Journal of Clinical Oncology (JCO) Podcast

Dr. Shannon Westin and her guest, Dr. Brian Slomovitz discuss the article "Pembrolizumab or Placebo Plus Adjuvant Chemotherapy With or Without Radiotherapy For Newly Diagnosed, High-Risk Endometrial Cancer: Results in Mismatch Repair-Deficient Tumors" recently published in the JCO and presented at the 2024 International Gynecologic Cancer Society. TRANSCRIPT The guest's disclosures can be found in the transcript. Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts and literature published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, gynecologic oncologist and JCO Social Media Editor by trade. I am thrilled because we are going to be talking about gynecologic cancer today. So, this is my jam. And specifically, we're going to be talking about a manuscript that's a simultaneous publication in the Journal of Clinical Oncology and presented at the Annual Meeting of the International Gynecologic Cancer Society on October 16, 2024. And this is "Pembrolizumab or Placebo, Plus Adjuvant Chemotherapy, With or Without Radiotherapy for Newly Diagnosed High Risk Endometrial Cancer: Results in Mismatch Repair Deficient Tumors." This is affectionately the KEYNOTE-B21 trial, also known as the GOG-3053 trial and the ENGOT-en11 trial. And we are joined today by the primary author in this manuscript, Dr. Brian Slomovitz, who is the Director of Gynecologic Oncology at Mount Sinai Medical Center in Miami Beach, Florida, and the clinical trial advisor in uterine cancer for the Gynecologic Oncology Group foundation. Welcome, Brian. Dr. Brian Slomovitz: Hey, thanks, Shannon, so much. It's a pleasure to be here. And thanks for giving us the opportunity to discuss this trial. Dr. Shannon Westin: Yes, it's a great trial and I'm so excited to talk about it. And I think we'll start just because this is a broad group that listens to this podcast, they're not all GYN oncologists, experts like yourself, so can you just level set a little bit and speak a bit about the incidence and mortality of endometrial cancer overall and the recent trends in this disease? Dr. Brian Slomovitz: Yeah, sure. So, and it is nice to speak about gynecologic cancers, as we know, endometrial cancer was and still is the most common of all gynecologic cancers. The numbers are going up. Right now, there's about 65,000 to 70,000 cases each year in the US diagnosed with endometrial cancer. The numbers are going up. A lot of its obesity related, some other factors, but as the population gets less healthy, those are some of the risk factors for the disease. The thing that, however, is quite surprising is that we're seeing the deaths due to endometrial cancer going up as well, while for other diseases, we're making slow, steady steps to try to decrease the mortality we're actually seeing an increase in mortality. And the most discouraging point, Shannon, as you know is the number of deaths from endometrial cancer is going to outnumber the number of deaths from ovarian cancer if it hasn't done it already. I mean, now's the time. So, we really need to come up with better treatment strategies to everything to decrease the incidence of disease, to help with prevention, but for those poor women who are diagnosed, to come up with better treatment options so we don't have to keep this increasing trend in mortality. Dr. Shannon Westin: Absolutely. And I think some of that is related and we don't need to get on a soapbox here, but the amount of funding that goes towards research in endometrial cancer, and of course you, you have been leading the way and really trying to get a ton of trials in this space and getting our industry partners and our government partners to really support this. So really just commending you on how much you've worked on, on this area. And to that end, we've had a huge renaissance with immunotherapy and endometrial cancer, a lot of really big trials. Why don't you give the audience a rundown of where, so far, this seems to be best utilized for people with endometrial cancer? Dr. Brian Slomovitz: Thanks for that. And as you sort of alluded to, it's been a revolution, really, with immunotherapy. We started off at immunotherapy looking at microsatellite instability or the dMMR patients. What we found is similar to other disease sites in the second and third line setting that we saw good activity with the single agent checkpoints, pembrolizumab dostarlimab, that's based on the earlier KEYNOTE data and the GARNET trial. Really, a landmark study in the second line was Vicki Makker and her colleagues put pembrolizumab and lenvatinib combination for those patients with the cold tumors. Not the dMMRs or MSI Highs, but the proficient mismatch repair. And that study in a second line setting found that it was better than chemotherapy for an overall survival advantage. So right there, we know that it works in the second line setting in the dMMR population, and we got an i

