittany Harvey: It's great to hear that there's this advance in the space, particularly for patients with these classical EGFR mutations that you mentioned. So what should clinicians know as they implement these new first-line recommendations? Dr. Jyoti Patel:  I think it's become more complex than ever. Certainly, we know again that patients should get osimertinib in the frontline setting. But we've been kind of stuck at progression-free survival that's between a year and a half and two years. And so we've really been looking at opportunities to intensify therapy. So one could certainly be with chemotherapy or switching over to amivantamab, the bispecific antibody that targets EGFR and MET plus lazertinib, an oral TKI that's very similar in structure to osimertinib. And when you're talking to a patient, it's really a conversation about balancing efficacy with toxicity. Unfortunately, as we know, there aren't that many free lunches. And so if we think about what a patient is hoping for in their therapy and how we can further personalize treatment options, really is important to look at some of the analyses for this study. So in the study of amivantamab plus lazertinib, we know that there were increased toxicities with a combination of both therapies. In fact, up to 75% of patients had over grade 3 toxicities, versus about 43% of patients with osimertinib monotherapy. And we know if we look back at FLAURA2, almost two thirds of patients with osimertinib and chemotherapy had grade 3 toxicities, compared to 27% of patients with osimertinib alone. So we certainly see an increase in toxicities. Then we have to ask ourselves, are those paper toxicities or ones that really impact patients? And we know that amivantamab, for example, causes significant cutaneous toxicities. With both of these therapies, whether it's chemotherapy or adding amivantamab, there's the burden of infusional visits and increased time in the doctor's office. Certainly with chemotherapy, there can be an increased incidence of myelosuppression. And so when we're thinking about advising our patients, certainly we need to talk about the toxicities. But one thing that we've been able to do is to look at the patients that were included in this trial. And what we really find is that in higher risk cohorts, particularly those that we know historically have done less well with standard osimertinib, so patients, for example, with CNS metastasis, for those patients with co-mutations, it may be that that additive benefit is significant. And so one example I think would be from the MARIPOSA study, again, the study of amivantamab and lazertinib versus chemotherapy. What we can say is that patients who had co-mutations, so patients with EGFR mutations as well as TP53, lazertinib and amivantamab led to a hazard ratio of 0.65 compared to osimertinib alone. So that was 18.2 months versus 12.9 months. And so this may be really important to patients. And we also see conversely that patients with wild type TP53, so those patients who didn't have the mutation, probably had equivalent survival regardless of therapy. So certainly, we need to prospectively study some of these high-risk cohorts. We've only seen progression-free survival in these studies. And so at this juncture, we can advise our patients about toxicity, the improvements in certain categories of progression-free survival, but we really still don't know how this pans out in overall survival. In many of these studies, all patients do not necessarily cross over to the study arm and so they may have lost the benefit of subsequent therapy. Brittany Harvey: Absolutely. It's very important to talk about that balance of benefits and risks and particularly those toxicities that you discussed. So I appreciate reviewing that recommendation and the considerations for clinicians for first-line therapy. This update also included a second-line treatment update. What is that update for patients with EGFR alterations? Dr. Jyoti Patel: So this is where it gets super tricky because we have a frontline option with amivantamab and now we've had an update in the second line option. So what we said is that for patients who have progressed on an EGFR TKI, and in the United States, certainly that's predominantly osimertinib, or those in other parts of the world that may have gotten an earlier generation TKI, but do not have evidence of T790M or other targetable mutations, we can offer patients chemotherapy with or without amivantamab. And so certainly we have seen that this again leads to improved survival. There have also been a number of studies looking at incorporation of PD-L1 and anti-VEGF therapies. And what we can say, I think pretty clearly is that multiple phase 3 trials have really shown no benefit of the addition of PD-1 to platinum chemotherapy. But there are some emerging bispecific antibodies that may target PD-1 as well as VEGF, or combinations of antibodies that target both of those pathways that may improve outcome. At this juncture, I think we feel that the evidence surrounding chemotherapy plus amivantamab is strongest, but there is certainly work in this space that will be of interest. Now, what happens if your patient received amivantamab and lazertinib in the frontline setting and then has progression? And so we're trying to understand resistance mechanisms and opportunities for treatment. What the panel decided to recommend, based on the available evidence, was that certainly those patients should get platinum-based chemotherapy, but there may also be a role for antivascular endothelial growth factor targeting therapy such as bevacizumab in patients in whom it would be safe. Brittany Harvey: Great. I appreciate you detailing those recommendations when it gets complicated in the second-line setting. So what should clinicians know as they implement these second-line recommendations too? Dr. Jyoti Patel: So certainly the frontline setting matters significantly. So if a patient gets osimertinib in the frontline setting, we generally suggest that patients undergo repeat testing to see if they have another targetable mutation. If they don't, then I think preferred therapy would be chemotherapy with or without amivantamab. And amivantamab leads to a significant improvement in progression-free survival and response rate at the cost of increased risk of toxicity. For patients who get FLAURA2 in the frontline setting, chemotherapy plus osimertinib, it's a little bit of an unclear space. Those patients most likely would get docetaxel with or without ramucirumab. But there are other agents that we hope to have available to our patients in the near future. For patients who receive amivantamab and osimertinib, we recommend that those patients get chemotherapy probably with anti-VEGF as demonstrated by multiple trials that have shown the improved progression-free survival with introduction of an anti-VEGF agent. And we've seen evidence of amivantamab in the third line setting, so it is likely that this question about sequencing really takes center stage in our next set of trials. When you're talking to a patient, I think again, it's absolutely important to discuss: What are their goals? How symptomatic or how fast is their progression? Are there ways in which patients may benefit from spot treatment oligoprogression such as radiation? When is the right time for introduction of amivantamab and when do we think patients need chemotherapy? Is it up front or predominantly in the second-line setting? Brittany Harvey: Definitely. And then you've just touched on the goals of treatment for individual patients. So in your view, what does this update mean for patients with stage IV non-small cell lung cancer and an EGFR alteration? Dr. Jyoti Patel: For patients, this is a time in which shared decision making really needs to take center stage. So our best patients are those patients that are best informed not only about their disease but also have a good understanding about what is important to them and their families in terms of care. And so bringing that shared understanding to the table again helps us think about this particular cancer as more of a journey rather than just a one off treatment. Therapy will hopefully be prolonged, and so it's absolutely important that we address toxicities, make therapies more tolerable, again, with the shared goal of living long and living well. Brittany Harvey: Absolutely. Those are key points to making sure that patients are living both longer and have a good quality of life during that time as well. So then, before you mentioned the possibility of future sequencing trials and other ongoing developments. What additional studies or future directions is the panel examining for future updates to this living guideline? Dr. Jyoti Patel: So certainly we're thinking about trials that look at, for example, cfDNA clearance. So are there patients that do well and can we detect that early on without having to intensify therapy on day 1 so it may be that we add chemotherapy a little bit later. I think really exciting are some of the new bispecific. The HARMONi-A trial was a trial in China of a novel bispecific, ivonescimab. And this drug targets both PD-1 and VEGF and it was combined with chemotherapy. And this trial found almost a doubling of progression-free survival with this drug in combination chemotherapy in an EGFR patient population. That study is being planned and being run in the United States to see if we have similar outcomes with a more diverse population. So certainly that's exciting. There are a number of antibody drug conjugates that are being studied in the post-chemotherapy setting as well. And I think we'll likely soon see a better understanding of what co-mutations and burden of disease really mean when we're thinking about assigning treatment. So which patients, again, need intensification of therapy and which patients may do really well on just an oral agent that they're taking at home with more tolerable toxicity than dual treatment. Brittany Harvey: Yes, we'll look forward to continued developments in these fields and seeing some of those studies come to fruition. So with that, I want to thank you for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Patel. Dr. Jyoti Patel: Thanks so much, Brittany. It's really an exciting time for lung cancer and we hope that these updates really help physicians decide the best treatments for their patients. Again, it's a rapidly evolving landscape which is fantastic, but it does become more cumbersome to stay ahead of the literature. Brittany Harvey: Definitely. And so we appreciate your time and the panel's time spent reviewing this literature and providing this much needed information to clinicians everywhere. So finally, thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the  Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

BUFFALO, NY - February 24, 2025 – A new #research paper was #published in Oncotarget, Volume 16, on February 18, 2025, titled “Robust p53 phenotypes and prospective downstream targets in telomerase-immortalized human cells." Researchers Jessica J. Miciak, Lucy Petrova, Rhythm Sajwan, Aditya Pandya, Mikayla Deckard, Andrew J. Munoz, and Fred Bunz from the Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins University School of Medicine studied the tumor-suppressing protein p53, which plays a key role in preventing cancer. Their findings reveal how p53 affects cancer cell growth, treatment resistance, and potential drug targets, providing new insights that could improve future cancer therapies. The p53 protein plays a crucial role in preventing cancer by stopping uncontrolled cell growth. However, many cancers mutate or suppress p53, allowing tumors to develop and resist treatment. In this study, researchers restored p53 function in colorectal cancer cells, which led to slower cellular growth, increased cellular aging (senescence), and greater sensitivity to radiation therapy. These findings suggest that p53 status influences cancer progression and response to treatment, making it a promising target for new therapies. The study also examined hTERT-RPE1 cells; a type of non-cancerous human cell used in research. When the TP53 gene was disrupted in these cells, they grew faster and became more resistant to radiation, reinforcing the idea that p53 helps prevent cancerous growth. Another key discovery was a previously unnoticed p53 mutation (A276P) found in a subset of hTERT-RPE1 cells. This mutation weakened p53's ability to regulate certain genes but did not affect its ability to control calcium signaling, a process important for cell survival. The unexpected appearance of this mutation suggests that even non-cancerous cells can acquire genetic changes that mimic early cancer development. This insight could help scientists better understand how cancers evolve and become resistant to treatment. "Cancers that retain wild type TP53 presumably harbor other clonal alterations that permitted their precursors to bypass p53-mediated growth suppression." A breakthrough in the study was the identification of two new p53-regulated genes that could be important for cancer treatment. The first, ALDH3A1, helps detoxify harmful substances and may impact cancer cell resistance to oxidative stress. The second, NECTIN4, is a protein found in many aggressive cancers, including bladder and breast cancer. Notably, NECTIN4 is the target of enfortumab vedotin, an FDA-approved drug for bladder cancer. These discoveries provide new potential drug targets and could lead to improved therapies for cancers that still retain some p53 function. In conclusion, this research highlights the critical role of p53 in cancer biology and suggests that restoring p53 function could make tumors more vulnerable to radiation and chemotherapy. The discovery of new p53-controlled genes provides new opportunities for targeted cancer therapies. With further research, these findings could lead to new precision medicine strategies that leverage p53's natural tumor-suppressing abilities. DOI - https://doi.org/10.18632/oncotarget.28690 Correspondence to - Fred Bunz - fredbunz@jhmi.edu Video short - https://www.youtube.com/watch?v=Psxj3ctbTuk To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Morbidity & Mortality (M & M) are common case conferences to learn from unfortunate cases to improve care in the future. This episode looks at two recently published case reports. 1. Fatal tumor lysis syndrome following a lack of venetoclax ramp-up in AML: https://www.jhoponline.com/issue-archive/2024-issues/december-2024-vol-14-no-6/rapid-onset-of-fatal-tumor-lysis-syndrome-in-a-patient-with-acute-myeloid-leukemia-receiving-azacitidine-and-venetoclax-without-a-ramp-up-schedule-a-case-report 2. CD4+ T-cell lymphoma harboring a CAR integration into TP53: https://www.nejm.org/doi/full/10.1056/NEJMoa2411507

In this week's episode we'll learn more about a phase 2 trial of first-line zanubrutinib, obinutuzumab, and venetoclax in TP53-mutated mantle cell lymphoma; early development of hyperdiploidy in multiple myeloma; and a phase 1 trial of the asparaginase pegcrisantaspase plus venetoclax in relapsed/refractory acute myeloid leukemia.Featured Articles:Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutationDevelopment of hyperdiploidy starts at an early age and takes a decade to completeA phase 1 study of the amino acid modulator pegcrisantaspase and venetoclax for relapsed or refractory acute myeloid leukemia

On today's episode of the Occult Symbolism and Pop Culture with Isaac Weishaupt podcast we head back to the Grey Lodge in this bonus Twin Peaks episode only for supporters! This episode we're covering Twin Peaks The Return Parts 17 and 18 (aka S3E17 and S3E18) "The Past Dictates the Future" and "What Is Your Name?" We're finishing Twin Peaks The Return in one episode because they were released the same night. We'll hear about an ancient evil that tells us more about Judy (*we're finally gonna talk about Judy), we reveal Diane's true character, symbolism of the number 8 in Buddhism and final revelation of the White and Black Lodges in full battle as it wraps up in Twin Peaks!EXCLUSIVE GREY LODGE SHOWS NOW UP ONLY ON AD-FREE SUPPORTER FEEDS!See images discussed on Isaac's Instagram: https://www.instagram.com/isaacweishaupt/Index of Twin Peaks Grey Lodge series: https://illuminatiwatcher.com/twin-peaks-occult-symbolism-guide-enter-the-grey-lodge/Links:SUPPORTER FEEDS: Go ad-free with 160+ bonus episodes, early access and books!Patreon.com/IlluminatiWatcher,VIP Section (*with comparsion of Apple vs Patreon vs VIP): https://illuminatiwatcher.com/members-section/Apple Podcasts Premium! You can now go ad-free with ALL the bonus episodes on the Apple app- just open up the podcast and subscribe!

In this two-part "Explore Cell Therapy" podcast episode, Coleman Lindsley, MD, PhD, and Corey Cutler, MD, MPH, FRCP(C), discuss recent and evolving research supporting the broad benefits of hematopoietic cell transplant (HCT) across all genetic subtypes of myelodysplastic syndrome (MDS), including for patients with high-risk mutations like TP53.  In Part II, experts stress the importance of early consultation to optimize treatment decisions and ensure equity in access to HCT for older patients in need of a curative treatment option.    To read bios on the panelists and to access additional resources related to this episode, visit Our Site. 

In this two-part "Explore Cell Therapy" podcast episode, Coleman Lindsley, MD, PhD, and Corey Cutler, MD, MPH, FRCP(C), discuss recent and evolving research supporting the broad benefits of hematopoietic cell transplant (HCT) across all genetic subtypes of myelodysplastic syndrome (MDS), including for patients with high-risk mutations like TP53. In Part I: Expanding Access to Older Patients, guests explore major advances in transplant for older patients with MDS, highlighting the recent expansion of coverage through the Centers for Medicare and Medicaid Services (CMS), a significant milestone driven by recent studies that demonstrate the safety and efficacy of HCT in patients over 65 years old. To read bios on the panelists and to access additional resources related to this episode, visit Our Site. 

In this JCO Precision Oncology Article Insights episode, Miki Horiguchi summarizes two articles: “Germline Susceptibility to Renal Cell Carcinoma and Implications for Genetic Screening,” by Dr. Kate I. Glennon et al. published on August 01, 2024, and "Incidental Pathogenic Variants in Renal Cell and Urothelial Carcinoma: Is It Time for Universal Screening?” by Dr. Salvador Jaime-Casas, et al. published on August 01, 2024. TRANSCRIPT Miki Horiguchi: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host Miki Horiguchi, an ASCO Journal's Editorial Fellow. Today, I'll be providing summaries of the article titled, "Germline Susceptibility to Renal Cell Carcinoma and Implications for Genetic Screening,” by Dr. Kate Glennon and colleagues. In the accompanying editorial titled, “Incidental Pathogenic Variants in Renal Cell and Urothelial Carcinoma: Is It Time for Universal Screening?” by Dr. Salvador Jaime-Casas and colleagues. Renal cell carcinoma (RCC) exhibits distinct clinical characteristics across its histological subtypes. Clear cell RCC accounts for approximately 75% of cases while the remaining non-clear cell RCC encompasses a diverse group of histology. Although a family history has been known to double the risk for RCC, genetic susceptibility, particularly across different histological subtypes and defined operations, has not been investigated well. Dr. Glennon and colleagues sought to identify risk genes for RCC within the Canadian population and investigate their clinical significance in comparison to cancer-free control populations. The authors conducted targeted sequencing of 19 RCC related genes and 27 cancer predisposition genes for 960 RCC patients in Canada. DNA samples were collected through the Ontario Tumour Bank between 2005 and 2019. For comparisons across histological subtypes, the cohort was divided into 759 patients with clear cell RCC and 201 patients with non-clear cell RCC, including all histological subtypes other than clear cell RCC. Non-cancer control data were obtained from a publicly available database which included over 118,000 cases from the European population. A total of 39 different germline pathogenic variants were identified in 56 patients representing 5.8% of the Canadian cohort. There was no significant difference in the overall number of germline pathogenic variants between the two groups. The most commonly identified germline pathogenic mutations were CHEK2, ATM/BRCA2 and MITF in the clear cell RCC group, and FH and CHEK2 in the non-clear cell RCC group. Compared to the non cancer control data, germline pathogenic variants in CHEK2 and ATM were significantly associated with an increased risk of developing clear cell RCC, while those in FH were significantly associated with non clear cell RCC. According to the bivariate association analysis between the presence of germline pathogenic variants and clinical characteristics, patients with metastatic RCC were strongly associated with pathogenic variants in BRCA1, BRCA2, and ATM. No other significant associations were observed. The authors then evaluated variations in germline pathogenic variants among RCC patients across the world using similar studies conducted in Canada, Japan, the United Kingdom, and the United States. Specifically, they compared the gene burden for significantly mutated genes in each of the cohorts against all other cohorts combined. Compared to the other cohorts, RCC patients from Japan were enriched for pathogenic variants in TP53 and depleted for pathogenic variants in CHEK2. The United States cohorts showed higher frequencies of patients with pathogenic variants in BAP1 and FH genes compared to other cohorts. In contrast, RCC patients from Canada and the United Kingdom were not enriched for any specific genes when compared with the other cohorts. After characterizing germline susceptibility to RCC, the authors evaluated how many of the RCC patients in the Canadian cohort did not meet existing referral criteria for genetic screening based on current clinical guidelines, aiming to help refine these guidelines. Among the 56 RCC patients with identified germline pathogenic variants in the Canadian cohort, 73% did not meet the referral criteria for genetic screening under current Canadian guidelines. The authors also applied the UK guidelines and the US American College of Medical Genetics guidelines to the same 56 RCC patients. Under these criteria, 80% and 64%, respectively, were not eligible for genetic screening. In an exploratory analysis, the authors examine the impact of raising the Asia onset threshold from less than 45 years to less than 50 years. This revision captured an additional five patients with pathogenic variants. In addition to more inclusive genetic screening guidelines, the study results suggest that expanding the current list of genes to include additional relevant genes such as BRCA1, BRCA2, CHEK2 and ATM could help identify more RCC patients who are affected by rare germline pathogenic variants in Canada. The authors concluded that these revisions would enable the identification of a higher number of at-risk patients and improve the management of RCC patients. In the associated editorial accompanying this research article, Dr. Salvador Jaime-Casas and colleagues emphasized that the findings from Dr. Glennon and colleagues' study are particularly worrisome as most RCC patients with incidental pathogenic variants are not being referred for genetic screening. Building on results from previous studies, the authors suggested the need to revisit and update the current screening guidelines for RCC patients. The authors also highlighted findings from other studies showing the prevalence of pathogenic variants in CHECK2, BRCA1, and BRCA2 at up to 6% in RCC patients and 11% in upper tract urothelial carcinoma patients. They noted that these rates are comparable to those of ovarian cancer and pancreatic cancer, which already have universal screening guidelines. The authors also discuss some challenges. While the prevalence of pathogenic variants is crucial for evaluating the impact of germline genetic testing, it's only one factor in devising screening guidelines for RCC and urothelial carcinoma. They emphasize the need for robust clinical trials to evaluate therapeutics targeting these pathways, as well as the importance of characterizing incidental pathogenic variants to guide patient selection for these trials. Thank you for listening to JCO Precision Oncology Article Insights and please tune in for the next topic. 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.