In this JCO Article Insights episode, Subodh Selukar interviews author Dr. Robert Maki on "Combining Response and Toxicity Data to Implement Project Optimus" by Maki, et al published in the Journal of Clinical Oncology September 11, 2024. TRANSCRIPT Subodh Selukar: Welcome to this episode of JCO Article Insights. This is Subodh Selukar, JCO's editorial fellow. Today, I am interviewing Dr. Robert Maki on his recent editorial, "Combining Response and Toxicity Data to Implement Project Optimus." At the time of this recording, our guest has disclosures that are available in the manuscript and will be linked in the transcript. Dr. Maki, welcome to our podcast. Dr. Robert Maki: Hi, Subodh. It's a pleasure to be able to take part. Subodh Selukar: Yeah, thank you. So, to start us off, would you give an overview of your article? Dr. Robert Maki: Yes. Well, it's not my article, but it's just an editorial which is a commentary on an article by authors Cheng and Associates. It's called, "Exposure-Response-Based Multiattribute Clinical Utility Score Framework to Facilitate Optimal Dose Selection for Oncology Drugs." That's a very technical title and so forth, and yet it's a JCO article because we think that it makes an important point that in oncological trials, we talk a lot about primary endpoints, oftentimes of overall survival or progression free survival, sometimes even just response rates, but most of the time, we don't take into account the toxicity of an agent. So, you can imagine that if a drug is relatively nontoxic, then what you see is what you get. Progression free survival could be associated with what is called some sort of so-called clinical benefit. However, if a drug is really toxic and you're just laid up on the couch all day or bed bound, or need transfusions three days a week, where is that really beneficial for the patient? But, by the same token, there's no quality of life without life itself. You have to have some sort of evidence that someone is going to be around for a longer period of time as an indication of benefit. So, these are ideas that have been played out to some degree for the better part of a quarter of a century. There's a biostatistician at MD Anderson named Peter Thall, who's one of the first people to think about this idea of combining toxicity data and response data as some sort of a combination primary endpoint for a trial. And where this comes into play for Project Optimus, this FDA initiative to come up with not just necessarily one dose or one dose and schedule, but rather a range or multiple doses and schedules for a drug based on the toxicity that's seen, is that this new paper by Dr. Cheng and colleagues provides one mechanism for doing this, for combining not just traditional clinical outcomes data, but also toxicity data. Subodh Selukar: So, you mentioned Project Optimus is an important component of all of this. So, can you tell a little bit about what Project Optimus is and maybe a little bit potentially about how Project Optimus has affected you so far? Dr. Robert Maki: I'd say it's having an effect mostly in the earlier phases of drug development. I'm not certain, but I think it was an outgrowth of some of the toxicity that was seen in some of the studies that were done over the course of the last 10 to 15 years with kinase-targeted drugs. The overall goal from the FDA Project Optimus was to work with companies, with academia, groups like ASCO and regulatory authorities, as well as patients to try and come up with dosing for everyone basically based on patient characteristics that they're focusing not just on those outcomes, such as progression, pre survival, overall survival, but also looking for quality of life and adding that into the mix in terms of how you choose a dose. So that's an effort that's been going on for the last several years now. There's been some nice articles on that from FDA on that and perhaps we could provide some links to those as well for people who are interested in some of the more introductory core information about Project Optimus. Subodh Selukar: Yeah, for sure. And so, I mean you're on the editorial board at JCO and you've written this editorial, but has Project Optimus affected your clinical research yet? Dr. Robert Maki: It's just beginning to. So, in phase 1 and 2 clinical trials, especially in phase 1, the goal is not necessarily to look for activity, but just to come up with a recommended phase 2 dose and schedule of a drug. Well, Project Optimus says, "Okay. Well, maybe there's more than one dose and schedule that should arise." And as I was alluding to earlier, this may have arisen out of what was seen previously where a number of the multi targeted tyrosine kinase inhibitors were developed. But when you got to the phase 3 trial, it was necessary to have dose reductions in 30%, 40%, 50%, 60%, even 70% of patients in some situations. So that to me represents a drug or a development pathway for that drug that was in essence incorre