Resilience and purpose shine through life's toughest challenges. In this episode of the Straight Out of Health IT podcast, cancer patient advocate Amanda Rose Ferraro shares her journey of surviving AML Leukemia, her advocacy work through Cancer is an A* LLC, and her mission to provide resources, support, and hope to cancer patients and their families. Diagnosed in 2017 after a misdiagnosis, she underwent intensive chemotherapy and celebrated remission in early 2018. However, a relapse due to a genetic mutation (Tp53) required another round of aggressive treatment and a life-saving Stem Cell transplant later that year. Today, Amanda is cancer-free and credits her survival to medical advancements, her donor in Germany, and an unwavering determination to overcome immense challenges. Her experiences inspired her to create "Cancer is an Asshole LLC" a resource platform for cancer patients and their families. Recognizing gaps in available support, Amanda's website provides practical tools such as information on legal aid, medical supplies, and emotional support. As a certified life coach, she also works directly with patients, offering guidance, advocacy, and a compassionate presence during medical appointments. Her advocacy aims to break the stigma around cancer and ensure no one feels alone in their journey. Amanda's transparency about the emotional and physical toll of cancer resonates with many, fostering a supportive community through social media and her motivational writings. She emphasizes the importance of persistence, mental health awareness, and accepting help. Amanda's message is clear: life is hard, but with support, hope, and determination, it's possible to navigate even the toughest challenges. Tune in and discover an inspiring journey of strength, advocacy, and hope!  --- Support this podcast: https://podcasters.spotify.com/pod/show/christopher-kunney/support

This week Jonathan is joined by Joshua Zeidner, Associate Professor of Medicine, University of North Carolina School of Medicine, USA. Together, they discuss findings from recent research and treatment options for acute myeloid leukaemia and myelodysplastic syndrome. Timestamps:     (00:00)- Introduction    (01:57)- Joshua's love for the New York Giants  (04:28)- Treatment outcomes in IDH1 and IDH2-mutated acute myeloid leukaemia (AML)  (08:05)- Safety and efficacy of new agents in AML  (17:00)- Treatments for patients with AML with a TP53 mutation  (22:02)- Reliance on transfusion in myelodysplastic syndrome (MDS)  (25:44)- The time from research lab to bedside in drugs to treat AML and MDS  (30:50)- Joshua's three wishes for healthcare   (35:13)- Outro   

In this week's episode, we'll learn about the role of a platelet-specific glycoprotein receptor in abdominal aortic aneurysm formation, the influence of TP53 mutations on outcomes for patients with 5q-deleted myelodysplastic syndrome, and a rational combination treatment intended to produce more durable responses in patients with refractory B-cell acute lymphoblastic leukemia who are treated with CAR T-cell therapy.Featured Articles:Soluble glycoprotein VI predicts abdominal aortic aneurysm growth rate and is a novel therapeutic targetInfluence of TP53 gene mutations and their allelic status in myelodysplastic syndromes with isolated 5q deletionA phase 1 clinical trial of NKTR-255 with CD19-22 CAR T-cell therapy for refractory B-cell acute lymphoblastic leukemia

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

BUFFALO, NY- October 11, 2024 – A new #editorial was #published in Oncotarget's Volume 15 on October 1, 2024, entitled, “Transplant or no transplant for TP53 mutated AML.” As highlighted in this editorial, TP53 mutations (mut) occur in 10–15% of acute myeloid leukemia (AML) cases, commonly associated with therapy-related AML (t-AML) and complex cytogenetics (CG). TP53-mut AML is inherently resistant to conventional chemotherapies and continues to show a poor prognosis, even with venetoclax-based therapies. Allogeneic hematopoietic stem cell transplant (allo-HCT) remains a potential curative option, though only 10–15% of patients receive it. In a recent study, allo-HCT was the only variable significantly improving survival, despite only 16% of patients successfully bridging to it. In their editorial, researchers Talha Badar, Moazzam Shahzad, Ehab Atallah, Mark R. Litzow, and Mohamed A. Kharfan-Dabaja from the Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program at Mayo Clinic (Jacksonville, Florida) evaluated the outcomes of TP53-mutated AML patients based on data from the Consortium of Myeloid Malignancies and Neoplastic Diseases (COMMAND). The study found a “dismal” survival rate of 8.5 months, with no significant difference among treatment types, and allo-HCT was the only variable associated with improved survival. The authors also report on the “better long-term outcomes” when allo-HCT was performed during Complete Remission 1 (CR1) in previous observations. They acknowledge the limitations of their retrospective analysis, including selection bias, data heterogeneity from participating institutions, and the lack of complete molecular data prior to allo-HCT that might have influenced the results. Nevertheless, the findings are encouraging and suggest that allo-HCT improves long-term outcomes in this poor prognostic disease, where effective therapies remain limited. “In summary, this study reported improved survival when allo-HTC was performed in CR1 versus after later lines of therapy.” DOI - https://doi.org/10.18632/oncotarget.28652 Correspondence to - Talha Badar - badar.talha@mayo.edu Video short - https://www.youtube.com/watch?v=OQue9gbqsxE Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28652 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, AML, TP53 mutation, allogeneic stem cell transplant About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Featuring perspectives from Dr Matthew S Davids, including the following topics: Introduction: Is Chronic Lymphocytic Leukemia (CLL) the New Chronic Myeloid Leukemia? Cases We Didn't Hear About Last Week (0:00) Case: A man in his early 70s with IGHV-unmutated CLL (trisomy 12, del[17p]) receives ibrutinib for several years and is switched to acalabrutinib to lower the risk of cardiotoxicity — Warren S Brenner, MD (16:39) Case: A man in his mid 70s with relapsed atypical del(17p) CLL who previously received ibrutinib receives venetoclax/obinutuzumab — Bhavana (Tina) Bhatnagar, DO (22:10) Case: A woman in her early 80s with IGHV-mutated CLL begins treatment with zanubrutinib and 6 months later develops altered mental status due to cryptococcal meningitis — Erik Rupard, MD (33:00) Case: A woman in her early 80s with relapsed CLL (del[17p]/TP53 mutation) develops Stevens-Johnson syndrome while receiving ibrutinib — Spencer H Bachow, MD (38:21) Case: A man in his mid 90s with del(13q) CLL under observation for 12 years begins treatment with zanubrutinib and develops significant bruising/ecchymosis — Dr Rupard (41:14) Case: A woman in her late 70s with relapsed del(13q) CLL receives acalabrutinib and develops hyperleukocytosis — Dr Bhatnagar (45:44) Case: A woman in her mid 80s with rising white blood cell counts and asymptomatic recurrence of CLL (trisomy 12) receives rituximab with subsequent addition of venetoclax — Dr Brenner (50:20) Transformed CLL; CAR T-Cell Therapy (53:38) Journal Club with Dr Davids (54:26) CME information and select publications

In this episode of the Oncology Brothers podcast, Drs. Rahul & Rohit Gosain are joined by Dr. Pallawi Torka from Memorial Sloan Kettering Cancer Center to discuss the current treatment landscape for low-grade lymphomas, specifically follicular and mantle cell lymphoma. Key Points Covered: •⁠  ⁠Follicular Lymphoma: The discussion includes the minimum workup required for treatment planning, frontline treatment options, nuances of PFS with different anti-CD20 agents, and considerations for relapse or refractory cases. •⁠  ⁠Mantle Cell Lymphoma: The conversation delves into initial treatment paradigms, the role of BTK inhibitors, considerations for TP53 mutations, and options for relapsed or refractory cases, including the growing importance of CAR T cell therapy. Highlights: •⁠  ⁠Treatment Options: From chemoimmunotherapy to novel agents like BTK inhibitors and CAR-T cell therapy, the podcast explores the evolving landscape of treatment options for these low-grade lymphomas. •⁠  ⁠TP53 Mutations: The discussion sheds light on how treatment decisions are influenced by the presence of TP53 mutations, with a focus on recent studies and promising combinations. •⁠  ⁠Relapse Management: Insights are shared on managing relapsed or refractory cases, including the role of BTK inhibitors, CAR-T cell therapy, and other emerging options. Join the Oncology Brothers as they navigate through the complexities of treating low-grade lymphomas with expert insights from Dr. Torka. Stay informed about the latest advancements in oncology and the changing standards of care for these challenging diseases. Website: http://www.oncbrothers.com/ Twitter: https://twitter.com/oncbrothers Contact us at info@oncbrothers.com

In this episode, listen to Floor J. Backes, MD, and Angeles Alvarez Secord, MD, MHSc, share their clinical insights and takeaways on new data presented for endometrial, ovarian, and cervical cancers presented at the 2024 annual meetings of the Society of Gynecologic Oncology and American Society of Clinical Oncology including:RUBY Part 1 Subgroup Analyses by MRR Status: Addition of dostarlimab to platinum-based therapy followed by dostarlimab maintenance in advanced endometrial cancerRUBY Part 2: Survival outcomes with addition of dostarlimab to platinum-based therapy followed by dostarlimab plus niraparib maintenance in advanced endometrial cancerSurvival Analyses From Phase III NRG GY018: Carboplatin plus paclitaxel with or without pembrolizumab as frontline treatment for patients with advanced endometrial cancerDUO-E: First-line therapy with carboplatin plus paclitaxel plus bevacizumab and durvalumab followed by maintenance with bevacizumab, durvalumab, and olaparib in newly diagnosed endometrial cancerLong-term Follow-up From SIENDO: PFS in TP53 wild-type and preliminary survival by molecular subgroups in patients with endometrial cancer and complete or partial response after ≥12 weeks of first line taxane/carboplatinSubgroup Analyses From the Randomized Phase III MIRASOL: Mirvetuximab soravtansine vs investigator's choice of chemotherapy in FR

Durante um evento sobre leucemia linfocítica crônica, os Doutores Lisa Ricci (CRM109006/SP) e o Dr Rafael Gaiola (CRM 102592/SP) discutem casos clínicos reais para ilustrar estratégias de tratamento baseadas em avanços recentes, especialmente em terapias com inibidores de BTK e combinações com anticorpos monoclonais. Destacaram-se as diferentes abordagens para pacientes jovens e idosos, considerando a presença de comorbidades e fatores de risco como mutações no gene TP53. BR-32879 - Material destinado a profissionais da saúde habilitados a prescrever e dispensar medicamentos. AGOSTO/2024

Dr Miller discusses findings from the SIENDO trial of selinexor maintenance therapy in patients with TP53 wild-type advanced endometrial cancer.

In this podcast episode, Farrukh Awan, MD, Jeremy S. Abramson, MD, MMSc, and Shuo Ma, MD, PhD, discuss real-world patient cases and how to align current clinical practice with the NCCN guidelines for CLL/SLL, including:Prognostic variables when deciding between regimensRole of MRD in CLLResults from the phase II CAPTIVATE trialChoosing among the available covalent BTK inhibitorsPreferred partner anti-CD20 antibody in CLL/SLLRole of the noncovalent BTK inhibitor, pirtobrutinib, in CLL/SLLUse of CAR T-cell therapy in CLL/SLLPresenters:Farrukh Awan, MDProfessor of Internal MedicineDirector of Lymphoid Malignancies ProgramHarold C. Simmons Comprehensive Cancer CenterUniversity of Texas Southwestern Medical CenterDallas, TexasJeremy S. Abramson, MD, MMScDirector, Center for LymphomaMassachusetts General HospitalAssociate Professor of MedicineHarvard Medical SchoolBoston, MassachusettsShuo Ma, MD, PhDProfessor of MedicineDivision of Hematology-OncologyDepartment of MedicineRobert H. Lurie Comprehensive Cancer CenterNorthwestern University Feinberg School of MedicineChicago, IllinoisContent based on an online CME program supported by educational grants from BeiGene; Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; and Lilly, and an independent medical education grant from AbbVie.Link to full program:https://bit.ly/3LzA2As

Drs. John Sweetenham and Marc Braunstein discuss practice-changing studies in hematologic malignancies that were featured at the 2024 ASCO Annual Meeting, including the ASC4FIRST trial in chronic myeloid leukemia and IMROZ and CARTITUDE-4 in multiple myeloma.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. On today's episode, we'll be discussing practice-changing abstracts and other key advances in hematological malignancies that were featured at the 2024 ASCO Annual Meeting. Joining me for this discussion is an old friend, Dr. Marc Braunstein, a hematologist and oncologist from the NYU Langone Perlmutter Cancer Center.  Our full disclosures are available in the transcript of this episode. Marc, it's great to have you back on the podcast again. There were some important studies in the heme space at the Annual Meeting this year, and we're very pleased that you're able to share your takeaways.  Dr. Marc Braunstein: Thank you, John. It's great to be back again. Dr. John Sweetenham: Let's start out, Marc, with LBA6500. This abstract reports the primary results of the ASC4FIRST trial, and this was a trial comparing asciminib with investigator selected tyrosine kinase inhibitors in newly diagnosed patients with chronic myeloid leukemia. Could you tell us a little about the trial and how you think it's going to impact clinical practice? Dr. Marc Braunstein: Absolutely. So, asciminib is an oral tyrosine kinase of the ABL kinase domain. As we know in CML, the BCR-ABL translocation is characteristic of the disease, and asciminib is approved for chronic phase CML with a T315I resistance mutation or for patients who have received 2 or more prior lines of therapy. So the ASC4FIRST trial was a randomized trial of 405 patients with newly diagnosed chronic phase CML who are randomized one to one to receive either asciminib at 80 milligrams once daily, or investigator's choice of a first generation TKI imatinib or one of three second generation TKIs nilotinib, dasatinib, or bosutinib. The primary endpoint of the study was the major molecular response, or MMR, at 48 weeks. Pretty much, the study met its primary endpoint with a 67% rate of MMR at 48 weeks, with asciminib versus 49% in patients treated with the investigator's choice of TKI. And in addition, the major molecular remission or MMR of 4.5, which is a deep remission, those rates were higher as well, with asciminib versus investigator's choice at a rate of 39% versus 21% when comparing the groups. Furthermore, when we looked at toxicity, there were fewer grade 3 or higher adverse events, with the asciminib at 38% versus either 44% with the first generation, or 55% with the second generation TKI, and fewer discontinuations as well with asciminib.  So I think this abstract is practice-changing. I think it offers compelling data to use asciminib upfront for chronic phase CML. Those who don't agree with that sentiment might argue that we want to see longer term follow up. There's a planned follow-up at 96 weeks. We would want to see the rate of progression to acute myeloid leukemia and of course overall survival as well. But I think the abstract certainly shows an improvement in outcomes with asciminib versus our current array of TKIs. Dr. John Sweetenham: Yeah, I think it certainly is, at least at minimum, potentially practice changing. I agree with you. Just one question, and this may be a little bit speculative, but do you have any thoughts about treatment free survival with asciminib and how that might line up against some of the other TKIs? Dr. Marc Braunstein: Yeah, that's a great question. The abstract did not necessarily address that, patients were treated until progression, but we know that with the current landscape of TKIs, that in patients who have achieved a deep MR of 4 or 4.5 for at least 2 years who discontinue their TKI, the rate of relapse is about 50%. The current study, the ASC4FIRST, doesn't address that, but I think it's a really good question about whether, for those patients who have achieved a deep remission, whether they can eventually stop asciminib down the line. Dr. John Sweetenham: Yeah, I guess it's one of those ‘watch this space' things.  So we'll see how the data mature out. And let's move on to what I think is another potentially practice-changing study, at least in certain parts of the world. And that's [the] LBA7000 study in classical Hodgkin lymphoma. As you remember, this was a German Hodgkin lymphoma study group trial which looked at the tolerability and efficacy of a novel regimen, BrECADD versus eBEACOPP for patients with advanced stage classical Hodgkin lymphoma in their study, which is known as GHSG HD21. Can you give us your thoughts and take home messages from this trial? Dr. Marc Braunstein: Yeah, John, absolutely. So the German HD21 study is a phase 3 study of 1,500 patients with classical Hodgkin lymphoma. The majority were stage 3 or 4, 84%, that compared two regimens BEACOPP to BrECADD. The major difference between these 2 groups being that the newer BrECADD regimen swaps out bleomycin for brentuximab vedotin, which is an anti-CD30 antibody drug conjugate. Also, in the BrECADD regimen they eliminate vincristine that's incorporated into BEACOPP. Those are kind of the global differences between these 2 regimens. And when comparing these, they looked at the primary endpoint of progression-free survival. Of note, in this study there was a PET adjusted approach where if patients achieved interim PET negativity after 2 cycles, that was followed by an additional 2 cycles of their treatment as opposed to 4 cycles if they were PET positive after the initial 2 cycles of their respective treatment. And of note, there were similar rates of PET2 negativity between both arms, about 58% in both arms.  So at a median follow-up of 48 months, the 4-year progression-free survival was significantly better with the brentuximab containing BrECADD regimen at 94% versus 91% with a hazard ratio of 0.66. And the overall survival of the BrECADD arm was 98.6%, which is very high and impressive. The 4-year overall survival was similar between the arms at around 98%, but of note, there were fewer severe adverse events with BrECADD, the brentuximab containing arm versus BEACOPP at about 42% versus 59% and interestingly less peripheral neuropathy with the brentuximab containing BrECADD. So we're doing extremely well in treating advanced stage classical Hodgkin lymphoma. So the bar is set very high. But in this study, the rates of progression-free survival and overall survival are very impressive.  While these intensive regimens tend to be used outside of the U.S., there are several notable benefits of the study, including greater than 50% PET2 negativity and high rates of progression-free survival at 4 years. In discussing this abstract, it's worth noting that there are other competing regimens, if you want to call it that, that are more commonly used in the U.S. So the ECHELON-1 study looked at brentuximab AVD compared with ABVD with bleomycin and it was a 94% versus 89% 6-year overall survival rate favoring the brentuximab containing A+AVD regimen. And lastly, more recently, the SWOG S1826 study that hasn't been published but was presented in abstract form looked at nivolumab AVD versus brentuximab AVD at a median follow up of 12 months showed a progression-free survival of 94% versus 86%. And that study still has yet to be published and needs to mature. But both of those regimens are in the NCCN guidelines. So, we're definitely pushing the bar higher in terms of improving responses in treating advanced classical Hodgkin lymphoma. Dr. John Sweetenham: I think that there's no question that these results from BrECADD are very impressive. But I'm taken back to what I think has been a kind of philosophic discussion in Hodgkin lymphoma now for a number of years about balancing disease control and efficacy against the potential short-term and long-term toxicity of the regimens, particularly when you have very effective salvage therapies for those patients who may suffer a relapse. So I think that this is a discussion over whether you take a very intensive, upfront approach to Hodgkin lymphoma versus something that may be less and slightly less intensive. I suspect that's a discussion that's going to continue for a long time. I don't know what you feel, but my own feeling about this is that this study will likely have a major influence over treatment of Hodgkin lymphoma, particularly in western Europe. Less likely in the US.., I would think. I don't know what your thoughts about that are. Dr. Marc Braunstein: Well, it's a great question. In SWOG S1826, that study did include pediatric patients. In HD21, the median age was 31 and did not include pediatric patients. So I think we have to be selective in terms of fitness and which patients may be better suited for different regimens. But I think what all these studies show is certainly when we incorporate novel immunotherapies, whether it's brentuximab vedotin, nivolumab, we improve progression-free survival and even overall survival. Dr. John Sweetenham: Absolutely.  So let's shift gears now and take a look at Abstract 7500, the IMROZ study. This was the study of isatuximab, bortezomib, lenalidomide and dexamethasone versus VRD alone for transplant ineligible patients with newly diagnosed multiple myeloma. I know we discussed this in our preview podcast a few weeks back, Marc, but I just wonder now, having seen the data in more detail, what do you think of the important takeaways? And again, are we looking at a new standard of care? Dr. Marc Braunstein: You know, there are many standards of care in multiple myeloma, but we're always looking to make improvements on the regimens we have at our disposal. So, just to recap, IMROZ is a phase 3 randomized study of the anti-CD38 monoclonal antibody isatuximab with the backbone of bortezomib, lenalidomide, dexamethasone or VRD versus VRD alone, specifically, in transplant ineligible newly diagnosed multiple myeloma patients age less than 80. They studied 446 patients in this study, randomized 3 to 2 to Isa-VRD versus VRD alone, with the primary endpoint of progression free survival. Now, similar to other studies where they included a monoclonal antibody up front, the study met its primary endpoint of improving progression-free survival with the quad regimen containing the monoclonal antibody isatuximab versus VRD alone.  So what was interesting about the study, it's really the first of its kind to be presented that specifically looked at transplant ineligible patients, which is presumably a less fit or perhaps more frail population that wouldn't go on to consolidation with stem cell transplant. And in this study, the progression-free survival at 5 years was 63% versus 45%, clearly superior when you included isatuximab. And the rates of complete remission and MRD negativity were all significantly improved, too. However, that was also met with slightly more grade 3 or higher treatment emergent adverse events, 92% versus 84% in the control arm. There are also 11% grade 5 treatment emergent adverse events with the isatuximab group versus 5.5% with VRD alone. Although there was no major difference in treatment discontinuation. One small caveat worth noting, too, is that high-risk patients in this study, when presented at ASCO, did not necessarily show a difference in benefit, although there wasn't necessarily a detriment either.  So, John, I think that clearly quadruplet regimens are superior in outcomes of efficacy to triplets, even in transplant-ineligible patients. But I think we have to tailor these treatments to individual patients because I think when it comes to transplant-ineligible patients, it's a spectrum of patients who may be more or less fit for quad regimens versus triplet regimens. It's also worth noting, though, that in this study, the patients are really only getting a quad regimen for 4 cycles. They get their Isa-VRD, and then you drop the bortezomib.  So when we think about quads, it's not that they're getting the quad regimen indefinitely, it's really for the induction cycles. But still, I think we have to be aware of potential safety issues. Dr. John Sweetenham: Okay, great. And let's stay on the theme of multiple myeloma, Marc, and talk a little bit about Abstract 7504, which was a subgroup analysis of the CARTITUDE-4 study. This is a report on the use of ciltacabtagene autoleucel versus standard of care in patients with functional high risk multiple myeloma. Can you give us your thoughts on this and maybe put it into a bit of context for us?  Dr. Marc Braunstein: Absolutely, John. It's really a great time to be in the field of multiple myeloma. We're making tremendous progress, but when we think about one of the unmet needs, it's just consistently the high-risk patients who have shorter responses and are at higher risk for poorer outcomes. Just to review, cilta-cel is one of the 2 available anti-BCMA CAR T-cell products available for the treatment of relapsed or refractory multiple myeloma. Very recently, the FDA approved cilta-cel for lenalidomide refractory patients after 2 or more prior lines of therapy based on the CARTITUDE-4 study, which was published by San-Miguel and colleagues in New England Journal of Medicine in July 2023. And that study randomized 419 patients with multiple myeloma with 1 to 3 prior lines of therapy to receive either cilta-cel or physician's choice of standard of care, which was either 1 of 2 triplet regimens, a pomalidomide, bortezomib, dexamethasone or daratumumab, pomalidomide and dexamethasone. It's worth noting that about 25% of the patients in the CARTITUDE-4 study had prior anti-CD38 antibody treatment previously and the carfilzomib was not included in one of the standard-of-care arms, and we know that those regimens containing carfilzomib do increase survival in relapsed myeloma.  Nevertheless, the primary outcome of progression-free survival was not reached in the CAR T-cell arm versus 11.8 months in the standard-of-care arm, with a significant reduction in progression of 74%. So clearly a positive study and CAR T-cell therapy is included in the NCCN guidelines for patients who have an early relapse from their myeloma. The current abstract by Costa et al focused specifically on a subgroup of 79 patients from CARTITUDE-4 in second line of treatment and looked at what they called functional high-risk myeloma, defined as progression of disease within 18 months of initial treatment or after stem cell transplant. Again, the study showed a retained benefit of cilta-cel with significant improvement in progression-free survival either not reached or 12 months with the control standard of care arm, as well as complete remission rate and rates of MRD negativity of 65% versus 10% in the control.  The overall survival outcome was still immature and not presented. Nevertheless, cilta-cel is clearly superior to standard-of-care triplet regimens. I think that for patients with high risk, they clearly derive a benefit from CAR T-cell therapy if they have short progression-free survival after initial therapy.  Dr. John Sweetenham: Thanks, Marc. So let's round this out by talking about another area of unmet need, I guess in a way in a difficult to treat patient group. And that's Abstract 7007, the SYMPATICO study. This is a study which looks at the efficacy and safety of ibrutinib and venetoclax in patients with mantle cell lymphoma who had a mutated TP53. Can you just briefly review this for us and tell us what you think we should be taking away from this studys? Dr. Marc Braunstein: So, mantle cell lymphoma typically has an aggressive behavior, but the subgroup of patients with a P53 mutation tend to have the poorest outcomes and do represent an area of unmet need. Although BTK inhibitors are making important improvements in mantle cell lymphoma, they have yet to be approved in newly diagnosed mantle cell lymphoma. Acalibutinib and zanubrutinib are FDA-approved BTK inhibitors for previously treated mantle cell lymphoma. Ibrutinib was withdrawn from the market in the U.S. for mantle cell lymphoma. Dr. Michael Wang's group presented late-breaking data from the phase 3 SYMPATICO trial at ASH 2023, in which 267 patients with relapsed refractory mantle cell lymphoma were randomized to receive either ibrutinib plus the BCL2 inhibitor venetoclax or ibrutinib plus placebo after 1 to 5 prior lines of therapy. And that study showed a 32 versus 22 months progression-free survival at a median follow up of 51 months. The current abstract, also by Dr. Wang and colleagues, looked at the subgroup of patients who had a P53 mutation and included an open label cohort of 44 patients in the first line of treatment and a relapse refractory cohort of 75 patients, and compared this subgroup of patients with P53 mutation to those without. When we look at the outcomes, the patients who did not have a P53 mutation clearly did better in terms of progression-free survival being not reached in first-line treatment compared to 22 months progression-free survival in those patients with first-line [treatment] with a P53 mutation. As well as in the relapsed refractory setting, the PFS without the P53 mutation was 47 months versus 21 months with the mutation. However, when you look at these patients treated with ibrutinib and venetoclax comparing whether they got treated in first line or the relapse refractory setting, the overall response rates are very similar at about 80% to 90% and the CR rates were very similar at about 55% to 58%, which to me suggests that although patients with P53 mutation do worse than those without it, whether they're treated in the first-line or the relapse setting with this combination of venetoclax, they tend to do somewhat similar, suggesting that you can overcome resistance to prior therapy in the relapse setting. So I think further data are certainly warranted to explore the role of combination therapies that include novel agents such as BTK inhibitors in the first line setting.  It's worth noting that the TRIANGLE study was recently published, and this study looked at including ibrutinib at various phases, including at induction in combination with intensive chemotherapy and during the maintenance phase. And that study showed encouraging outcomes in patients who received ibrutinib even without stem cell transplant compared to those who received stem cell transplant. So the role of BTKIs in mantle cell lymphoma is certainly evolving, and I think it offers a very effective intervention without the same kind of toxicities we see with cytotoxic chemotherapy that's traditionally used in mantle cell lymphoma. But I think the subgroup of patients with P53 mutation in this disease still represent an area of unmet need that unfortunately have worse outcomes. But novel agents may be able to overcome some of those adverse outcomes. Dr. John Sweetenham: Yeah, I agree. I think these are intriguing data, and obviously it needs more follow-up and probably more prospective studies. But nevertheless, I think there are some signals there for sure that need to be followed up on.  Marc, as always, it's great to have your insights on key advances in the heme space from ASCO. An important year this year, and we really appreciate your time and effort in sharing with us your thoughts on what we've learned this year. So thank you as always. Dr. Marc Braunstein: My pleasure. Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstract discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's guest:  Dr. Marc Braunstein  @docbraunstein    Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures:  Dr. John Sweetenham:  Consulting or Advisory Role: EMA Wellness  Dr. Marc Braunstein:  Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp  Speakers' Bureau: Janssen Oncology  Research Funding (Institution): Janssen, Celgene/BMS   

In this JCO Article Insights episode, Alexandra Rojek provides a summary on "Anti-CD19 Chimeric Antigen Receptor T-cell therapy for Richter's Transformation: An International, Multicenter, Retrospective Study by Kittai, et al published in the Journal of Clinical Oncology March 29th, 2024.  TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing an original report published in the June 10th issue of JCO titled, “Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study,” by Kittai et al. This report addresses the real world efficacy of CAR T-cell therapy for patients with Richter transformation of CLL to large B cell lymphoma, which represents a high risk group of patients with an unmet need for novel and more effective therapeutic agents than are currently available. Richter's represents the transformation of chronic lymphocytic leukemia, or CLL, to an aggressive lymphoma, most often a large B cell lymphoma, most similar to diffuse large B cell lymphoma or DLBCL. Treatment for Richters is often modeled after treatment practices for DLBCL. However, there's no clear standard of care and outcomes for these patients lag behind those of large B cell lymphoma patients otherwise. An important advance in recent years in the DLBCL field is the approval of anti CD19 CAR T-cell therapy in the second and third line settings. However, patients with Richter transformation were largely excluded from these pivotal trials. This study in JCO thus set out to address what the real world outcomes were for patients with Richters who were treated with CAR T-cell therapy across 12 centers internationally. The study included 69 patients across these twelve sites, with a median age of 63 years at diagnosis of Richters and a median of six years after initial CLL diagnosis. Included patients received a median of four prior lines of therapy for either CLL or Richters, with a median of two prior lines of therapy for Richters, although two patients had not received any prior therapy for their Richter transformation. The most recent prior treatments included chemoimmunotherapy in 29% of patients, followed by BTK inhibitors in 19%, as well as combinations of BTK inhibitors and BCL2 inhibitors in 12%. 17% of patients had not received prior therapy for their CLL before their diagnosis with Richters, 58% of cases had known TP53 mutations at time of transformation, and 41% exhibited deletion 17p by FISH. Prior to receiving CAR T-cell therapy, 86% of patients required additional bridging therapy, most commonly with a BTK inhibitor or chemoimmunotherapy. A diverse set of commercial CAR T-cell products were represented in this study, with the majority of patients at 64% receiving axi-cel, 25% receiving tisa-cel, 10% receiving liso-cel, and one patient received brexu-cel in an investigational setting. Median time from apheresis to CAR T infusion was 34 days, and 59% of patients continued on a BTK inhibitor throughout CAR T-cell therapy. When we move on to look at responses, 66 out of 69 patients were available for response. Three patients died related to adverse events after infusion and before response assessment, with the best overall response of complete response or CR in 46% of patients and partial response or PR in 17% for an overall response rate of 63%. With a median follow up time of 24 months, the median PFS in the study was 4.7 months and the median OS was 8.5 months. For those who achieved a CR, the median duration of response was an impressive 27 months, and for those achieving PR, the median duration of response was only two months. The two year PFS rate was thus 28%, and the two year OS rate was 38%. Four patients who achieved a CR went on to receive an allogeneic stem cell transplant. Among those whose disease progressed, 8% had relapse involving the CNS, compared to 10% of patients having CNS involvement prior to CAR T in this study population. The authors were also able to look at minimal residual disease, or MRD testing for CLL in a subset of 27 patients in this study. MRD was undetectable by PCR or flow in either blood or bone marrow in 81% of these 27 patients. However, not all of these patients had paired pre and post CAR T samples available for comparison, thus limiting more detailed interpretation. In an analysis of risk factors linked to adverse outcomes, the study authors found in a multivariable analysis for overall survival that a greater number of prior lines of therapy for Richters, a higher Ki-67 proliferation index, and a higher baseline LDH and CRP were all associated with shorter OS. They did not find an association between patterns of BTK inhibitor use, whether prior to apheresis, as a part of bridging, or concurrent with CAR T-cell therapy, to be associated with either PFS or OS. In evaluating rates of toxicities for patients with Richters treated with CAR T, the authors find that grade 3 or higher cytokine release syndrome or CRS occurred in 16% of patients and grade 3 or higher neurotoxicity or ICANS occurred in 37%. They did not find any baseline features associated with higher risk of severe CRS, however, did find that prior venetoclax exposure was associated with severe ICANS. Overall, the authors find that CAR T-cell therapy is a feasible and effective therapy for Richter transformation of CLL to large B cell lymphoma, thus contributing data to support this additional therapeutic option in a high risk patient population with unmet therapeutic needs. While the PFS and OS rates are lower than those of their large B cell lymphoma counterparts, overall response rate of 63% and particularly the CR rate of 46% with a duration of response of 27 months for this group is quite promising. Those who achieved less than a CR had a much shorter duration of response and progressed quickly, and overall, the median overall survival of the whole study population is only over eight months, which reflects the high risk and poor outcome nature of treatment for Richters with currently available therapies. As the authors discuss, it is likely that the efficacy of CAR T-cell therapy is somewhat overstated in their results by virtue of not being able to include patients who were intended for CAR T-cell therapy but could not receive it in this retrospective study. This represents one of the many real world challenges patients and clinicians treating Richters face. However, the promising results for those who were able to receive CAR T-cell therapy represent a path forward for future investigations for Richters patients. One of the avenues of future pursuit is the addition of BTK inhibitors to CAR T-cell therapy. A subset of patients included in this study received BTK inhibitors for CLL before, during, and after CAR T-cell therapy, and although limited by subgroup analysis and statistical power constraints, this study's authors did not find a difference in outcomes for those who received BTK inhibitors in these settings. Toxicities with severe CRS and ICANS were higher than rates reported in large B cell lymphoma CAR T trials. However, as the authors note, these were comparable to the study of liso-cel toxicity in CLL patients. Higher rates of infection related deaths were also noted compared to large B cell lymphoma patient counterparts, however, in line with comparable CLL patient studies and thus likely related to the unique biology of Richters arising from CLL rather than de novo large B cell lymphoma. In summary, this important work evaluating the outcomes of patients with Richter's transformation treated with anti CD19 CAR T-cell therapy in the commercial setting provides important evidence as to the efficacy of this therapy among patients with an unmet need for efficacious and novel therapies to improve outcomes. As this group of patients is often excluded from clinical trials, this data is particularly important and should drive forward future studies focusing on and or including patients with Richters, given the benefits seen for a subset of patients who achieve a response in the study. While the antecedent CLL distinguishes Richters from de novo large B cell lymphoma biologically along with differences in prior treatment regimens, this study in JCO suggests that future strategies targeting improving baseline disease factors prior to CAR T-cell therapy, including successfully bridging patients to CAR T, reducing risk of CRS and ICANS with treatment, and improving long term efficacy after CAR T with novel constructs, and CAR design, may all be promising next steps in the advancement of CAR T-cell therapy for patients with Richter transformation. This is Alexandra Rojek. Thank you for listening to JCO Article Insights. 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.  

At the 2024 European Hematology Association (EHA) Congress, CancerNetwork® spoke with a variety of experts in the hematologic oncology space about optimizing outcomes across different patient populations and subgroups based on updated research they presented at the meeting.  Manali Kamdar, MD, an associate professor of medicine-hematology and clinical director of Lymphoma Services at the University of Colorado Anschutz Medical Campus, in Colorado, spoke about data from the phase 1 TRANSCEND NHL 001 trial (NCT02631044) supporting the use of lisocabtagene maraleucel (liso-cel; Breyanzi) in earlier lines of therapy for patients with relapsed/refractory mantle cell lymphoma (MCL).1  Specifically, Kamdar highlighted how research should continue to focus on the potential utility of liso-cel in MCL subgroups such as those with TP53 mutations or blastoid morphology. Additionally, she stated that liso-cel may need to be further tested in earlier lines of therapy for patients with diffuse large B-cell lymphoma, including those with double-hit lymphoma. Michael R. Grunwald, MD, chief of the Leukemia Division and director of the Transplantation and Cellular Therapy Program at Atrium Health's Levine Cancer Institute, in North Carolina, discussed findings from the Prospective Observational Study of Patients With Polycythemia Vera (PV) in US Clinical Practices Trial (REVEAL) exploring risk factors for disease progression in patients with polycythemia vera (PV).2 According to Grunwald, a history of thromboembolic events, elevated white blood cell counts, and higher variant allele frequencies may contribute to a patient's likelihood of experiencing progression to myelofibrosis or acute myeloid leukemia (AML). Additionally, he highlighted ongoing research into the potential molecular factors that may prognosticate disease transformation in PV among a small cohort of patients enrolled on the REVEAL trial.3 Harry P. Erba, MD, PhD, a professor of medicine in the Division of Hematologic Malignancies and Cellular Therapy and the director of the Leukemia Program and Phase I Development in Hematologic Malignancies at Duke Cancer Institute, in North Carolina, discussed the clinical implications of data from the phase 3 QuANTUM-First study (NCT02668653).4  Specifically, findings demonstrated that continuation therapy with quizartinib (Vanflyta) elicited a more pronounced survival benefit vs placebo in patients with newly diagnosed FLT3-ITD–positive AML who did not undergo allogeneic hematopoietic stem cell transplant (allo-HSCT). However, Erba noted that survival outcomes were not significantly different in the quizartinib and placebo arms among patients who received allo-HSCT. References 1.        Palomba ML, Siddiqi T, Gordon LI, et al. Subgroup analyses in patients with R/R MCL treated with lisocabtagene maraleucel by prior lines of therapy and response to Bruton tyrosine kinase inhibitor from the TRANSCEND NHL 001 MCL cohort. Presented at the European Hematology Association (EHA) 2024 Congress; Madrid, Spain; June 13-16, 2024. P1126. 2.        Grunwald M, Zwicker J, Gerds A, et al. A real-world evaluation of risk factors for disease progression in patients with polycythemia vera (PV) enrolled in REVEAL. Presented at the 2024 European Hematology Association (EHA) Congress; June 13-16, 2024; Madrid, Spain. Abstract P1047. 3.        Crowgey E, Timmers C, Xue Z, et al. Analysis of molecular mechanisms and predictive biomarkers of disease transformation in polycythemia vera. Presented at the 2024 European Hematology Association (EHA) Congress; June 13-16, 2024; Madrid, Spain. Abstract S217. 4.        Sekeres MA, Erba H, Montesinos P, et al. QuANTUM-First: efficacy in newly diagnosed patients with FMS-like tyrosine kinase 3-internal tandem duplication–positive (FLT3-ITD+) acute myeloid leukemia (AML) who received continuation therapy. Presented at the 2024 European Hematology Association (EHA) Congress; June 13-16, 2024; Madrid, Spain. Abstract S142.