Host Dr. Davide Soldato and Dr. Shelia Garland discuss the JCO article "Randomized Controlled Trial of Virtually Delivered Cognitive Behavioral Therapy for Insomnia to Address Perceived Cancer-Related Cognitive Impairment in Cancer Survivors." TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato. I am a Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today we are joined by JCO author Dr. Sheila Garland. She's a Professor of Psychology and Oncology at Memorial University, and she's the director at the Sleep, Health, and Wellness Lab and Senior Scientist at the Beatrice Hunter Cancer Research Institute. Dr. Garland will be discussing the article titled, "Randomized Controlled Trial of Virtually Delivered Cognitive Behavioral Therapy for Insomnia to Address Perceived Cancer-Related Cognitive Impairment in Cancer Survivors." Thank you for speaking with us, Dr. Garland. Dr. Sheila Garland: Thank you so much for having me. Dr. Davide Soldato: So, Dr. Garland, you designed a study that relied on cognitive behavioral therapy to treat insomnia, and then you assessed whether improvement in insomnia would be associated with an improvement in cancer related cognitive impairment. So I wanted to ask if you could give us a little bit of context and explain the rationale between these studies. So how common are these symptoms among cancer survivors, and why do we think that improving insomnia would also improve cognitive function? Dr. Sheila Garland: Yeah, thank you very much. That's a really, really good question. And so cognitive behavior therapy for insomnia has been used to successfully treat insomnia in cancer survivors for quite some time. I think JCO was one of the first publishers to really demonstrate the potency of this intervention to improve insomnia. But as we know, patients will often present not just with insomnia, but insomnia comorbid with pain, fatigue, and very commonly cognitive impairment. If we take a look at the experimental research in sleep, we know that sleep quality and quantity is associated with very important cognitive functions. And so we've had clear sleep deprivation studies where if you're not able to successfully get sufficient quality or quantity of sleep, you're going to have impairments in attention and concentration and memory. So it really makes sense that if we're able to improve sleep in cancer survivors, that we're also able to address maybe some of the other concerns that they would have related to sleep. So this is an important clinical question for the patient's quality of life, but I also think it has important system implications where if we're looking at like resources and efficiency of allocating those resources, if we have an intervention that can treat multiple problems, that means that we can more effectively address lots of symptoms and use fewer resources in doing so. So that was the thought in designing this trial. Dr. Davide Soldato: Thank you very much. That was very, very clear. So you spoke about the intervention that you implemented in the clinical trial. So I was wondering if you could give us a little bit of context. How long was the intervention? What were the main points addressed? Because you said that, in the end, we already have some data regarding cognitive behavioral therapy for treating insomnia. So I was wondering, did you personalize in any way, the program or the intervention to fit more to the cancer survivors population? Dr. Sheila Garland: Yeah. So it is based on a protocol that has been well researched and has a great deal of evidence of efficacy. But we delivered this intervention over a course of seven weeks. So individuals had individual sessions with a trained therapist, and those sessions lasted about an hour and were over roughly about two months or so. Seven sessions over two months. And because they were delivered individually, there was some adaptation based on the clients' presenting problems. So while there's sort of a standard protocol, if the client is also presented with levels of fatigue or pain or anxiety or depression, the therapist was able to integrate those concepts into the therapy as well. There was nothing for cognitive impairment. So there was no additional intervention for cognitive impairment at all. We weren't doing any memory training or anything like that. So it was strictly the sleep and other symptoms looking at the impact of improving that on not only your perception of your cognitive abilities, but also on performance on a number of neuropsychological test measures. Dr. Davide Soldato: So thank you very much for the detail. And I think that it's very interesting what you said, that the personalization of the intervention would also allow to treat some other symptoms t

In this episode of JCO Article Insights, Dr. Giselle de Souza Carvalho interviews Dr. Hatem Azim and Dr. Ann partridge on their JCO article "Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy," TRANSCRIPT Giselle Carvalho: Welcome to the JCO Article Insights episode for the August issue of the Journal of Clinical Oncology. This is Giselle Carvalho, your host. I'm a Medical Oncologist in Brazil focusing on breast cancer and melanoma skin cancers, and one of the ASCO editorial fellows at JCO this year. Today, I will have the opportunity to interview Dr. Hatem Azim and Dr. Ann Partridge, two of the authors of the POSITIVE trial. We will be discussing their trial on "Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy," which was published in May this year. Hello, Dr. Azim and Dr. Partridge. Welcome to our podcast. Dr. Ann Partridge: Hi. Thanks. Dr. Hatem Azim: Hello. Giselle