Dr. Neeraj Agarwal and Dr. Jeanny Aragon-Ching discuss promising combination therapies and other compelling advances in genitourinary cancers in advance of the 2024 ASCO Annual Meeting. TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I'm the director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News. I'm delighted to be joined by Dr. Jeanny Aragon-Ching, a GU medical oncologist and the clinical program director of genitourinary cancers at the Inova Schar Cancer Institute in Virginia. Today, we will be discussing some key abstracts in GU oncology that will be featured at the 2024 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode. Jeanny, it's great to have you on the podcast. Dr. Jeanny Aragon-Ching: Thank you so much, Dr. Agarwal. It's a pleasure to be here. Dr. Neeraj Agarwal: So, Jeanny, let's start with some bladder cancer abstracts. Could you tell us about the Abstract 4509 titled, “Characterization of Complete Responders to Nivolumab plus Gemcitabine Cisplatin versus Gemcitabine Cisplatin Alone in Patients with Lymph Node Only Metastatic Urothelial Carcinoma from the CheckMate 901 Trial.”  Dr. Jeanny Aragon-Ching: Of course, Neeraj, I would be delighted to. First, I would like to remind our listeners that the CheckMate 901 trial was a randomized, open-label, phase 3 study, in which this particular sub-study looked at cisplatin-eligible patients with previously untreated, unresectable, or metastatic urothelial carcinoma who were assigned to receive the combination of gemcitabine and cisplatin, followed by up to 2 years of nivolumab or placebo. Based on the data presented at ESMO 2023 and subsequently published in the New England Journal of Medicine, which shows significantly improved progression-free survival and overall survival in patients receiving the combination of gemcitabine, cisplatin, and nivolumab, this regimen was approved in March 2024 as a first-line therapy for patients with unresectable or metastatic urothelial carcinoma.  In the abstract that will be featured at ASCO this year, Dr. Matt Galsky and colleagues present a post-hoc analysis that aims to characterize a subset of patients with complete response as well as those with lymph node-only metastatic disease. In patients receiving the experimental treatment, 21.7% achieved a complete response, while 11.8% of the patients in the control arm achieved a complete response.  Among these complete responders, around 52% had lymph- node-only disease in both arms. Furthermore, when characterizing the subgroup of patients with lymph-node-only disease, those receiving the combination of gemcitabine-cisplatin plus nivolumab had a 62% reduction in the risk of progression or death and a 42% reduction in the risk of death compared to those treated with gemcitabine-cisplatin alone.  The median overall survival in the experimental arm in this subgroup was around 46.3 months, while it was only 24.9 months in the control arm. The ORR in patients with lymph-node-only disease receiving gem-cis plus nivo was about 81.5% compared to 64.3% in those treated with gem-cis alone. Dr. Neeraj Agarwal: Thank you, Jeanny, for the excellent summary of this abstract. We can say that nivolumab plus gemcitabine-cisplatin induced durable disease control and clinically meaningful improvements in OS and PFS compared to gem-cis alone in patients with lymph- node-only metastasis, and deserves to be considered as one of the options for these patients.  In a similar first-line metastatic urothelial carcinoma setting, Abstract 4502, also reported data on a recently approved combination of enfortumab vedotin and pembrolizumab. Can you tell us more about this abstract, Jeanny? Dr. Jeanny Aragon-Ching: Sure, Neeraj. So, as quick reminder to our audience, this regimen was tested in the EV-302 phase 3 trial, where patients with previously untreated, locally advanced or metastatic urothelial carcinoma were randomized to receive enfortumab vedotin, plus pembrolizumab or gemcitabine plus either cisplatin or carboplatin. These data were also first presented at ESMO 2023 and subsequently published in the New England Journal of Medicine. They showed that this immune based combination significantly improved both progression free survival and overall survival, which were the primary endpoints compared to chemotherapy. In this abstract, Dr. Shilpa Gupta from the Cleveland Clinic and colleagues present the results of patient reported outcomes based on quality-of-life questionnaires in this trial.  Time to pain progression and time to confirm deterioration were numerically longer in patients treated with EV plus pembro, and patients with moderate to severe pain at baseline receiving this combination had a meaningful improvement in the Brief Pain Inventory Short-Form worst pain from week 3 through 26. Dr. Neeraj Agarwal: Thank you, Jeanny. This means that patients treated with EV plus pembro did not only have improved survival compared with platinum-based chemotherapy, but also improvement in their quality-of-life and functioning, further supporting the value of this combination for patients with locally advanced or metastatic urothelial carcinoma. This is terrific news for all of our patients.   Before we wrap up the bladder cancer section, would you like to tell our listeners about Abstract 4565, which provides the data on the efficacy of trastuzumab deruxtecan in patients with bladder cancer? Dr. Jeanny Aragon-Ching: Yes, Neeraj; this is timely given the recent FDA approval, which we will talk about. The abstract is titled, “Efficacy and Safety of Trastuzumab Deruxtecan in Patients with HER2 Expressing Solid Tumors: Results from the Bladder Cohort of the DESTINY-PanTumor02 Study.” And as a quick reminder, the DESTINY-PanTumor02 was a phase 2 open-label study where trastuzumab deruxtecan, an antibody-drug conjugate targeting HER2 expression on cancer cells, was evaluated in patients with HER2-expressing locally advanced or metastatic disease who previously received systemic treatment or who had no other treatment options. The expression of HER2 was evaluated on immunohistochemistry by local or central testing.   The primary endpoint was confirmed objective response rate by investigator assessment. Secondary endpoints included duration of response, progression free survival, disease control rate, and safety. The primary analysis, which was published in the Journal of Clinical Oncology, showed an ORR of 37.1% and responses across all cohorts and the median duration of response was 11.3 months. Based on these results, fam-trastuzumab deruxtecan-nxki was just granted accelerated FDA approval for unresectable or metastatic HER2-positive solid tumors in April 2024.  So, back to this abstract; Dr. Wysocki and colleagues report the results of the bladder cancer cohort. This study included 41 patients with urothelial cancer and at a median follow up of around 12.6 months, the objective response rate among these patients was 39%, the median PFS was 7 months, and the duration of response median was 8.7 months. The disease control rate at 12 weeks was around 71%. Regarding the safety profile, 41.5% of patients experienced grade ≥3 drug related adverse events and interstitial lung disease or pneumonitis did occur in about 4 patients. Although there was no statistical comparison between different groups, the ORR was numerically highest among the HER2 3+ group with 56.3%.  Dr. Neeraj Agarwal: Thank you, Jeanny. So, these data support consideration of trastuzumab deruxtecan as a salvage therapy option for pre-treated patients with HER2 expressing urothelial cancers and show that we are extending our treatment options to include therapies with novel mechanisms of action. This is definitely exciting news for patients with bladder cancer. Dr. Jeanny Aragon-Ching: Yes, absolutely, Neeraj. Now, let's switch gears a bit to prostate cancer. Could you tell us about Abstract 5005 which is titled, “EMBARK Post Hoc Analysis of Impact of Treatment Suspension on Health Quality-of-Life?” Dr. Neeraj Agarwal: Of course, I'd be happy to. So, enzalutamide was recently granted FDA approval for the treatment of patients with non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high-risk of metastasis, based on the results of the EMBARK trial, which was a phase 3 study where patients with high-risk biochemical recurrence were randomized to receive either enzalutamide with leuprolide, enzalutamide monotherapy, or placebo plus leuprolide. The primary endpoint was metastasis-free survival with secondary endpoints including overall survival and safety.  Results showed that patients receiving enzalutamide alone or enzalutamide plus leuprolide had significantly improved metastasis-free survival compared to those treated with leuprolide alone while preserving health-related quality-of-life.   One important aspect in the design of the trial was that patients who achieved undetectable PSA at week 37 underwent treatment suspension. The treatment was resumed if PSA rose to more than 2 ng/ml for patients who underwent radical proctectomy or when PSA rose to more than 5 ng/ml for those who did not undergo surgery.  In this abstract, Dr. Stephen Freedland and colleagues present a post-hoc analysis of health-related quality-of-life outcomes after treatment suspension between weeks 37 and 205. They found that treatment was suspended in 90.9% of patients receiving enzalutamide plus leuprolide, 85.9% of those receiving enzalutamide monotherapy, and 67.8% of those receiving leuprolide monotherapy. Among those patients who stayed on treatment suspension, a trend toward numerical improvement in health-related quality-of-life after week 37 was seen in all 3 arms and this reached clinically meaningful threshold at week 205 in pain questionnaires, physical well-being, urinary and bowel symptoms. For hormonal treatment side effects, all arms reached clinically meaningful improvement at the subsequent assessments of week 49 to week 97. However, patients slowly deteriorated, with clinically meaningful deterioration at week 205 relative to week 37 in patients receiving the combination of enzalutamide and leuprolide and those treated with leuprolide.    Concerning sexual activity, a clinically meaningful improvement was reported only in patients receiving enzalutamide plus leuprolide, possibly because sexual function was better preserved prior to suspension in the enzalutamide monotherapy arm and thus there was less opportunity for “improvement” while on suspension.  Dr. Jeanny Aragon-Ching: Thank you, Neeraj, for this great summary. This analysis confirms that treatment suspension in good responders might lead to a clinically meaningful improvements in health-related quality-of-life.   Now, moving on to patients with metastatic castration-resistant prostate cancer, what can you tell us, about Abstract 5008 titled, “Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore”?  Dr. Neeraj Agarwal: Sure, Jeanny. The PSMAfore trial was a phase 3 study that compared the efficacy of 177Lu-PSMA-617 versus an ARPI switch in patients with mCRPC and prior progression on a first ARPI, and not previously exposed to docetaxel chemotherapy. The primary endpoint was rPFS and OS was an important secondary endpoint. The primary analysis presented at ESMO 2023 showed a significantly prolonged rPFS in patients receiving lutetium. In the abstract that will be featured at the 2024 ASCO Annual Meeting, Dr. Johann De Bono and colleagues present an exploratory analysis regarding the associations between baseline circulating tumor DNA and outcomes.  ctDNA fraction was evaluated in all samples as well as alterations in key prostate cancer drivers prevalent in more than 10% of participants.  The investigators sought to interrogate the association of ctDNA fraction or alterations with rPFS, PSA response, and RECIST response at data cutoff. They showed that median rPFS was significantly shorter in patients with a ctDNA fraction >1% compared to those with a fraction < 1% regardless of the treatment arm. Furthermore, ctDNA fraction >1% was also associated with worst RECIST response and PSA50 response. Regarding prostate cancer drivers, median rPFS was significantly shorter in patients with alterations in the AR, TP53 or PTEN in both treatment arms. There was no significant association between ctDNA alterations and PSA or objective responses. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So, these results show that the presence of a ctDNA fraction >1% or alterations in AR, P53 and PTEN were all associated with worse outcomes regardless of treatment with lutetium or change in the ARPI. These data are definitely important for counseling and prognostication of patients in the clinic and may guide the design of future clinical trials. Let's move on to kidney cancer. Neeraj, do you have any updates for us?  Dr. Neeraj Agarwal:  Sure. In Abstract 4512 titled, “A Multi-institution Analysis of Outcomes with First-Line Therapy for 99 Patients with Metastatic Chromophobe Renal Cell Carcinoma,” Dr. Sahil Doshi and colleagues present a retrospective, multi-institutional study comparing survival outcomes, including time-to-treatment failure and overall survival, between different first-line treatment options in patients with metastatic chromophobe renal cell carcinoma, where limited clinical trial data exists to guide systemic therapy. They categorized patients into 4 treatment groups: and immune checkpoint inhibitors + targeted therapy doublets (such as ICI VEGF TKI); pure immune checkpoint inhibitor monotherapy and doublets (such as ipilimumab plus nivolumab); targeted therapy doublets (such as lenvatinib plus everolimus), and targeted monotherapy (such as sunitinib).  They identified 99 patients, of whom 54 patients received targeted monotherapy, 17 received ICI VEGF-TKI, 14 received targeted doublet, and 14 patients received only ICI therapies. So the patients treated with any doublet containing a targeted agent had a 52% decrease in the risk of treatment failure and a 44% decrease in the risk of death compared to those treated with targeted monotherapy. The median time to treatment failure was 15 months with IO-targeted doublet, and the median overall survival was 56 months. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. So, these results show that targeted doublet regimens resulted in a longer time to treatment failure and overall survival compared to any monotherapy in patients with chromophobe metastatic RCC and definitely provides valuable insights on treatment selection, albeit I would say there's still a small number of patients that were included in this retrospective analysis. Dr. Neeraj Agarwal: I completely agree this is a relatively small number of patients, but I decided to highlight the abstract given how rare the cancer is, and it is highly unlikely that we'll see large randomized clinical trials in patients with metastatic chromophobe renal cell carcinoma.  So, before we wrap up the podcast, what would you like to tell us about Abstract 5009 which is titled, “A Phase II Trial of Pembrolizumab Platinum Based Chemotherapy as First Line Systemic Therapy in Advanced Penile Cancer: HERCULES (LACOG 0218) Trial.” Dr. Jeanny Aragon-Ching: I'm glad you brought this up, Neeraj. As our listeners may know, advanced penile squamous cell carcinoma has a poor prognosis with limited treatment options. From this perspective, the results of the LACOG 0218 trial are very important. As you mentioned, this was a phase 2 single-arm study evaluating the addition of pembrolizumab to platinum-based chemotherapy as first-line treatment in patients with metastatic or locally advanced penile squamous cell carcinoma not amenable to curative therapy. Patients enrolled received chemotherapy, namely 5-Fluorouracil with cisplatin or carboplatin and pembrolizumab 200 mg IV every 3 weeks for 6 cycles, followed by pembrolizumab 200 mg IV every 3 weeks up to 34 cycles. The primary endpoint was confirmed overall response rate by investigator assessment.  In the 33 patients eligible for the efficacy analysis, the confirmed ORR by investigator assessment was 39.4% and included one complete response and 12 partial responses. The confirmed ORR was 75% in patients with high TMB and 55.6% in patients positive for HPV16, making TMB and HPV16 potential predictive biomarkers for efficacy in this study. Concerning the toxicity profile, any grade treatment-related adverse events were reported in around 92% of patients, and grade 3 or more treatment-related adverse events occurred in 51% of patients. 10.8% of patients discontinued treatment due to adverse events.  Dr. Neeraj Agarwal: Thank you, Jeanny. I would like to add that HERCULES is the first trial to demonstrate the efficacy of an immune checkpoint inhibitor in advanced penile squamous cell carcinoma with a manageable safety profile. Thus, the combination of ICI with platinum-based chemotherapy is a promising treatment for advanced penile squamous cell carcinoma and warrants further investigation.  Dr. Jeanny Aragon-Ching: I agree, Neeraj. Any final remarks before we conclude today's podcast? Dr. Neeraj Agarwal: Jeanny, I really want to thank you for your participation and valuable insights. Your contributions are always appreciated, and I sincerely thank you for taking the time to join us today. Dr. Jeanny Aragon-Ching: Thank you, Neeraj. It was a pleasure.  Dr. Neeraj Agarwal:  As we bring this podcast to an end, I would like to acknowledge the significant advances happening in the treatment of patients with genitourinary cancers. During our upcoming 2024 ASCO Annual Meeting, there will be an array of different studies featuring practice-changing data presented by researchers and physicians from around the globe. I urge our listeners to not only participate in this event to celebrate these achievements, but to also play a role in sharing these cutting-edge data with healthcare professionals worldwide. Through our collective efforts, we can surely optimize the benefits of patients on a global scale.   And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you very much.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers:  Dr. Neeraj Agarwal  @neerajaiims  Dr. Jeanny Aragon-Ching    Follow ASCO on social media:   @ASCO on Twitter     ASCO on Facebook     ASCO on LinkedIn       Disclosures:    Dr. Neeraj Agarwal:     Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences    Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas     Dr. Jeanny Aragon-Ching:  Honoraria: Bristol-Myers Squibb, EMD Serono, Astellas Scientific and Medical Affairs Inc., Pfizer/EMD Serono  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis,   Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics. 

Dr. John Sweetenham and Dr. Marc Braunstein look ahead at key abstracts across the spectrum of hematologic malignancies that will be presented at the 2024 ASCO Annual Meeting, including the OPTIC trial in chronic myeloid leukemia, treatment options for transplant-ineligible patients with multiple myeloma, and the 7-year analysis of the ECHELON-1 trial in classical Hodgkin lymphoma. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and the host of the ASCO Daily News Podcast. I'm delighted to be joined again this year by Dr. Marc Braunstein, a hematologist and oncologist at the NYU Perlmutter Cancer Center in New York. We're going to be discussing some of the key abstracts in hematologic malignancies that will be featured at the 2024 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod.  Marc, it's great to have you back on the podcast. Dr. Marc Braunstein: It's a pleasure to be back, John.  Dr. John Sweetenham: There are some exciting abstracts to be presented at this year's meeting, and I would like to begin, if we can, with Abstract 6501. As you know, this reports the four-year results from the OPTIC trial of ponatinib in patients with chronic-phase CML and the T315I mutation. Can you tell us about the trial and about these latest follow-up results? Dr. Marc Braunstein: Sure. Well, we've made tremendous progress in managing patients with CML in the past two decades using these oral tyrosine kinase inhibitors such as ponatinib. Ponatinib is a third-generation TKI that has activity in both Philadelphia-positive ALL as well as CML, and can overcome the resistance mutation you mentioned, called the T315I mutation, which is sometimes found following prior TKI therapy. The OPTIC study is a multicenter phase 2 randomized study of various doses of ponatinib in 283 chronic phase CML patients who had received 2 or more prior lines of therapy or those who had the presence of a T315I mutation, with the current analysis examining the major remission at 48 months, PFS, as well as OS. Of note, in this study, after patients have achieved a major remission with a transcript level of 1% or less, the study allowed for dose reduction of ponatinib from the original dose of either 45 milligrams or 30 milligrams to a reduced dose of 15 milligrams.  So, when we look at the results, we find that the patients who had the highest overall response rates and higher rates of molecular remission were those who received the 45-milligram dose. And remember, these patients were allowed to be dose-reduced to the 15-milligram dose once they achieved a molecular remission of 1% or less. In addition, the rates of overall survival were highest in the 45-milligram dose as well. When looking at the T315I subgroup, the rates of molecular remission, the depth of remission, and the rates of progression-free survival, in general, were lower in that subgroup, but still higher in the 45-milligram dose than the 35- milligram dose.  Furthermore, when looking at the rates of treatment-emergent adverse events leading to discontinuation, they were 8% in the 45-milligram dose compared to 14% in the 30-milligram dose and 5% in the patients who only received the 15-milligram dose. The authors have concluded that the 45-milligram dose, with the potential to be reduced to 15 milligrams after achieving 1% or less of the BCR-ABL transcript level, seems to be the right balance between efficacy and safety.  Dr. John Sweetenham: Thanks, Marc. In the longer term, do you think that this study will, in any way, affect the position of ponatinib in the treatment algorithm for CML? Is it going to remain as a second or third-line option, or do you think there's any chance it will be moved up? Dr. Marc Braunstein: Well, that's a great question. There are other TKIs, such as asciminib, that also target the T315I mutation, and that mutation tends to develop after prior first-line or second-line TKI therapy. But given its activity in both ALL and CML, I think it's certainly reasonable to expect that ponatinib will be used in earlier lines of therapy given its efficacy in later lines. Dr. John Sweetenham: Let's change gears and move the focus to acute myeloid leukemia. There has been a lot of discussion around frailty in many different malignancies, but the impact of frailty on outcomes in AML is maybe something that hasn't been quite so well studied. In Abstract 6506, investigators did a population-based study in Ontario, Canada, that assessed the patient's frailty risk and the impact that might have on outcomes. What are your takeaways from this study, and how do you think these data will help optimize treatment decisions?  Dr. Marc Braunstein: Yeah, I'm glad we're talking about this abstract John, because frailty scores are increasingly being used in hematologic malignancies to help guide goals and intensity of care. And as opposed to using age or performance status alone, these composite frailty assessment tools, such as the MFI tool that they used in this particular study, take into account multiple variables that are both physiologic, such as the patient's comorbidities, as well as social, and what kind of support system do they have, and things of that nature. And that accounts for their overall fitness. So, in this retrospective cohort study that was a population-based study in Ontario between 2006 and 2021, they looked at 5,450 patients retrospectively with acute leukemia and grouped those patients into 3 categories based on this frailty index. Patients who are either fit, somewhere in the middle between fit or frail, which they call pre-frail, or frail. And they looked at outcomes such as overall survival, comparing patients who got intensive chemotherapy regimens for induction or those who got non-intensive therapy for induction. Patients in either group could have been assigned to either fit, pre-frail, or frail although there are much more fit patients than those who got intensive induction.  And so, looking at their findings, it was noted that patients who were in the frail category, not entirely unexpectedly, had lower overall survival when compared to those who were fit or pre-frail. I think the value of a study like this is not just to highlight the benefit of frailty scores to help predict which patients may ultimately have a shorter survival, but also to help potentially guide which patients may be more suitable for intensive versus less intensive induction. I will note that this study was conducted in an era where we didn't have the same sorts of less intensive induction that are very effective in less fit patients, such as the combination of azacytidine and venetoclax, which is commonly used in less fit patients nowadays. So, the study may encompass patients who didn't have access to that therapy because it wasn't available during that time. But I think it still, overall, does highlight the fact that assessing fitness or frailty in acute myeloid leukemia is important for predictive value. Dr. John Sweetenham: I agree. Marc, I don't know what your thoughts are on this, but it goes either way. I mean, I think that, if I remember the numbers correctly, 25% of fit patients received non-intensive therapy. So, is there a missed opportunity there for that group of patients who actually may have tolerated the intensive therapy but it was never offered? Dr. Marc Braunstein: That's an excellent point, John, and I think that highlights the importance of frailty indices because they take into account much more than one particular factor, or even just a subjective assessment of the patient in real time when they're first presenting. And they may have disease-specific features that are decreasing, say one element of their assessment such as their performance status. So, really taking these composite fitness scores into account may actually allow you to escalate therapy in a patient who may actually be fit but maybe perceived as less fit when they present. Dr. John Sweetenham: Yeah. So, I think, as you mentioned, there are better treatment options out there now maybe than there were at the time this study was conducted. Nevertheless, there may still be that opportunity for more intensive therapy for some of these patients when they are more holistically assessed.  Let's move on and switch gears once again and talk about a study in multiple myeloma, the so-called IMROZ study, which is Abstract 7500. So, this is a study looking at treatment options for transplant-ineligible patients with newly diagnosed multiple myeloma. Some of these patients may not have a chance for subsequent therapy if they are not eligible for transplant. What are your thoughts on this study? Do you think we're closer to a new standard of care for patients who are not going to proceed to an autologous stem cell transplant?  Dr. Marc Braunstein: It seems like every year there's a new standard of care for newly diagnosed multiple myeloma because there's so much data emerging, which is just wonderful. So, I think as background, at the 2023 ASH meeting, the IsKia study was presented, which is a randomized phase 3 study in newly diagnosed transplant-eligible patients. And that was using isatuximab with carfilzomib, lenalidomide, and dexamethasone upfront and that study did show a benefit in terms of reducing minimal residual disease compared to carfilzomib, lenalidomide, and dexamethasone alone. But that study was looking at fit newly diagnosed patients who were going on to stem cell transplant. Right now, the standard of care for patients who are not eligible for transplant is generally to use a 2 or 3-drug regimen, such as daratumumab, lenalidomide, and dexamethasone, based on the phase 3 MAYA study. But this study is really unique in that it looks at using a quadruplet regimen in patients who are transplant ineligible or not intended to go for transplant.  So, the phase 3 IMROZ study was a randomized study of 446 patients that compared isatuximab, bortezomib, lenalidomide, and dexamethasone to bortezomib, lenalidomide, and dexamethasone alone. So, a quad versus a triplet regimen. The primary endpoint in this study was progression-free survival, but they also looked at secondary endpoints, such as complete response rate and minimal residual disease negativity.   Just to quickly highlight the results and then discuss the standard of care, the median duration of treatment in this study was 53 months in the quad regimen and 31 months in the control arm. At a median follow-up of about 60 months, the progression-free survival was not reached with the quad regimen versus 54 months in the triplet, and that was a significant difference. In addition, the safety profile was pretty much consistent with the class, there were a bit more grade three or higher treatment-emergent adverse events with the ESA-containing regimen, 92% versus 84%, but no difference in adverse events leading to discontinuation in either arm.   So, this study is certainly compelling in terms of using quadruplet-based regimens that contain an anti-CD38 monoclonal antibody for newly diagnosed patients who are not intended to undergo transplant. I think at the meeting, I will be interested to see the patient population that was included. Patients who are over the age of 80, for example, are excluded. So, I would like to know more about their fitness level and performance status. But I think it's clear, John, that using quad regimens over triplet regimens is just consistently superior in terms of efficacy outcomes. Dr. John Sweetenham: Right. I guess that, even though maybe we can't focus on the specific agents right now, it looks as if quad regimens are going to be the standard of care regimens for the future in this group. Do you think that is fair?  Dr. Marc Braunstein: Very likely. Dr. John Sweetenham: Absolutely. Well, that's a pretty challenging group of patients.   And so to move on again, let's talk about another, perhaps equally challenging group - patients with mantle cell lymphoma, particularly those who carry certain mutations. The so-called SYMPATICO study, which is reported in Abstract 7007, presents data on the efficacy and safety of ibrutinib and venetoclax in patients with mantle cell lymphoma who carry a TP53 mutation. We know that this mutation confers a high risk of early progressive disease and poorer outcomes when these patients are treated with standard chemoimmunotherapy for mantle cell. Trials to date have been limited to small single-arm studies. Can you tell us a little bit about this study and the outcomes and what you think it means for the future?  Dr. Marc Braunstein: As a background, although BTK inhibitors such as ibrutinib have yet to be approved for newly diagnosed mantle cell lymphoma, acalabrutinib and zanubrutinib, which are second-generation BTK inhibitors, are FDA-approved for previously treated mantle cell lymphoma. Ibrutinib was withdrawn from the market. The lead author of this abstract, Dr. Michael Wang, had presented a late-breaking data from the phase 3 SYMPATICO trial at ASH last year, in which 267 patients with relapsed or refractory mantle cell lymphoma after one to five prior lines of therapy were randomized to receive the combination of ibrutinib plus the BCL-2 inhibitor venetoclax or ibrutinib plus placebo. That study showed there was a 32 versus 22-month progression-free survival with a hazard ratio of 0.65 at a median follow-up of 51 months, indicating the PFS benefit of the combination of ibrutinib and venetoclax compared to ibrutinib with placebo.   So that leads us to this subgroup analysis in the current study being presented at ASCO, in which they looked at a subgroup of patients with mantle cell lymphoma who are at very high risk for treatment failure and early relapse - those are patients who have a mutation in TP53, which again is high risk for treatment failure. This abstract examined an open-label cohort of 44 first-line patients, as well as 75 patients who were in the relapse/refractory cohort, and compared to patients who either did or did not have the P53 mutation. When we look at the progression-free survival outcomes, the median progression-free survival in the first-line cohort of patients who did not have a P53 mutation was not reached, whereas those with the P53 mutation had a median progression-free survival of 22 months, which is still meaningful but still less than those who did not have a P53 mutation. Which again is not entirely unexpected. But the overall response rate of the combination of ibrutinib and venetoclax was very high at 90%, and the median duration of response was about 21 months.  Now comparing this to the relapse/refractory cohort, in those without a P53 mutation, the progression-free survival of the combination of ibrutinib and venetoclax was about 47 months versus those who don't have the P53 mutation was about 21 months with an overall response rate of 80%. I think one takeaway looking at this comparison of the first-line and relapse/refractory setting is that patients seem to do very similar in terms of overall response rate and progression-free survival, whether they were in the first line or in the later lines of treatment if they had the P53 mutation, which says that the combination of ibrutinib and venetoclax is effective no matter which phase of the disease the patient might be in, indicating its overall activity and being strong.    Dr. John Sweetenham: Yeah, I thought that was an interesting observation, actually, how similar the outcomes were in those two groups.  Dr. Marc Braunstein: No, I agree. And I think although patients with TP53 mutations did comparatively worse than those without the mutation according to progression-free survival, overall response rate, or complete remission rates, they did seem to be similar whether a patient was in first-line or relapsed refractory if they were P53 mutant and were treated with this combination. So, I think we need further data in the first line, such as the data that's awaiting publication from the TRIANGLE study, which is examining upfront ibrutinib. But certainly, BTK inhibitors have significant activity in either the first line or the relapse setting of mantle cell lymphoma.  Dr. John Sweetenham: Great. Thanks, Marc.  Let's wind up with one more abstract, and this is Abstract 7053. It's a 7-year analysis of the so-called ECHELON-1 study. This was a study comparing the standard of care, ABVD, with the same regimen with bleomycin substituted by brentuximab vedotin for patients with previously untreated advanced-stage classical Hodgkin lymphoma. The study at the time it was originally reported, resulted in a significant practice change in the first-line therapy of Hodgkin's lymphoma. We now have mature follow-up. What are your take-homes from this study? Dr. Marc Braunstein: The ECHELON-1 study has certainly been a practice-changing clinical trial where, as you said, brentuximab with the backbone of AVD was compared to ABVD, which was the prior standard. And this was examined in newly diagnosed patients with classical Hodgkin lymphoma who were at advanced-stage, stage 3 or 4. The publication, first of the progression-free survival, and more recently, in the New England Journal of Medicine in 2022, where we saw the 6-year overall survival was 94% with the brentuximab-containing arm versus 89% in the control arm, established the brentuximab AVD, or otherwise called AAVD, as the standard of care in advanced stage newly diagnosed classical Hodgkin lymphoma. The current study is now reporting 7-year follow-up on about 1,300 randomized patients who were enrolled in this impressive study.   Though at a median follow-up of 89 months now, the 7-year overall survival was quite similar, 94% versus 89%, again favoring the brentuximab-containing arm. In particular, this was driven by patients who had stage 4 disease or those patients who were aged less than 60 in subgroup analyses. So, what I take away from this abstract in the 7-year follow-up of the ECHELON-1 is that brentuximab with AVD remains the standard of care for previously untreated advanced-stage classical Hodgkin lymphoma. It is worth noting that the SWOG S1826 study that was presented at ASCO last year compared nivolumab with AVD compared to brentuximab AVD and did show a slight PFS advantage of 94% versus 86% with nivolumab AVD. Obviously, these were different studies with different patient populations enrolled, so we're really just cross-comparing different studies. But I think brentuximab AVD, given the survival benefit that is retained now at seven years in the current abstract, still remains the standard of care for advanced-stage classical Hodgkin lymphoma. The role of immune checkpoint inhibitors like nivolumab is making headway in terms of treating newly diagnosed patients as well. Dr. John Sweetenham: Yeah, thanks, Marc. I mean, one of the observations that I thought was of interest in this study was the outcome for patients who were PET-2 positive, when you compare AAVD and ABVD. It does seem as if even in those patients who are PET-2 positive, having had AAVD, they still apparently have a better outcome than those who received ABVD in that situation who were PET-2 positive. So, I think that's another interesting observation. I'm not quite sure what it means, except speaking to the overall superior efficacy of that regimen. Dr. Marc Braunstein: You make a great point, John, because it's worth noting that in ECHELON-1, a PET scan was done after cycle 2, but the study was not PET-adapted. So even if you had a positive PET, you continued for the full six cycles of treatment. But PET-2 status is often used in various studies of Hodgkin lymphoma to guide whether to give additional cycles or escalate therapy. So, I think the benefit of presenting those subgroups is that even if you were PET-2 positive, you still did better by continuing on the brentuximab-containing regimen. Dr. John Sweetenham: Yeah, exactly. I mean, the other important takeaway message, I think, is that the outcome for patients with advanced Hodgkin lymphoma seems to continue to steadily improve, which is great news and also really remarkable. And I'm excited to see there may be some additional data presented at one of the late-breaking abstracts in this year's meeting, so it will truly be interesting to see what that shows us as well.  Dr. Marc Braunstein: Incredible. Dr. John Sweetenham: Well, Marc, as always, thank you for sharing your insights with us today on the ASCO Daily News Podcast. We look forward very much to hearing the updated data from these abstracts at the meeting.  Dr. Marc Braunstein: As do I and thank you so much for inviting me again.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's guest: Dr. Marc Braunstein @docbraunstein   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures:  Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness   Dr. Marc Braunstein: Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp Speakers' Bureau: Janssen Oncology Research Funding (Institution): Janssen, Celgene/BMS

Dr Kummar discusses the significance of targeting TP53 Y220C in solid tumors and early data reported with rezatapopt in TP53 Y220C–mutant solid tumors.

Circulating tumor DNA, more commonly referred to as ctDNA, has emerged as an attractive and potentially highly sensitive biomarker for patients with colorectal cancer. But what exactly is ctDNA, does it have any prognostic value for patients with colorectal liver metastasis, and how can it be incorporated into the management of said patients? In this episode from the HPB team at Behind the Knife, listen in on the discussion about ctDNA and its role in the perioperative management of colorectal liver metastasis.   Hosts Anish J. Jain MD (@anishjayjain) is a T32 Research Fellow at the University of Texas MD Anderson Cancer Center within the Department of Surgical Oncology. Timothy E. Newhook MD, FACS (@timnewhook19) is an Assistant Professor within the Department of Surgical Oncology. He is also the associate program director of the HPB fellowship at the University of Texas MD Anderson Cancer Center.  Jean-Nicolas Vauthey MD, FACS (@VautheyMD) is Professor of Surgery and Chief of the HPB Section, as well as the Dallas/Fort Worth Living Legend Chair of Cancer Research in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center Learning Objectives: -Develop an understanding of what circulating tumor DNA (ctDNA) is.  -Develop an understanding of what makes ctDNA unique from other “tumor markers” like CEA. -Develop an understanding of the prognostic value of ctDNA for colorectal liver metastasis (CRLM).  -Develop an understanding of the current role of ctDNA in the perioperative treatment of patients with CRLM. -Develop an understanding of how ctDNA can be incorporated into future treatment algorithms for patients undergoing hepatic resection for CRLM. Papers Referenced (in the order they were mentioned in the episode): 1)    Newhook TE, Overman MJ, Chun YS, et al. Prospective Study of Perioperative Circulating Tumor DNA Dynamics in Patients Undergoing Hepatectomy for Colorectal Liver Metastases. Ann Surg. 2023;277(5):813-820. https://pubmed.ncbi.nlm.nih.gov/35797554/ 2)    Nishioka Y, Chun YS, Overman MJ, et al. Effect of Co-mutation of RAS and TP53 on Postoperative ctDNA Detection and Early Recurrence after Hepatectomy for Colorectal Liver Metastases. J Am Coll Surg. 2022;234(4):474-483. https://pubmed.ncbi.nlm.nih.gov/35290266/ Please visit https://behindtheknife.org to access other high-yield surgical education podcasts, videos and more.   If you liked this episode, check out our recent episodes here: https://app.behindtheknife.org/listen

BUFFALO, NY- April 29, 2024 – Oncotarget is a contributing #sponsor at the 19th International p53 Workshop, organized by the International Center for Genetic Engineering and Biotechnology (ICGEB), which takes place from May 13–16, 2024, in Trieste, Italy. “Groundbreaking research and cutting-edge advancements in the field of the most studied human gene and most frequently mutated gene in cancer, will take center stage at the 19th International p53 Workshop.” – ICGEB.org Among the 24 invited speakers at the 19th International p53 Workshop, 18 speakers have published new research on p53 in Oncotarget. These distinguished speakers who have published with Oncotarget include Dr. Andrei Gudkov — one of Oncotarget's founding Editors-in-Chief. Dr. Gudkov will be speaking in the session on “p53 Inflammation and Immunity” and moderating the session on “Targeting p53 in Human Disease.” “The event will gather leading scientists, clinicians, and researchers from around the world providing a unique opportunity to delve into the latest discoveries and innovations related to TP53 biology and explore the intricate role of TP53 in cancer and its potential for transformative impact in oncology.” – ICGEB.org About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Crossref is a non-profit organization that logs and updates citations for scientific publications. Each month, Crossref identifies a list of the most popular Oncotarget papers based on the number of times a DOI is successfully resolved. Below are Crossref's Top 10 Oncotarget DOIs published in 2023. 10: Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC) DOI: https://doi.org/10.18632/oncotarget.28355 Authors: Md Maksudul Alam, Janmaris Marin Fermin, Mark Knackstedt, Mackenzie J. Noonan, Taylor Powell, Landon Goodreau, Emily K. Daniel, Xiaohua Rong, Tara Moore-Medlin, Alok R. Khandelwal, and Cherie-Ann O. Nathan 9: Novel inflammation-combined prognostic index to predict survival outcomes in patients with gastric cancer DOI: https://doi.org/10.18632/oncotarget.28353 Authors: Noriyuki Hirahara, Takeshi Matsubara, Shunsuke Kaji, Hikota Hayashi, Yohei Sasaki, Koki Kawakami, Ryoji Hyakudomi, Tetsu Yamamoto, and Yoshitsugu Tajima 8: Crosstalk between triple negative breast cancer and microenvironment DOI: https://doi.org/10.18632/oncotarget.28397 Authors: Karly Smrekar, Artem Belyakov and Kideok Jin 7: Systemic AL amyloidosis: current approach and future direction DOI: https://doi.org/10.18632/oncotarget.28415 Authors: Maroun Bou Zerdan, Lewis Nasr, Farhan Khalid, Sabine Allam, Youssef Bouferraa, Saba Batool, Muhammad Tayyeb, Shubham Adroja, Mahinbanu Mammadii, Faiz Anwer, Shahzad Raza, and Chakra P. Chaulagain 6: Deciphering the mechanisms of action of progesterone in breast cancer DOI: https://doi.org/10.18632/oncotarget.28455 Authors: Gaurav Chakravorty, Suhail Ahmad, Mukul S. Godbole, Sudeep Gupta, Rajendra A. Badwe, and Amit Dutt 5: Targeting cellular respiration as a therapeutic strategy in glioblastoma DOI: https://doi.org/10.18632/oncotarget.28424 Authors: Enyuan Shang, Trang Thi Thu Nguyen, Mike-Andrew Westhoff, Georg Karpel-Massler, and Markus D. Siegelin 4: Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells DOI: https://doi.org/10.18632/oncotarget.28382 Author: Mikhail V. Blagosklonny, M.D., Ph.D. 3: The immunoregulatory protein CD200 as a potentially lucrative yet elusive target for cancer therapy DOI: https://doi.org/10.18632/oncotarget.28354 Authors: Anqi Shao and David M. Owens 2: Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss DOI: https://doi.org/10.18632/oncotarget.28376 Authors: Maroun Bou Zerdan, Prashanth Ashok Kumar, Elio Haroun, Nimisha Srivastava, Jeffrey Ross, and Abirami Sivapiragasam 1: Using cancer proteomics data to identify gene candidates for therapeutic targeting DOI: https://doi.org/10.18632/oncotarget.28420 Authors: Diana Monsivais, Sydney E. Parks, Darshan S. Chandrashekar, Sooryanarayana Varambally, and Chad J. Creighton Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed. For media inquiries, please contact media@impactjournals.com.

Dr Lunning sits down with Kami J. Maddocks, MD, of The Ohio State University Comprehensive Cancer Center––James, to discuss the management of MCL in the up-front setting, including practice-changing findings from the SHINE and TRIANGLE trials; how these trial data have altered the role of first-line BTK inhibitors in chemotherapy-free regimens for patients with MCL; and how patient characteristics, such as age and TP53 mutation status affect up-front treatment feasibility.

This episode features a conversation between Dr. Shastri, an Assistant Professor of Medicine at the Montefiore Einstein Comprehensive Cancer Center in the Bronx, New York, and The HemOnc Pulse host, Chadi Nabhan; MD; MBA; FACP; on the latest news in myelodysplastic syndromes (MDS), including the final readout from the COMMANDS trial and the clinical implications of TP53-mutated MDS.

Featuring perspectives from Dr Richard M Stone, including the following topics:  • Introduction: ASH 2023 Update — Key Oral Presentations (0:00) • Case: A woman in her early 90s with dementia who presented with anemia and was diagnosed with low-risk myelodysplastic syndromes (MDS) with ring sideroblasts, now receiving luspatercept — Eric H Lee, MD, PhD (9:09) • Case: An African American woman in her early 60s with high-risk del(5q) MDS who receives oral decitabine/cedazuridine — Henna Malik, MD (26:05) • Case: A man in his late 60s with therapy-related acute myeloid leukemia (AML) with a FLT3-ITD mutation — Rebecca L Olin, MD, MSCE (34:49) • Case: A woman in her early 70s with PMH of inflammatory breast cancer diagnosed with FLT3-ITD AML who achieved a complete response (CR) with azacitidine/venetoclax, followed by gilteritinib maintenance for 2 years — Zanetta S Lamar, MD (40:43) • Case: A man in his mid 30s who presents with pathologic spinal fracture, is diagnosed with myeloid sarcoma and receives induction CLAG-M with CR followed by consolidation high-dose cytarabine — Anna Halpern, MD (43:56) • Case: A man in his mid 80s with MDS, complex cytogenetics and a TP53 mutation treated with azacitidine/venetoclax — Neil Morganstein, MD (46:40) • Case: A woman in her early 70s with newly diagnosed, poor-risk AML, ineligible for intensive chemotherapy (ECOG PS 2) who receives a hypomethylating agent/venetoclax — Amany R Keruakous, MD, MS (49:56) • Case: A man in his early 70s with relapsed AML (SRSF2, IDH1, ASXL1 mutations) after azacitidine/venetoclax, now receiving ivosidenib — Dr Halpern (55:23)   CME information and select publications  

OMG! In this extra fun holiday episode, we are joined by lymphoma experts Tycel Phillips and Aaron Goodman to review the most impactful and controversial lymphoma abstracts from ASH! Stay tuned for a lively discussion! Abstracts Discussed! SYMPATICO (Ibrutinib + Ven in R/R MCL): https://ash.confex.com/ash/2023/webprogram/Paper191921.html Nivo-AVD in elderly Hodgkin Lymphoma: https://ash.confex.com/ash/2023/webprogram/Paper180114.html BOVEN - Zanubrutinib + Obi + Ven in TP53 mutant MCL: https://ash.confex.com/ash/2023/webprogram/Paper180069.html CAR-T in CNS Lymphoma: https://ash.confex.com/ash/2023/webprogram/Paper174883.html (EBMT data), https://ash.confex.com/ash/2023/webprogram/Paper184345.html (Multicenter retrospective study) Synthetic Control Arms: https://ash.confex.com/ash/2023/webprogram/Paper177708.html POLARIX Subgroup Analysis (shout out to the Blood Cancer Talks crew!): https://x.com/Eddie_Cliff/status/1733901400822993257?s=20

Ripped from the pages of the popular Wildfire Magazine anthology, Igniting the Fire Within, we've curated this special mini podcast for you. Each Friday, hear a new bite-sized episode. Featuring “just the stories” from the book read by the authors. Think of this as your dynamic audiobook version of Igniting the Fire Within. Enjoy! This episode features Whitney O'Connor reading her essay “The Cancer Gene.” Whitney O'Connor. Licensed Professional Counselor and Founder of The Boobie Queen Company. Diagnosed at 30 and 32. IDC, Stage III and Stage I, HER2+, TP53+. Augusta, GA. Buy the Wildfire book Igniting the Fire Within: Stories of Healing, Hope & Humor, Inside Today's Young Breast Cancer Community: https://www.amazon.com/dp/B0BJVJ629F?ref_=pe_3052080_397514860More about Whitney: https://www.instagram.com/boobiequeenchronicles/Hear Whitney's story followed by a conversation with April Stearns on The Burn: https://player.captivate.fm/episode/ac2d9319-3fb7-4e93-8ea6-fd4436398b1eGet the free Wildfire email newsletter: https://www.wildfirecommunity.orgLearn about Wildfire writing workshops: https://www.wildfirecommunity.org/workshopsShop Wildfire merch & more: https://www.wildfirecommunity.org/shopSend your voice recording testimonial to editor@wildfirecommunity.org*Free* Get Wildfire and The Burn freebies here: https://www.wildfirecommunity.org/freeFollow Wildfire Magazine:https://www.instagram.com/wildfire_bc_magazine/https://www.facebook.com/wildfirecommunityEpisode URL for Captivate: https://www.wildfirecommunity.org/shop

This past weekend, the CURE® staff was busy covering the American Society of Hematology (ASH) Annual Meeting. ASH is the largest blood cancer conference in the country, and thousands of abstracts were presented. Now, we're bringing you some of the highlights from the conference. And, to view all of our conference coverage, be sure to check out curetoday.com/conference Navitoclax Plus Jakafi Improves Spleen Volume Reductions in Myelofibrosis Spleen enlargement is a common and often problematic symptom of myelifbrosis. However, recent findings from the phase 3 TRANSFORM-1 trial found that combining the novel drug, navitoclax with Jakafi was successful in reducing spleen volume in this patient population. The main outcome that the researchers were looking at in this study was the percentage of patients who had a spleen volume reduction of 35% or more at certain time points. Findings showed that by week 24, 64.2% of patients who had the navitoclax regimen experienced this level of spleen reduction, compared to only 31.5% of patients who received placebo plus Jakafi — that's a significant overall difference of 31%. Navitoclax is not currently approved in any indication, but AbbVie, the pharmaceutical company behind the agent, plans to submit the drug for FDA approval in 2023, pending study results. Brukinsa Lengthens Time to Progression in Relapsed/Refractory CLL, SLL There are currently three BTK inhibitors for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL and SLL, respectively), though a lack of research exists that compares these drugs head-to-head. Now, the phase 3 ALPINE trial was the first study to directly compare two BTK inhibitors, Brukinsa and Imbruvica, in patients with relapsed or refractory CLL or SLL. Findings showed that after about 39 months of follow-up, patients given Brukinsa tended to live longer before death or disease progression — a statistic experts refer to as “progression-free survival.” In the general patient population, Brukinsa reduced the risk of disease progression by 32%, and for patients with 17p deletion and/or TP53 mutations — subtypes that typically indicate aggressive disease — there was a 48% reduction in the risk of disease progression. Abecma May Improve Quality of Life in Previously Treated Myeloma The phase 3 KarMMA-3 trial showed that Abecma significantly improved symptoms, functioning and health-related quality of life in patients with relapsed or refractory multiple myeloma who previously underwent two to four prior treatments. Abecma is a CAR-T cell therapy, which is a newer type of treatment for blood cancers. It involves taking patients' blood out, and re-engineering their T cells to find and fight cancer. After they're multiplied, those new T cells are infused back into the patient. Findings from the KarMMA-3 trial showed that Abecma led to improvements in fatigue and pain compared with other standard regimens in this patient population.

On today's episode we'll discuss the findings from a phase 2 study of sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML, learn more about the inhibition of PLK4 in TP53-mutated AML, and discuss the role of CD44 in Plasmodium falciparum infection.

On this episode we welcome back Charlotte and talk bison basics. This is part 1 of 2 of our American Bison series. Give it a listen and share with your friends!Find us on all the things: http://linktr.ee/bearsandbrewspodcast Sources Cited:Coffey, Rebecca. “Bison versus Mammoths: New Culprit in the Disappearance of North America's Giants.” Scientific American, 1 Mar. 2011. Dekel, Yaron, et al. “Dispersal of an ancient retroposon in the TP53 promoter of Bovidae: Phylogeny, novel mechanisms, and potential implications for cow milk persistency.” BMC Genomics, vol. 16, no. 1, 2015, https://doi.org/10.1186/s12864-015-1235-8. Harington, C.R. “Mammoths, Bison and time in North America.” Developments in Palaeontology and Stratigraphy, 1984, pp. 299–309, https://doi.org/10.1016/s0920-5446(08)70078-5. Mintoo, Abdul Awal, et al. “Draft genome of the River Water Buffalo.” Ecology and Evolution, vol. 9, no. 6, 2019, pp. 3378–3388, https://doi.org/10.1002/ece3.4965. “Plains Bison (BISON BISON BISON.” U.S. Fish & Wildlife Service, www.fws.gov/species/plains-bison-bison-bison-bison. White, P.J, and Katrina L. Auttelet. Yellowstone Bison Conserving an American Icon in Modern Society. Yellowstone Association, 2015. “Wood Bison Restoration in Alaska.” Alaska Department of Fish and Game, 2023, www.adfg.alaska.gov/index.cfm?adfg=woodbisonrestoration.herdupdates#:~:text=With%20the%20addition%20of%2028,150%20in%20November%20of%202022. Hosted on Acast. See acast.com/privacy for more information.

Dr. Shannon Westin and her guest, Dr. Nanda Horeweg and Dr. Carien Creutzberg, discuss the paper "Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer" recently published in the JCO. TRANSCRIPT  The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. I'm your host Shannon Westin, Social Media Editor for the JCO and GYN Oncologist by trade. And I'm so excited about today's topic because it is a GYN Oncologist dream. Before I start, please note that none of the authors have any conflict of interest. We are going to be discussing molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early-stage endometrioid endometrial cancer. And this was published in the JCO on September 20th, 2023. And we're going to be speaking to two of the lead authors. First is Nanda Horeweg. She's a senior researcher in the Department of Radiation Oncology at the Leiden University Medical Center in the Netherlands. Welcome. Nanda Horeweg: Thank you. Happy to be here. Shannon Westin: And Dr. Carien Creutzberg. She's professor at the Department of Radiation Oncology at the Leiden Medical Center as well. Carien Creutzberg: Thank you. Shannon Westin: So, let's get into it. And I want to really level set because we have a mixed audience here. So, why don't you start by speaking about the incidents and mortality of endometrial cancer? Nanda Horeweg: Yes, of course. Endometrial cancer is the sixth most common cancer in women with around 400,000 new diagnoses made globally each year. And a woman's lifetime risk to get endometrial cancer is around 3%, and the median age, the diagnosis is 61 years. Most of the women who are diagnosed with endometrial cancer are diagnosed at an early stage, around two thirds, and they have an excellent prognosis. Actually, the five-year survival rates are around 92%. For stage 2 disease, this is actually already going down a bit to 74%. Therefore, stage 3 disease is only 48%. Women that are diagnosed with advanced disease have only a five-year survival, 15%. Shannon Westin: So, given that we know the majority of endometrial cancers are diagnosed at this early stage, prior to your evaluation, what was known about the optimal way to treat this early-stage patient population? Carien Creutzberg: Well, of course, the PORTEC trials were done … were started PORTEC-1 in the 19th of the last century, and PORTEC-2 in 2002. So, at that time, there were still many, many women treated adjuvantly with external beam radiation therapy. And we just developed risk factors to decide on their risk and the incidents for radiotherapy. And in PORTEC-2, because in PORTEC-1 we had seen that most of the recurrences in these early stage cancers were in the vaginal fold, we compared local vaginal brachytherapy only three sessions within full course of pelvic radiotherapy and showed that it had similar pelvic control and survival. Of course, this study, which Nanda conducted, was a long-term analysis with many new factors known from the translational research in the tissue samples of these patients who participate in PORTEC-1 and 2. And in the meantime, we've developed much more knowledge on the molecular factors and other important factors such as LVSI, which tell us much more about the individual prognosis to patients. So, the treatment has been developing greatly in the past 20 years. Shannon Westin: Yeah, and I think this is a great case of less is more, right? We were doing so much for so many people that really didn't need it. And so, really tailoring who needs less treatment, who doesn't need any treatment, and then also, conversely, who may need more treatment that would be missed by the traditional risk factors that you're speaking of. So, I think that brings us right into my next question, which is just bringing the audience up to date on the cancer genome atlas and how that's changed the way we classify endometrial cancer. Nanda Horeweg: Yes, I think the molecular classification of the TCGA has shaped the way we think about endometrial cancer, and has huge impact on decisions on adjuvant treatments in the years to come. The TCGA performed an extensive characterization of the endometrial cancers and found that in fact, this disease exists of four different groups. And the first of the groups I'd like to discuss is the ultra-mutated group, which is characterized by POLE mutations. And this group is shown to have an excellent prognosis in many independent studies. A second group that also has a high mutational burden is characterized by microsatellite instability, and mismatch repair deficiency and has shown to have an intermediate prognosis. Then there's another group that has a low mutational burden with high copy number alterations and frequent TP53 mutations, and these have a poor prognosis. And then lastly, there's a group that does not have any of the classifying features and is often called non-specific molecular profile or TP53 wild type. And this group also has an intermediate prognosis. And then finally, there's a small group of cancers that has more than one of these classifying features, the so-called multiple classifiers. And the WHO 2020 has developed an algorithm which can be used to classify them into the four groups. And that's first on the POLE status. And for the POLE wild type tumors, they are assigned according to mismatch repair deficiency status. And for those that are mismatch repair proficient than POLE wild type, they are classified according to the TP53 status into NSMP or p53 abnormal. Carien Creutzberg: Yeah, that is because of in the ultra-mutated and hyper mutated groups, many of the other mutations are secondary mutations in the context of the ultra-mutated stage, and they behave like the first molecular group. Shannon Westin: Yeah. So, that POLE mutation is going to trump anything else, and it's so important. And I will just say as a sidebar, it's been challenging with the price of next gen sequencing sometimes to get that for everyone. So, sometimes for us when we see a p53 mutation, we actually go back and do the full next gen sequencing to make sure that we're not going to act on that core prognostic feature when it really is in the setting of that more simplistic or that more positive prognostic place. So, this is great, we already kind of highlighted a little bit PORTEC-1 and 2, but if you don't mind, I would love to get the audience a little bit more information just maybe about the populations that were included as we were figuring out how aggressive to be with radiation just to remind people of that, or to teach them that if they haven't gotten a chance to look at those studies. Carien Creutzberg: Yeah, that's important to know because PORTEC-1 was still in the era that we also treated intermediate risk stage 1 endometrial cancer patients. So, deep invasion with grade 1 and 2 or superficial invasion with grade 2 and 3. That's what we defined at that point. Then we compared external beam radiation or no further treatment, showing no survival difference, but a higher risk of recurrence with higher risk being older age over 60, grade 3 for deep myometrial invasion. And we kept those high intermediate risk factors as also similarly found by GOG-99 at the time to do PORTEC-2. So, at the time, about 50% of patients did not have an indication for adjuvant therapy anymore, and with a high intermediate risk population for PORTEC-2, we compare external beam or vaginal brachytherapy and found the benefit of vaginal brachytherapy. A simple outpatient treatment, very short with almost no side effects ensuring local control. And nowadays, using the molecular classification of PORTEC-4a, we've compared achieving treatment with or without use of the molecular factors to designated treatment. So, the standard arm is vaginal brachytherapy and investigational arm is first, a molecular risk profile. And then we give no radiotherapy for those with a favorable profile, then a brachytherapy for the intermediate ones, and for the small group is either extensive LVSI or TP53 mutation or L1 chem overexpression external beam. And we hope to show that less overtreatment and less undertreatment will benefit these patients. Shannon Westin: Yeah, I'm very much looking forward to the results of PORTEC-4a. But let's circle back and talk a little bit about your amazing work here. So, how did you leverage those patient populations from PORTEC-1 and 2 for the current study? Nanda Horeweg: Yes. Well, the PORTEC-1 and 2 study provided a unique opportunity to look into differential treatment effects for radiotherapy. And that is because these are randomized trials, so the groups are comparable, and we have long-term follow-up data that's of very high-quality. In addition, as Carien said earlier, she had the vision already back in the nineties to directly ask the patients permission for the collection of the tissue. So, we have a broader complete biobank for both of these trials, which is quite unique. And our colleagues, Professor Smit and also Charlene Goseff from the pathology department, they have done extensive work on molecular classification, and have molecularly characterized all these cases. So, this allowed us to include 880 patients in this study, which is the largest so far. And besides like the very good starting point that we have of PORTEC-1 and 2 is that we also chose a design that was optimized to conduct like real causes, the causal effects of the molecular class on radiotherapy response. So, we tried to preserve this randomization effect, the exchangeability of the groups as much by working with the intention to treat population and not excluding any patients, except for when they did not have the molecular classification assessed. And also, we looked at areas in the body that were irradiated in one group and not in the other one to really observe the effect of radiotherapy as much as possible. So, looking to the entire pelvis, so local and regional recurrences in PORTEC-1 and looking at pelvic recurrences in PORTEC-2. Shannon Westin So, how were the intervention outcomes in this study different based on the TCGA classifiers? Nanda Horeweg: Before I tell you the results of biomolecular group, I think it's good to have the starting point of the analysis here. So, the no hypothesis of my study was to see whether there was any difference, and no hypothesis is that there's no difference. So, if we find a significant effect, then we can actually say that we found something. And if we start with the POLE group, we did not find any significant difference between the groups allocated to radiotherapy or not. But we did see not a single recurrence in any of the patients that we included from both of these trials. So, technically speaking, we did not find a predictive effect of the molecular classifier, but a prognostic effect. There's no one's having recurrence, so we can deduct from that, that radiotherapy is probably over treatment. Then for the MMRd group, we did observe some recurrences, but these were not significantly different between these three groups. So, based on this study, we cannot draw conclusions on which type of radiotherapy we should give to the patients or whether we should give radiotherapy at all. This was very different for the p53 group. There, the patients had lots of recurrences, unfortunately, as we expected, but we saw a big difference in outcome compared between no radiotherapy at all if it's vaginal brachytherapy where we still had lots of recurrences, and EBRT where we hardly saw any recurrences in the pelvis. And that difference was significantly different. So, that's an indication that these patients need more than just vaginal brachytherapy, even though it's only stage 1 endometrioid endometrial cancer. And then in the last group, the NSMPs, we saw even a different pattern where patients who had had external beam radiotherapy or vaginal brachytherapy, both had an excellent local regional control, and the ones that did not receive any treatments had more recurrences. And this was also very significant. So, there, you would conclude that both therapies are appropriate, but of course, the toxicity profile for vaginal brachytherapy is much more favorable than that of EBRT. Shannon Westin: We really are getting kind of consistent data around p53 needing more treatment. And I think the natural question that comes here, for me at least, and I know we can't answer it with the work, is would chemo be — would that be that extra treatment, when we saw with PORTEC-3 that the group needed the chemotherapy the most. So, I think we'll have to continue to work through that and determine is any more treatment what we need or specific treatments really the best. So, this is so intriguing and it's nice that it's consistent, that we're seeing that across these different studies that really kind of lends strength and validity, I think to what we're finding. So, one of the actions that we're kind of moving towards and that you advocate certainly in your paper is omitting therapy for patients with POLE mutations. Are there any ongoing studies around that that will help us confirm that this is safe for our patients? Nanda Horeweg: Yeah, that's a very good point. I think the evidence is strong enough now to conduct prospective trials. And of course, these are ongoing, the PORTEC-4a trial was already briefly mentioned there. The patients with poor mutations will be randomized between observation and vaginal brachytherapy. So, that will give us a good indication whether in this high intermediate risk early-stage group omission is safe. And in addition to that, we are also conducting with the RAINBO Consortium, the RAINBO-BLUE trial, wherein patients also with high-risk features, so non-endometrioid isotypes, LVSI and higher stages are included. And also in those patients, we investigate whether the de-escalation of treatment is safe. So, we're definitely looking forward to those results to be able to transfer this knowledge to clinical practice later on. Carien Creutzberg: And maybe it's nice to add that RAINBO BLUE is connected to the Canadian Taper trial. Taper being a general de-escalation trial where the POLE patients in that trial are also feeding into the RAINBO-BLUE. And I know that in North America, many centers will participate in the Taper trial. Shannon Westin: Yes, I think everyone is very excited and I think it'll be nice to have these two very strong studies that will help us really confirm that that is 100% a test that needs to be done, cost are not — and that will help avoid overtreatment of patients. So, in line of that, have you all experienced any challenges with implementing molecular testing across patients with endometrial cancer? Any thoughts on how we could potentially simplify? You talked about the rational promise algorithm, which I think is excellent, but I'm just curious to hear your thoughts on this. Nanda Horeweg: The implementation of the molecular classification can be challenging. We have to be honest about that. And usually, it's the assessment of the POLE status that's causing the problems because that's usually done with NGS, which is quite expensive. It requires a lot of knowledge in the laboratory and it's also a bit time-consuming. So, that is the bottleneck for most laboratories and for most settings. But this is already changing in a couple of places, like in the UK and the Netherlands, it's being reimbursed by healthcare insurances, and also, in many tertiary care centers in other countries, they're already systematically performing this test. But of course, there will always be places where this is not feasible. And luckily, there are also cheaper alternatives coming up and are already available at the moment. So, one of them is, for example, standard sequencing, which is not so expensive, but a bit labor intensive. Some colleagues we work with from India have implemented that in their clinical practice and are perfectly able to molecularly classify the endometrial cancers in daily practice. Another alternative is a test that we've developed in Leiden that's called the QPOLE test, which is based on qPCR, so that's a technology which we use for our COVID test around the world, so that can be done almost anywhere. And with that, you have a very high accuracy to detect unknown pathogenic variants. And this is also published in JCO Global Oncology, and can be implemented in any center after a local validation step. And even like more companies nowadays are realizing that this is important. So, I think commercial tests are already becoming available and very more on the market soon. So, I am really hoping that it'll be more available to endometrial cancer patients. Carien Creutzberg: And they'll offer them at a very low cost and also a rapid turnaround because NGS can take like 10 days. But realizing on a more national level, if you have found one patient with a POLE mutation, the omission of cycles of chemotherapy with all of the patient care around in the hospital is worth much more than just a few POLE tests. So, we have to look at this and that's I think why our healthcare reimbursement came through that if you look at a population level, it is cheaper, and we'll do an extensive cost analysis in PORTEC-4 just to show this. Shannon Westin: That is such a good point. I love that and all of the downstream issues that happen potentially with radiotherapy or with chemotherapy, that's really brilliant. And I'm going to take that back, I love these podcasts. I always learn stuff that I immediately start to use. So, I guess then the last question is, what's next for this particular research and how might we validate what you found? Nanda Horeweg: Yes. Well, as mentioned earlier, for POLE, we have already put the next step in place. So, PORTEC-4a has completed accrual almost two years ago, and we're very much looking forward to do the final analysis within one to one and a half years. So, that will be one of the important next step. And of course, the POLE-BLUE trial is open at the moment, and within a couple of years, we also hope to learn more about this group. So, that's very exciting. Then for the mismatch repair deficient group, while we did not find any particular sensitivity for radiotherapy, and I also don't think that we will conduct another large randomized radiotherapy trial in this group — I think the results that we've observed in the metastasized setting, were really impressive results with immunotherapy are the way forward for this molecular class. And I think the next thing we should do now is prove whether this works or not in the adjuvant setting. And if that's starting with the high-risk patients, which is something we are currently doing in the MMRd-GREEN trial, which is ongoing in the Netherlands, and soon, will open internationally. And from there on, we can work forward if we see that also in this setting the immunotherapy works well. Shannon Westin: And I think GY020 also — NCI trial is also looking at the addition of immunotherapy to radiotherapy in that irony at risk. Carien Creutzberg: Absolutely. Nanda Horeweg: Yeah. And the KEYNOTE-B21 as well — oh, well, already complete accrue. Shannon Westin: The B21, yeah. So, I think those are good. Yeah, that's a really good point for that MMRd group that the immunotherapy really is the way to go, and then more work to be done with the no specific molecular profile. Nanda Horeweg: The NSMP, I think like for the early-stage group, it's quite clear that vaginal brachytherapy is a therapy of choice. But you can of course, try to identify those at such a low risk that you could deescalate treatment. And that's of course what's being done in the Taper trial and also in part, investigated in the PORTEC-4a trial. Carien Creutzberg: And those with higher risk NSMP that we are revisiting hormonal treatments because 90% are estrogen receptor positive, and they have a clearly better prognosis than those with estrogen receptor negative tumors. So, those with estrogen receptor positive tumors can in RAINBO-ORANGE, which will be run led by the UK group, see if we can improve quality of life with less intensive adjuvant treatment. And then you came to the p53 group, that's a good one to stop with. Nanda Horeweg: Yeah, we have very good indications that radiotherapy and chemotherapy is working well for this group. And this is also in line with the guidelines that have been issued in the last few years by many societies. So, I don't think we should change this base of the treatment consisting of radiotherapy and chemotherapy. But since the prognosis is still rather poor, we need to add systemic agents to reduce the risk of metastasis. And preferably, this should be like well-designed based on a proper biological underpinning, plus something that's not too toxic since we're combining the three therapies together. So, this is what we try to do in the RAINBO-RED trial where we will investigate the addition of a PARP inhibitor to chemoradiation in the p53 group. Shannon Westin: Oh, I love that. That's been my whole career, is adding PARP inhibitors wherever I can. Carien Creutzberg): We might also want to mention the HER2 inhibitors, which are also in about 20% of the p53 group has HER2 overexpression. And there is a trial being set up in NCI with trastuzumab and pertuzumab. Shannon Westin: My only concern with that one is I think that the antibody drug conjugates are so much more powerful, the TDX data that we just saw from DESTINY is so impressive. And so, I do wonder, like if we need to move on from kind of some of the older HER2, and get with the program and use some of these more powerful drugs. But with that, I just want to thank Dr. Creutzberg and Horeweg. This was such a great discussion, and obviously, near and dear to my heart talking about endometrial cancer, but I hope our audience enjoyed as well. Just as a reminder, this was a discussion on molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early stage endometroid endometrial cancer, published in the JCO on 9.20.23. I am your host, Shannon Westin, and I hope you'll check out more JCO After Hours 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.    

In this "Podcast Takeover," Dr. Lidia Schapira guest hosts to discuss with Dr. Shannon Westin her own JCO paper, which reports on the DUO-E Trial. Dr. Ramez Eskander also joins in this lively discussion. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor of the JCO and Gynecologic Oncologist by trade. And actually, I'm super excited today because we are going to have a podcast takeover because we are discussing my own work, which was simultaneously presented at the European Society of Medical Oncology 2023 Congress and published in the Journal of Clinical Oncology on October 21st, 2023. And this was the DUO-E trial, “Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer.” Because we're discussing this work and we wanted you to have an unbiased podcast discussion, Dr. Lidia Schapira, who is a Professor of Medical Oncology at Stanford University and an Associate Editor of JCO and the Art of Oncology podcast host, is going to take over this podcast and really just pepper me with questions about this exciting work.  Welcome, Dr. Schapira.  Dr. Lidia Schapira: Thank you so much. It's such a pleasure to be with you. Dr. Shannon Westin: And before I turn over the reins, I also want to introduce one of my colleagues, who's going to be providing quite a bit of insight on this topic, Dr. Ramez Eskander, who is Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Diego. And you will know he's the principal investigator of the GY-018 study, which established pembrolizumab and chemotherapy as the new standard of care in endometrial cancer. Welcome, Ramez.  Dr. Ramez Eskander: Thank you. Thank you, Dr. Westin. It's a pleasure to be here. And congratulations again to you and your study team for this exceptional work.  Dr. Shannon Westin: Thank you. And congratulations to you.  Dr. Schapira, thank you for being here and please do take it away. Dr. Lidia Schapira: So let's start by having you tell us a little bit about the standard of care for women with endometrial cancer and advanced endometrial cancer prior to this study. Ramez, I'm going to direct this question to you first. Dr. Ramez Eskander: For many years, actually since about 2012, carboplatin and paclitaxel, which ironically is a chemotherapy backbone really across all of our gynecologic tumors, emerged as the preferred doublet chemotherapy regimen for the management of advanced-stage metastatic or recurrent endometrial cancer. It evolved through a series of different clinical trials, in fact taking us from whole abdominal radiation, systemic chemotherapy, comparing single agents to doublets and then triplet regimen of TAP to carboplatin and paclitaxel, which ultimately, then, following the presentation of GOG Protocol 209 and its publication, as the chemotherapy backbone, being carboplatin and paclitaxel. And it's been that way for many, many years. Dr. Lidia Schapira: And how effective is the regimen? Dr. Ramez Eskander: The response rates to carboplatin and paclitaxel are actually quite reasonable in the patients who have advanced-stage disease, particularly if they haven't had prior systemic chemotherapy. Response rates in the 50% to 60% range. The issue is that the responses tend to be limited and disease recurrence is an expectation in these patients who have advanced-stage disease. And so that really highlighted the importance of trying to continue to advance therapeutic opportunities in these patients to improve long-term outcomes.  Dr. Lidia Schapira: As we think about improved long-term outcomes, we're thinking about a better treatment and also a kinder treatment, perhaps one that is also less toxic. Can you talk a little bit about the population of women with endometrial cancer? Are these older women? Do they have comorbidities?  Dr. Ramez Eskander: What we're seeing is, interestingly, there has been an evolution a bit in this space. Historically, we used to think about endometrial cancer as—the phrases we used to use are type I and type II. These type I tumors, we would say, are estrogen-driven malignancies; they tend to be seen in overweight or obese patients. And we would identify them in a theoretically younger patient population. And then we had these type II, or what we termed estrogen-independent malignancies, that we would see in an older patient population. Of course, with obesity came metabolic syndrome and other cardiovascular comorbidities, etc. But really, that narrative has evolved dramatically, and that's really something that will be highlighted in, I think, our discussion of these studies today, where the nomenclature that we used to historically use has evolved because of our understanding of the molecular characterization of this disease. So we've really gone away from that, and now we understand that we're seeing all of these different heterogeneous endometrial cancer types amongst patients of different ages, different comorbidities, different races and ethnicities. And so it's created a more complex picture for us. But certainly, there are comorbidities that these patients face, and that's important as we look to identify treatments strategies that are both effective and tolerable. Dr. Lidia Schapira: My final question before we jump into this very exciting study is about the Cancer Genome Atlas work. Can you tell us how that's changed the thinking and the design of the studies? Dr. Ramez Eskander: It was a seminal publication, really, back in 2012/2013 looking at an assessment of endometrial cancers to try and determine whether or not all of these "endometrial cancers" that we used to enroll on a single study are similar or divergent. And it's important because the study I referenced that really established the standard of care, GOG Protocol 209, as carboplatin and paclitaxel, there was no real consideration of molecular characterization at all. We enrolled all patients onto this study without thinking about these variables, of course, because it was designed, conducted, and completed before the TCGA data emerged. But what we learned from the TCGA is there appeared to be four distinct molecular subgroups. There were the POLE-mutated patient population. There was the mismatch repair deficient or MSI-high endometrial cancer population. There was the copy number-high or what we say are the p53-mutated. And then the last cohort was called the NSMP (no specific molecular profile). But now, that's even evolved; some people term it TP53 wild type. That's a bit of even a heterogeneous cohort amongst itself. So we're going to take these subsets, independent of POLE and an MSI-high, and we're going to look at TP53 or copy number-high, and that will probably be divvied out further, and the NSMP, and that will probably be subdivided. But really, it gave us these four components, which has then evolved. Many of you may have heard of the ProMisE algorithm or ProMisE Plus, which looked to take the data from TCGA so that we can start to really look at it in clinical practice. So it's really revolutionized how we think about these patients, how we think about the disease, and how we design trials.    Dr. Shannon Westin: And I just want to add to that because I think that it's so important, what Ramez said about the way we were developing trials, the way we were designing trials. We knew that these classifiers—we were learning these classifiers are prognostic. Now what we're really trying to hone in on is how predictive they are. And certainly, one of the major classifiers that we're going to talking about today is mismatch repair status, and that is most definitely predictive of response to therapies. But we're still learning about the other classifiers and how we might adjust the way we treat people, even deescalating care for certain patients. That is still being proven in clinical trials, although we suspect that it's going to be borne out as other clinical trials report. Dr. Lidia Schapira: It's a perfect segue to this current trial. Tell us a little bit about the objectives and the design of DUO-E. Dr. Shannon Westin: As Ramez said, the standard of care was chemotherapy. And so we wanted to see if there was a way to improve outcomes for these women with advanced and recurrent endometrial cancer in a really clinically relevant, meaningful fashion for patients. And so we knew that this TCGA classifier, the mismatch repair, was so important, and we thought that the addition of immunotherapy to chemotherapy would most certainly work in that population but could even work in the entire population because, generally, endometrial cancer seems to be a little bit more responsive to immunotherapy and to activation of the immune system than, say, some of our other gynecologic malignancies. And so we set out to see what the addition of durvalumab, which is a PDL-1 inhibitor, would add to chemotherapy. And this was two chemo as well as followed by durvalumab maintenance.  But even further, we had some really kind of exciting science data from our lab that said that if we combined a PARP inhibitor with immunotherapy that we could accentuate on the response to therapy and we could get more benefit. And there's kind of a lot behind that, but essentially, what we thought was that the damage that's caused by the PARP inhibitors would create an activation of different immuno-pathways, like STING pathway and activating cytokine release, and that we would get this synergistic activity. So one of the other objectives was to see if the addition of the olaparib, the PARP inhibitor, to durvalumab in that maintenance setting could even further improve benefit. So we had a dual primary endpoint looking at progression-free survival, so the amount of time people live without their cancer coming back. And that endpoint was first, the durvalumab-alone arm to control, and then the second portion of that was the durvalumab/olaparib arm back to control. Dr. Lidia Schapira: So before you tell us about the results, tell us a little bit about the study itself. I mean, I was very impressed that you did it in so many different locations. Tell us about that effort.  Dr. Shannon Westin: This was a huge collaborative effort both with the GOG Foundation, the Gynecologic Oncology Group Foundation, as well as ENGOT, which is our European colleagues that do amazing clinical trials. But in addition to that, we really worked very closely with our industry partner to really make sure we spanned the globe. And so we had groups from all over the world that participated and really were exceptional. The care that was taken and the hard work that went into this type of study across the world really can't be overstated. We were very lucky to have a wonderful infrastructure group. We met weekly for a long time, just keeping an eye on the data and making sure that everything was as positive as possible and, of course, that we were watching the outcomes of the patients very closely and making sure that there was no evidence of harm or issue. And so it really did take a village, truly, to run this study and to ensure that at the end of it, we got really great data that we can trust. Dr. Lidia Schapira: So tell us the results. Dr. Shannon Westin: So DUO-E was positive for both of its primary endpoints, which was very thrilling. So for the first analysis, which is the durva-alone arm to control, we saw a reduction in the risk of progression of 29%, so a hazard ratio of 0.71. And then the addition of olaparib seemed to further enhance this benefit, so a 45% reduction in the risk of progression for a hazard ratio of 0.55. But what's really exciting is our follow-up time was pretty long; it was about 17 months, so we were able to look at a couple of different analyses, including an 18-month landmark analysis where we saw approximately 50% of the patients were still alive progression free at 18 months, as compared to only 21% of patients being alive progression free in the control arm. So there was a doubling in that progression-free survival time point at 18 months, which is thrilling. Dr. Lidia Schapira: So Ramez, as an expert in the field, what was your reaction when you read or heard these results?  Dr. Ramez Eskander: It's exciting, honestly. So we have gone a long time without seeing really significant successes in the endometrial cancer space, a testament to the fact that we hadn't yet developed our understanding of how we could move this needle forward. But Dr. Westin and the DUO-E team conducted an exceptional clinical trial, as you mentioned, international study, rational and important hypothesis to adjudicate. And what we saw here was both now we had other studies—the RUBY trial, the GY018 trial, the  AtTEnd—and now here DUO-E, which added this hypothesis of PARP maintenance in addition to checkpoint to try to augment response and consistent, really provocative data, exciting, in line with what we've seen and hopefully will continue to drive the science in this space, most importantly. Dr. Lidia Schapira: So let me ask you a follow-up question to that. What kind of scientific questions are in the air now as a result of this trial and what the trial found? Dr. Ramez Eskander: Oh, goodness. Shannon and I could both take this, I'm sure. But I think in the dMMR population, we recognize that there's a ton of data that is supportive of the fact that these tumors are immune responsive, particularly in dMMR endometrial cancer, whether it's an epigenetic promoter hypermethylation, or a mismatch repair gene mutation. I think the data has emerged that immunotherapy is here to stay for these patients in the newly diagnosed advanced stage, even chemo naïve, who need adjuvant therapy.   The pMMR population, this is where we're seeing more and more questions emerge because we realize that that may be a cohort of different cancers. And I'll let Shannon speak to this briefly, but even the incorporation of the PARP inhibitor, in addition to the checkpoint, there's a biologic rationale for combining those two together to augment response. And to see the benefit in that trial—arm three and arm two, we can look at descriptively and look at the differences, but who are those patients? Where is the PARP and the checkpoint most effective? How do we expand that to a larger population of patients potentially? These are questions that emerged because, as Dr. Weston will allude to, I know we also talk about HRR mutations, which are captured, but we even have a lot to understand about that in endometrial cancer, where we've had more research in the ovarian cancer space. Dr. Shannon Westin: Being mindful of time, because I have, like, 1,000 hypotheses that have been generated by this study, which, I think, shows it's a great study, right? Because you get some answers, and as our colleague Brad Monk says, “The only definitive study is the negative studies.” This most certainly was not that. But just kind of expanding on what Ramez said, the interesting thing about DUO-E is that really the biggest benefit for the combination of the durvalumab and olaparib was in that mismatch repair proficient group. And I personally thought that we were going to see accentuation of the impact in the mismatch repair deficient group based on the science, but that just wasn't borne out by the data. It doesn't seem that the combination has that much to add in that mismatch repair deficient group. And when we tease out the mismatch repair proficient group, I think that's where a lot of interesting information is going to come because, to Ramez's point, we're going to tease out: Is it driven by the P53-mutant population? Is it driven by the population that has homologous recombination deficiency? How do we even measure homologous recombination deficiency in endometrial cancer? So I'm super excited about what we found and how that may help us to make those decisions for the patient in front of us.  The other thing I think needs to be made mention of—and this was something we saw in DUO-E as well as AtTEnd—we had a large population of patients that were recruited in Asia, 30%. Interestingly, when we look at the forest plot, that group doesn't seem to benefit as much from the addition of the olaparib. So we really need to tease out what's different about that population because what Nicoletta Colombo presented around AtTEnd, it looked like they didn't benefit from the atezolizumab either in that study. So there's clearly something different about that population, and we have a really big opportunity to look at that since we had such a large proportion of patients that were enrolled there. So that's another, I think, really intriguing question. Dr. Lidia Schapira: So how does this fit in the context of endometrial cancer treatment, and what are we going to do with patients in the clinic? I'd love to hear both of your perspectives, starting with you, Ramez. Dr. Ramez Eskander: It's an evolving answer, to say the least. What we can say definitively is that we have a United States FDA approval for the regimen of dostarlimab plus carboplatin and paclitaxel in the mismatch repair deficient, advanced-stage/recurrent or metastatic patient cohort. And again, that's because the magnitude of benefit that we saw in the RUBY trial, which looked at that, was actually analogous to what we saw in 018, AtTEnd, and DUO-E, again, consistently highlighting the benefit of the IO and the dMMR. We have yet to see how this is going to evolve the landscape in the larger patient population, which is the pMMR patient population. And it may be that based on the data that we have, we will see immunotherapy plus carboplatin and paclitaxel as the new standard of care in the pMMR cohort, or it may not. That's yet to be defined. And I think Dr. Westin will add to this, but I think that's also going to depend on the perception of how we view the cohort. Is it one group of patients? Are we going to have to think about subsets within the pMMR population? That is an active conversation. Dr. Shannon Westin: I would just add, having treated patients on this combo regimen with the durvalumab and olaparib, I have multiple patients that still remain on study, and this—we're looking at three and four years out. I just never saw anything like that before with standard chemotherapy, so there's definitely something here. So I want to know who those patients are, who benefits really the best from the combination, and who could we just give the immunotherapy to and get that same benefit. So we obviously always want people to live as long as possible. That's the bottom line. But we don't want to overtreat. And so I think balancing that is really important. Dr. Ramez Eskander: The point that was made earlier: We have yet, aside from MMR response to checkpoint, within the pMMR population, we understand that there may be subsets, but we have yet to prospectively validate that these molecular cohorts within the pMMR population are truly defining response to a particular therapeutic strategy. So we have to be cautious not to limit the treatment opportunities for these patients without having the data that we need to do so because, as Dr. Westin mentioned, for us—whether it was the Gy018 trial, the RUBY, the DUO-E trial—what we saw is there are pMMR patients who have a dramatic response even though they are “biomarker negative.” They're pMMR, they're TMB low, they're not POLE mutated, but yet they still derive a dramatic benefit. And so that goes back to the hypothesis about why we're even combining checkpoint with chemotherapy in which, for example, in lung cancer, there's been established success and approval. So I think we're all eager to see these strategies emerge as treatment opportunities for the pMMR patients as we work to still develop additional effective opportunities. Dr. Lidia Schapira: So, based on all of this and sort of the new twists on the scientific hypotheses that are now generated, what are the next steps? Dr. Shannon Westin: Well, I think we have to see if these drugs are available for patients. So looking at things like compendium listing and regulatory approvals obviously is going to be very important. But from the things that I can control, we are looking at the different molecular subtypes and understanding the different mutation status and trying to tease out who may be driving the biggest benefits so that we can help advise and make sure that we're doing the right thing for the patients. Dr. Lidia Schapira: And wearing my supportive care hat, I have to ask you, Shannon, about the tolerability. We often find that the quality of life and studies come out after, sometimes months or years after, the original trials are published. So let me take this opportunity to ask you now: How did women tolerate these drugs? Dr. Shannon Westin: The bottom line, Lidia, is, as expected, when you add additional drugs, you see additional side-effects. I think the good thing is that we're very comfortable with immunotherapy and we're very comfortable with PARP inhibition in gynecology because we have had access to these agents and so we know how to manage the toxicities. And so, from a standpoint of incidence, there was a higher incidence of grade three and higher adverse events in the group that had durvalumab/olaparib. But this was primarily driven by anemia, which is as expected and is usually pretty time-limited at the start of olaparib. From a long-term standpoint, there was a slightly higher proportion of patients that discontinued therapy, but it actually wasn't as much as I was worried about. So we saw a 19% discontinuation rate in the group that was just the control arm, and that went up to 24% in the dual arm, so definitely higher, but not that much higher. And when we moved to maintenance, which is really where—that's where the arm becomes unique, it was much lower at about 12%. And so that's exciting to me, that patients were able to stay on a drug and were able to tolerate it.  And then, to your other point, we do have a very nice patient-reported outcomes plan, and that is actually being analyzed as we speak with the hope of presenting it at the next major meeting, our Society of GYN Oncology meeting in March. So not right away, but I think in a pretty timely fashion, we'll have those data. Dr. Lidia Schapira: Congratulations, Shannon, on leading and presenting this wonderful study. So it's been a real pleasure to chat with the two of you. Dr. Ramez Eskander: Thank you. Dr. Shannon Westin: Thanks so much, Lidia. I really appreciate it. Thanks, Ramez, for being here.  And I will just say thank you to all of our listeners. We really hope you enjoyed this episode of JCO After Hours, where we discussed the DUO-E trial, which is a phase III trial evaluating durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer. And again, please do enjoy this publication that was online at the Journal of Clinical Oncology on October 21st, 2023. And do check out our other podcast offerings wherever you get your podcasts. Have a wonderful 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.      

This week, we sit down with Erica Kirschner and Jenn Perry to discuss Li-Fraumeni Syndrome and the Li-Fraumeni Syndrome Association.Erica is a former educator who has been undergoing treatment for metastatic breast cancer for the past eleven years. After being diagnosed at 27, she was referred for genetic testing and found to have Li-Fraumeni Syndrome. LFS is a hereditary TP53 variant that predisposes children and adults to a wide array of cancers. She currently works with the nonprofit Li-Fraumeni Syndrome Association as a patient advocate.Jenn is a breast cancer survivor who was diagnosed with Li-Fraumeni syndrome. She is the President of the Li-Fraumeni Syndrome Association. Through the association, Jenn knew she had finally found an avenue to make a difference and effect change in an area that has affected not only many members of her family but many families around the world. She envisions a world someday where her children, grandchildren, and future family won't have to live in fear of the disease we know as cancer.You can find more information on the Li-Fraumeni Syndrome Association here:https://www.lfsassociation.org/

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. 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. Guests' 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. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In this podcast, Dr. Allison Kurian and genetic counselor Kristen Mahoney Shannon talk about what people should know about genetic testing and hereditary breast cancer, including what to expect when meeting with a genetic counselor, ways to reduce your risk of developing cancer, and talking about genetic test results with family.  Dr. Kurian is a Professor of Medicine and of Epidemiology and Population Health at Stanford University School of Medicine, and Director of the Stanford Women's Clinical Cancer Genetics Program. She is also the 2023 Cancer.Net Specialty Editor for Breast Cancer. Ms. Shannon is a senior genetic counselor and Director of the Cancer Center Genetics Program and Director of Genetic Counseling for the Massachusetts General Hospital Department of Medicine. She is also a 2023 Cancer.Net Advisory Panelist. View disclosures for Dr. Kurian and Ms. Shannon at Cancer.Net. Dr. Allison Kurian: I'm Allison Kurian. I am a professor of medicine, oncology, and epidemiology and population health at Stanford University. And I am speaking today with my colleague, Kristen Shannon, who will introduce herself. Kristen Shannon: Hi, it's great to be here. My name is Kristen Shannon. I am a genetic counselor and the director of cancer genetics at Massachusetts General Hospital in Boston. And I have no financial relevant disclosures to report. Dr. Allison Kurian: Thank you, and I have no relevant financial disclosures either. Very good. So today we will be talking about breast cancer and inherited risk and genetic testing. And let me start by providing a definition of a genetic or hereditary condition. So the way we think about this is something that has a high risk for developing a disease, not a certainty, but a high risk, and runs in families, generally because of a genetic finding that we can identify. And that typically is identified through sequencing, testing of blood or saliva samples, and typically allows us to find a change that we know is clearly associated with disease. A good example for breast cancer are the genes BRCA1 and BRCA2, which some may have heard of, and we will talk about further. So that is just an example, and we will get into more of the details of this as we go on. But I think the point is something that runs in families often is seen with the trait, so for BRCA1 or BRCA2, that would be breast cancer or ovarian cancer, affecting people in every generation. And having what we call for these kinds of genes an autosomal dominant inheritance pattern, so inherited from either parent. And taking only 1 copy that is not functioning to give a person higher risk of the condition. So that's sort of a bit of the basics here on genetic or hereditary risk. And just to give a sense of how common hereditary breast cancer is, we think that in general this may account for, I would say, somewhere between 5% to perhaps 10% of cases of breast cancer. And Kristen, please jump in and tell me if you think differently. But that would be my ballpark. And I think probably the majority of those are the BRCA1 and BRCA2 genes that I mentioned, although there are others that we are recognizing are playing more of a role than we thought, and we'll discuss those, too. So let me give you a chance to continue and respond, Kristen. Kristen Shannon: Yeah, no, I totally agree. And I was thinking that maybe I could talk a little bit about some of the features that are suggestive that there could be one of these inherited breast cancers in the family, because recognizing these signs of hereditary breast cancer can be super important for early detection and prevention of breast cancer. So first, multiple cases of breast cancer within the family, especially among close relatives like parents, siblings, children, those can be a sign that the cancer is inherited. Another important sign is early age of onset of disease. So breast cancer diagnosed at a young age, typically before the age of 50, might point towards hereditary risk. And it's not always the case, but it's something to be aware of. Also, if there is a history of ovarian cancer in the family, especially if you see it in conjunction with breast cancer cases, that's a significant sign that there could be something inherited in the family. And while it's rarer, male breast cancer can also be associated with hereditary gene mutations. So if there's a history of male breast cancer in the family, it's definitely something to think about in terms of hereditary risk. Multiple cancer types in the family can also be another clue. It's not always just breast and ovarian cancer. If you see a family history of both breast and ovarian cancer or pancreatic cancer or prostate cancer within the same family, that also might be a sign of an inherited cancer syndrome. For individuals of Ashkenazi Jewish descent, it's worth noting that they have a higher prevalence of certain gene mutations in specific genes, specifically BRCA1 and BRCA2, which Dr. Kurian has mentioned before. So a family of history of breast or ovarian cancer in an Ashkenazi Jewish individual should be noted as a higher sign that this cancer could be due to an inherited gene. And lastly, if someone has had breast cancer in both breasts, that's called bilateral breast cancer, and that might indicate hereditary risk. It's important, though, to remember that it's not just about any single sign in isolation. You really need to take a look at the bigger picture and the bigger context of the family. So if you notice any of these signs in your family, it's a good idea to seek guidance from a health care professional, like a genetic counselor or a medical oncologist, and they can help assess the family's risk and recommend genetic testing if needed. Dr. Kurian, did I forget anything or leave anything off? Dr. Allison Kurian: Perfect as always. I will just add a little bit here in terms of the specific gene names that we think about, because sometimes it helps people to have sort of a list in their minds, not that we expect you to remember the whole alphabet soup of these different genes. And let me just say that I think it's always a bit of a hodgepodge, some of these names. I used to wonder how people come up with these names, and often there's a bit of a history there. But I will just go through a few of them. We now have some practice guidelines, and they are basically put together by a group of experts who review all the evidence frequently and come up with recommendations. And so there is a list in these guidelines of basically which genes we think are appropriate to test for breast cancer in families, because there's enough evidence to suggest that. And so in addition to BRCA1 and BRCA2, the ones that I think of as the most important, and I'll want to hear Kristen's thoughts about this, too, but the ones that we see most often are called ATM. Sounds like a cash machine, unfortunately not, but ATM. CHEK2, C-H-E-K-2, and then one called PALB2, which stands for Partner and Localizer of BRCA2, and is a lot like BRCA2 in its risks. There are some other genes that give breast cancer risks that are less common. One of them, CDH1, is a gene that also causes an increased risk of stomach cancer. There are a few others that we always keep in mind. There's one called PTEN that's very rare that causes a syndrome called Cowden syndrome that I certainly haven't seen much of. Kristen may have seen more, but it's not something we see often and goes with a lot of other features in families. There are 2 genes that I think we recognize more in recent years and like to be sure we test, called RAD51C and RAD51D, and those both give increased risks. And then another one that I always think of as important here is TP53, and that is a gene that causes something called Li-Fraumeni syndrome, which has probably the highest cancer risks of which we know. There's another one, STK11, that gives some risk, NF1. We see these as being less frequent contributors. Those are the ones that I kind of keep in mind. And again, there will not be a quiz on the alphabet soup, but just so you're aware of what kinds of names you might hear. Kristen, please jump in if I've forgotten any or anything else you want to say. Kristen Shannon: No, I think that that's important. I think the only thing that I would add is that some people think when they go in for breast cancer genetic testing, they only are getting the BRCA1 and BRCA2 gene. And it's just important for people to realize that that's not really a complete test at this point, as you mentioned, Dr. Kurian. Dr. Allison Kurian: Totally agree, and thank you. Kristen Shannon: Should we move into how to prepare for a genetic counseling appointment? Dr. Allison Kurian: Please, yes. Kristen Shannon: Sure, okay. So preparing for a genetic counseling appointment for breast cancer risk can be helpful. First and foremost, we suggest that you gather your family health history. So reach out to your relatives and compile as much information as possible about your family's health background. Pay special attention to any instances of breast cancer and ovarian cancer, prostate cancer, pancreatic cancer in the family. And if any family members have had genetic testing, it's really helpful to jot down those test results as well and bring them with you to the appointment. The other thing is to think about your own personal medical history. You know, think about if you've had any past diagnosis, any treatments, surgeries, or medical conditions, especially those related to breast cancer, your genetic counseling appointment will include a discussion of those. The other thing is, you know, if you've had any medical tests related to cancer, it's important to gather those records if they're not already in your hospital's medical record system that you are going to. Another good idea is to just prepare a list of questions that you might want to have answered. So what do you want to know? Are there specific concerns or specific things you're curious about? It's also important to understand what you want to get out of this genetic counseling encounter. Do you want to just clarify your risk of having a gene? Do you want to consider genetic testing? Or do you want to talk about just managing your risk for breast cancer? That's super important to have that in mind before you actually go into your appointment. Lastly, I would consider bringing along a person, a supportive person with you to the appointment. Having someone with you can help provide emotional support because sometimes these visits can get emotionally charged, but it also can help to have someone remember important details that you will discuss with your health care provider. So it's really important to just arm yourself with information, questions, and support so that the appointment is as productive and informative as it can be. Do you have anything else you'd like to add, Dr. Kurian? Dr. Allison Kurian: It's wonderful to have your expert perspective on this. And I guess any thoughts about really what's inside the box? I think sometimes people just sort of wonder what's going to happen when I go in that room. Sometimes we have patients come in and say, “What are you guys going to do to me? Will there be surgery done?” And we reassure them that we are not doing anything that wild. And so maybe just a sense of kind of walking people through what will happen when they go to meet with genetic counselors. Kristen Shannon: Absolutely, thanks for bringing that up. So during the initial meeting, first you'll probably discuss your personal health history, again, any past diagnoses, surgeries, medical conditions. And then typically a genetic counselor or a medical professional will dive right into your family health history. So they'll ask a whole bunch of questions about your close and extended family members to build a really comprehensive picture of your family and the cancer diagnosis in it. They'll want to know if anyone in your family has had cancer, and they'll also want to know what type of cancer that person has had and also the age at which that person was diagnosed. So those are the 3 pieces of information that your health care provider will want to get from you. The genetic counselor will also probably ask you about what you want to get out of this encounter to make sure that you're both on the same page. Again, do you want genetic testing? You know that already. Or do you want to just talk through the process? So the big part of the initial meeting is really education. The genetic counselor will explain what Dr. Kurian described at the very outset of this discussion, what's the genetic basis of hereditary breast cancer, including all the specific genes that Dr. Kurian—the alphabet soup that we talked about. Talk about inheritance patterns and the implications of having a genetic mutation. The genetic counselor will probably also first assess your risk of having a mutation in one of the genes, and then they'll also talk to you often about genetic testing. So if genetic testing is on the table and you and the genetic counselor both agree that it's a good step, they'll walk you through the process of informed consent. And so this ensures that you understand what the testing entails, the potential outcomes, the implications of the test results. And then if you decide to go through with genetic testing, you will provide a blood or a saliva sample. And then it's a waiting game because these test results can take several weeks, usually about 3 to 4 weeks to get the test results back. When the test results come back, you'll typically have a follow-up appointment, either in-person or on the phone with your genetic counselor. And that's when they spend a lot of time interpreting the test results, explain what they mean for you and your health, as well as discussing the appropriate risk management strategies, if necessary. And if a gene mutation is identified, a genetic counselor will guide you on how to manage these risks. But it will depend on the specific mutation that is identified. And then the other thing that the genetic counselor can help with is just the emotional support. Some people have a harder time than others hearing this information. And also to talk about how to tell your family members about this. So in a nutshell, the initial meeting with the genetic counselor is about gathering information, assessing risk, and potentially deciding on whether or not you're going to have genetic testing. And then after that step, it's about interpreting the test results, talking about next steps, and providing emotional support. Dr. Allison Kurian: Thank you, Kristen. That was wonderful and very complete. And as I was listening to you, first of all, I was thinking about my general admiration for genetic counselors, which is huge. They taught me everything I know about this field. But so also kind of highlighting the key things that a meeting with a genetic counselor will do for you, as you so nicely did. And I think it's getting the right test ordered, making sure that the results make sense to you, and going beyond the patient. But I think those are sort of the key aspects that you communicated really well of the things that we want to get done there. Kristen Shannon: Well said, well said. And I couldn't agree more. Dr. Allison Kurian: And what do you think about the family part in terms of how that gets done? Kristen Shannon: Right, so discussing your genetic test results with family members can be hard and challenging, but it's really, really important. In terms of talking to your family members, I think first, determine the way you're going to notify your family members. So are you going to talk to them? Are you going to send them a letter or an email? And how you share the information may be different based on your relationship with that person. So for example, you may sit down over coffee with a close family member to talk about your test results, but you may choose to write a letter to someone that you don't have that much contact with. The next thing that I think is really important is to be prepared. So before you even start to have this conversation, make sure that you have a clear understanding of your genetic test results, the implications to you and to the family member. That's super important before you even start to have the conversation so that you can explain things to people in simple terms without too much medical jargon and make sure you keep it straightforward. It's really helpful to have a copy of your genetic test results and to provide that to your relatives if you're comfortable doing so, because then they can take that information with them to their genetic counseling or genetic testing appointment, which can be incredibly essential in terms of making sure that they get the correct test at the right time and the test results are interpreted correctly. The only other suggestion I have is just to keep in mind that family members are going to react very differently to this information. And some people will be very matter of fact about it. Some people might get a little distracted by this whole thing. So just to be patient with people and keep the conversation open. Allow them to call you if you're willing to do that so that the conversation can develop over time because, you know, really, in the end, the goal is to make sure that everyone in the family is well informed and makes decisions based on their own health and their well-being. Dr. Allison Kurian: Thank you. I couldn't agree more. And we sometimes, as people may have heard, call this “cascade genetic testing.” So a patient is tested. Somebody who's already had cancer maybe is tested. But then we have the opportunity to have this cascade of beneficial genetic testing, where we can get to people before they have cancer and work on prevention and screening, which I'll talk about in a minute. And I will say that, in general, we here in the United States, and certainly other places as well, don't do as well as we would like with cascade testing despite all best efforts of everyone. And so just to emphasize that family notification is super important, genetic counselors are wonderful at helping people to do that. And I think also additional strategies and interventions are underway to try to help make that easier. So if I may, I'll talk just a little bit about kind of what we do when we find something. Is that okay to do? Kristen Shannon: That sounds great. Talk about people, you know, what they can do about their test results. Dr. Allison Kurian: Good. Yeah, so I always think that's important. I'm an oncologist by training. I'm not a geneticist. And again, it's only thanks to the brilliance of genetic counselors like Kristen that I have learned what I have for the last 2 decades working in the field. But so I tend to think in terms of what can we do to treat this person differently if they have cancer to prevent or reduce the risk of a future cancer. And so what I would say is increasingly over the last few years for a person with breast cancer, as well as some additional cancers, it started to matter what these results are in terms of how we treat the person, whether we might give different medications. And that's really exciting because for years in this field, we didn't have that, and now we do. And so the drugs that are increasingly important are called PARP, P-A-R-P, inhibitors. And sometimes, if a person has a BRCA1 or BRCA2 gene mutation, we might even offer those drugs to treat a breast cancer or, in other cases, ovarian, prostate, or pancreatic cancer. So I think the testing can matter like never before in terms of what we might do to take care of people's cancer. Sometimes we might also choose a different surgery. So sometimes a woman who has a diagnosis of breast cancer might choose to do a more extensive breast surgery, she might choose a double mastectomy to reduce her risk of getting a second breast cancer. That's never required. She certainly doesn't have to do so extensive a surgery if she doesn't choose, but it is an option that some people might choose. And there might also be other cancer risks to manage in somebody who had breast cancer. BRCA1 and BRCA2, for example, give a high risk of ovarian cancer. And so we might talk with someone about the possibility of removing ovaries to prevent an ovarian cancer, which often is recommended with BRCA1, BRCA2, and other such gene mutations. I will say that I think for somebody who hasn't had cancer yet, or hopefully ever, particularly as we think about breast cancer, we're often thinking about intensive screening. So starting often earlier than a person would if she didn't have high risk and generally adding magnetic resonance imaging, MRI, to screening with mammogram alone. And that really is, I think, the cornerstone for women at high risk is adding that breast MRI screening. For pretty much all of the genes I mentioned, that would be clinically indicated and covered by insurance and important to do. MRI has no radiation, very effective at finding breast cancer early. So I think to summarize, it's really all about understanding risk based on a particular gene mutation, understanding if a different kind of treatment is needed for the cancer that a person has, understanding if any sort of preventive measure is needed for future cancer risk, and making sure that the screening we have for breast and for other cancers is appropriate to the level of risk. Anything to add there, Kristen? Kristen Shannon: No. No, I think that that's great. Dr. Allison Kurian: Absolutely. Yeah, so I think it's wonderful to have this opportunity to speak about the importance of genetic testing, which is I think more important than it ever has been at this time for the care of patients with breast cancer and their families. And so as we move into breast cancer awareness month, it's great to be able to talk about this. Thanks so much. Kristen Shannon: Thank you so much. I agree. And if you have any questions, I would suggest you reach out to your doctor or look up on the ASCO website for a referral to a genetic counselor. ASCO: Thank you, Dr. Kurian and Ms. Shannon. Learn more about hereditary breast cancer and genetic testing at www.cancer.net/hboc. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

BUFFALO, NY- October 25, 2023 – A new editorial perspective was published in Oncotarget's Volume 14 on March 24, 2023, entitled, “Genetic modifiers of p53: opportunities for breast cancer therapies.” Each day our cells encounter a wide range of genomic damage and the p53 protein arbitrates decisions of cell cycle arrest to allow repair of DNA or promote elimination of cells with malignant potential through apoptosis. In this new editorial perspective, researchers Prabin Dhangada Majhi, Aman Sharma and D. Joseph Jerry from the University of Massachusetts, Pioneer Valley Life Sciences Institute and Rays of Hope Center for Breast Cancer Research discuss TP53 mutations. The prevalence of TP53 mutations in nearly all tumors emphasizes its role as a formidable barrier that must be breached to allow oncogenic transformation. Inherited mutations in TP53 are also the primary genetic lesions found in Li-Fraumeni Syndrome (LFS), a familial cancer predisposition characterized by tumors in many tissues. However, tissues are not all equally vulnerable to disruptions in p53 function. Among women with inherited mutations in TP53, breast cancer is by far the most common tumor (Figure 1). Somatic mutations in TP53 are also prevalent in sporadic breast cancers, especially in the triple-negative subtype. The proportion rises to nearly 50% of breast cancers that exhibit impaired function of the p53 pathway based on gene expression signatures as a surrogate biomarker of p53 activity. Therefore, the breast epithelium appears to be uniquely sensitive to alterations in p53 function. “Genomewide association studies (GWAS) have identified over 300 polymorphisms that contribute to breast cancer risk [38–41]. These provide a rich resource of candidate polymorphisms that may modify the consequences of mutations in TP53.” DOI - https://doi.org/10.18632/oncotarget.28387 Correspondence to - D. Joseph Jerry - jjerry@vasci.umass.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28387 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, p53, Li-Fraumeni syndrome, genetic modifiers, breast cancer, DNA repair About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Featuring perspectives from Dr Naval Daver, including the following topics: Introduction: Biology, Classification, p53, Magrolimab (0:00) Case: A man in his early 70s with acute myeloid leukemia (AML) with a TP53 mutation, myelodysplastic syndromes (MDS)-related changes and complex cytogenetics who received CPX-351receives azacitidine/venetoclax and is now in palliative care — Anna Halpern, MD (9:06) Case: A woman in her late 50s with multiple comorbidities and FLT3-ITD-positive AML who experienced disease progression on azacitidine/venetoclax now receives gilteritinib — Bhavana (Tina) Bhatnagar, DO (17:01) Case: A woman in her early 70s with AML with FLT3-ITD and IDH1 mutations receives a hypomethylating agent with ivosidenib — Amany R Keruakous, MD, MS (29:10) Case: A man in his early 60s with newly diagnosed MDS with ring sideroblasts receives oral decitabine/cedazuridine — Khuda Dad Khan, MD, PhD (33:54) Case: A man in his mid 60s presents with copper deficiency and ring sideroblasts; genetic analysis reveals SF3B1 and DNMT3A mutations — Rachel J Cook, MD (42:25) Case: A woman in her early 70s with a history of extensively treated follicular lymphoma develops AML and receives CPX-351 — Ranju Gupta, MD (46:05) Case: A woman in her late 70s with newly diagnosed AML receives decitabine/venetoclax with concurrent voriconazole — Rebecca L Olin, MD, MSCE (51:05) Case: A woman in her late 90s is diagnosed with multiple myeloma and del(5q) MDS — Erik Rupard, MD (54:26) Journal Club with Dr Daver (57:28) CME information and select publications

In this week's episode, we'll discuss the findings from the final analysis of the CLL2-GIVe trial, learn how NOTCH2 mutants promote resistance to chemotherapy in diffuse large B-cell lymphoma, and discuss the role of DBY/HLA class II complexes in chronic graft-versus-host disease.

Go online to PeerView.com/UTY860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how CLL expert Jennifer Woyach, MD, employs patient treatment history, prognostic information, and other clinically relevant factors to develop comprehensive treatment plans for her patients and get up to date on the latest evidence with BTK inhibitors for CLL by participating in this video activity. Dr. Woyach will focus on enhancing your understanding of the mechanistic, selectivity, and safety differences between covalent and non-covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i), the mechanisms of intolerance and BTK resistance, and how BTKi fit into personalized treatment plans informed by the use of validated techniques such as next-generation sequencing, FISH, and karyotype testing. Learners will also be exposed to resources from the CLL Society that can be used to help educate patients on the latest therapeutic advances in customized CLL care. Upon completion of this activity, participants should be better able to: Summarize the mechanistic, selectivity, and safety differences among covalent and non-covalent BTKi, including off-target effects, therapeutic intolerance, and mechanisms of BTK resistance; Cite validated techniques, including next-generation sequencing, to identify prognostic and predictive markers such as del(17p)/TP53, BTK mutations, and minimal residual disease status to inform treatment decisions; Develop team-based management strategies that include patient treatment history, prognostic information, and other clinically relevant factors; and Implement team-based strategies to educate patients on their prognosis, facilitate clinical trial enrollment, and address dosing and safety considerations when using BTKi strategies.

Go online to PeerView.com/UTY860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how CLL expert Jennifer Woyach, MD, employs patient treatment history, prognostic information, and other clinically relevant factors to develop comprehensive treatment plans for her patients and get up to date on the latest evidence with BTK inhibitors for CLL by participating in this video activity. Dr. Woyach will focus on enhancing your understanding of the mechanistic, selectivity, and safety differences between covalent and non-covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i), the mechanisms of intolerance and BTK resistance, and how BTKi fit into personalized treatment plans informed by the use of validated techniques such as next-generation sequencing, FISH, and karyotype testing. Learners will also be exposed to resources from the CLL Society that can be used to help educate patients on the latest therapeutic advances in customized CLL care. Upon completion of this activity, participants should be better able to: Summarize the mechanistic, selectivity, and safety differences among covalent and non-covalent BTKi, including off-target effects, therapeutic intolerance, and mechanisms of BTK resistance; Cite validated techniques, including next-generation sequencing, to identify prognostic and predictive markers such as del(17p)/TP53, BTK mutations, and minimal residual disease status to inform treatment decisions; Develop team-based management strategies that include patient treatment history, prognostic information, and other clinically relevant factors; and Implement team-based strategies to educate patients on their prognosis, facilitate clinical trial enrollment, and address dosing and safety considerations when using BTKi strategies.

Go online to PeerView.com/UTY860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how CLL expert Jennifer Woyach, MD, employs patient treatment history, prognostic information, and other clinically relevant factors to develop comprehensive treatment plans for her patients and get up to date on the latest evidence with BTK inhibitors for CLL by participating in this video activity. Dr. Woyach will focus on enhancing your understanding of the mechanistic, selectivity, and safety differences between covalent and non-covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i), the mechanisms of intolerance and BTK resistance, and how BTKi fit into personalized treatment plans informed by the use of validated techniques such as next-generation sequencing, FISH, and karyotype testing. Learners will also be exposed to resources from the CLL Society that can be used to help educate patients on the latest therapeutic advances in customized CLL care. Upon completion of this activity, participants should be better able to: Summarize the mechanistic, selectivity, and safety differences among covalent and non-covalent BTKi, including off-target effects, therapeutic intolerance, and mechanisms of BTK resistance; Cite validated techniques, including next-generation sequencing, to identify prognostic and predictive markers such as del(17p)/TP53, BTK mutations, and minimal residual disease status to inform treatment decisions; Develop team-based management strategies that include patient treatment history, prognostic information, and other clinically relevant factors; and Implement team-based strategies to educate patients on their prognosis, facilitate clinical trial enrollment, and address dosing and safety considerations when using BTKi strategies.

Featuring perspectives from Ms Kristen B Battiato and Dr Jennifer Woyach, including the following topics: Introduction (0:00) Case: A woman in her early 70s responding to ibrutinib for 4 years (27:07) Case: A woman in her early 80s with TP53-mutant, del(17p) disease responding to acalabrutinib (38:02) Case: A man in his mid 50s with chronic lymphocytic leukemia/small lymphocytic leukemia treated for a year with obinutuzumab followed by venetoclax; no evidence of disease for 3 years (43:29) Case: A Cuban woman in her mid 60s with multiregimen-recurrent disease, now receiving venetoclax (53:17) NCPD information and select publications

Featuring perspectives from Dr Emmanuel S Antonarakis, Prof Karim Fizazi, Dr Rana R McKay, Dr Alicia K Morgans and Dr A Oliver Sartor, including the following topics: Current Management of Nonmetastatic Prostate Cancer Introduction (0:00) Case: A man in his early 70s diagnosed with localized prostate cancer who underwent a radical prostatectomy in 2010 experiences rising prostate-specific antigen (PSA) from 0.18 to 0.4; PSA doubling time 7 months; PSMA PET-negative for other sites of disease — David S Morris, MD (1:26) Case: A man in his early 70s with M0 hormone-sensitive prostate cancer (HSPC) with PSA persistence after radical prostatectomy received androgen deprivation therapy (ADT) intensification with abiraterone/prednisone and went to the ER with hypertension, palpitations, headache and abnormal liver function tests — Sandy Srinivas, MD (15:58) Faculty presentation: Dr Morgans (19:29) New Considerations in Treatment Intensification for Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) Case: A man in his mid 60s with localized prostate cancer and biochemical recurrence 5 years after neoadjuvant and adjuvant leuprolide and intensity-modulated radiotherapy to the whole pelvis — Neeraj Agarwal, MD, FASCO (28:59) Case: A man in his early 80s who underwent radical prostatectomy 15 years ago and received radiotherapy and ADT for biochemical recurrences is now diagnosed with M0 castration-resistant prostate cancer with quickly rising PSA levels — Dr Morris (33:02) Faculty presentation: Prof Fizazi (41:54) Available and Emerging Strategies for Newly Diagnosed Metastatic Castration-Resistant Prostate Cancer (mCRPC) Discussion (53:41) Case: A man in his mid 60s diagnosed with metastatic HSPC and PSMA positivity in the pubic ramus, bilateral external iliac nodes and lungs — Dr Srinivas (57:03) Faculty presentation: Dr McKay (1:03:01) Identification and Management of mCRPC with a Homologous Recombination Repair (HRR) Gene Abnormality Case: A man in his early 50s with mCRPC after enzalutamide receives olaparib; somatic BRCA2 mutation; TP53 mutation on liquid biopsy — Dr Agarwal (1:18:21) Case: A man in his early 70s with high-grade localized prostate cancer treated with proton beam therapy and ADT for 2 years now has rising PSA and CT scan positive for retroperitoneal node; somatic BRCA2, TP53, FOXA1 and MEN1 mutations; microsatellite stable — Dr Morris (1:21:59) Faculty presentation: Dr Antonarakis (1:30:22) Management of Progressive mCRPC Case: A man in his late 70s with multiregimen-refractory mCRPC and a gBRCA2 mutation receives olaparib with a sustained response for several years — Dr Srinivas (1:43:10) Faculty presentation: Dr Sartor (1:48:35) CME information and select publications