Carvalho: So, beginning with our interview for breast cancer survivors, in addition to the treatment itself, aging is one of the major contributors to infertility. The optimal duration of adjuvant endocrine therapy in patients with hormone positive early breast cancer ranges from five to ten years, depending on patient and tumor characteristics. This time interval can be critical for women who wish to attempt pregnancy. One of the main concerns in daily breast cancer oncology practice is whether breast cancer recurrence rates are increased either by temporary interruption of endocrine therapy for pregnancy or by the use of assisted reproductive technologies. Dr. Azim, what about assisted reproductive technology is worrisome regarding breast cancer outcomes? And how do the POSITIVE study results address the concern about worsening breast cancer outcomes either with assisted reproductive technology or endocrine therapy interruption? Dr. Hatem Azim: So, in the primary analysis of the POSITIVE trial, we tried to address one of these questions, whether temporary interruption with endocrine therapy affects breast cancer outcome. And what we found was that interruption did not appear to have a detrimental impact at the median follow up of 41 months. So in the current manuscript, we addressed the second question, whether assisted production of fertility preservation has an impact as well on breast cancer outcome. And we did not find any worsening of outcomes in patients who underwent these procedures compared to those who had a spontaneous pregnancy. Of course, we have relatively short follow up, but at least the outcomes at the median follow up of around 3 to 4 years appears to be reassuring. Giselle Carvalho: I see. Thank you. These are really important outcomes regarding premenopausal patients. So, moving on, results from your study show that after 24 months, 80% of women under 35 years old had at least one successful pregnancy, while the same was true for 50% of women aged 40 to 42. These results are particularly impressive considering that over 60% of women over 35 had undergone chemotherapy. Dr. Partridge, other than age, what factors did you find were associated with a successful pregnancy? Dr. Ann Partridge: Yeah. The biggest factor, other than age, that was associated with successful live birth pregnancy was use of assisted reproductive technologies. So either having gone through IVF prior to diagnosis and banking eggs or embryos prior to diagnosis and then using them during the study, for undergoing stimulation of the ovaries during the study and then using it during the study. And that's what we also looked at in this most recent analysis of the initial POSITIVE data. Giselle Carvalho: I see. Thank you. The group of patients who underwent embryo oocyte cryopreservation at diagnosis were more likely to be nulliparous and treated with chemotherapy. Presumably these represent the patient group most afraid they will be infertile, as they would be receiving chemotherapy, and most desirous of pregnancy, as they had not yet had any children. Fertility preservation techniques are expensive and not easily available for all patients, particularly in less wealthy countries. Is there any group of your breast cancer patients with a high enough likelihood of pregnancy without assisted reproductive technology that you would not recommend this? Dr. Ann Partridge: Sure. So we are so glad to have assisted reproductive technologies available in many places, but as you know, they're not available everywhere. And even where they're available for some people, it's either inaccessible for a number of reasons or it doesn't feel right emotionally or ethically. And then finally, sometimes people need fairly quick treatment and they just don't have the time, even though we don't think there are long delays. And so we do and are able to know who can get pregnant after standard chemotherap

Host Dr. Davide Soldato interviews Dr. Sana Raoof to discuss the JCO article Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures. TRANSCRIPT Dr. Davide Soldato: Hello, and welcome to JCO After Hours, the podcast where we sit down with others from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by JCO author Dr. Sana Raoof, Physician at Memorial Sloan Kettering, to talk about her article, "Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures." Thank you for joining us today, Dr. Raoof. Dr. Sana Raoof: Thank you so much. It's lovely to be here. Dr. Davide Soldato: So, Dr. Raoof, I just wanted to start a little bit about the theme of your article, which is really centered around multi-cancer early detection tests. And this comes from the results of several studies that showed their reliability and efficacy in identifying cancer in the average risk population. But I just wanted to ask you if you could give us and our readers a brief overview of how these tests work and how they were designed for this specific population. Dr. Sana Raoof: Of course. Well, there's an interesting story. The origin of multi-cancer early detection tests actually begins with insights that come from the field of obstetrics and gynecology. So about six or seven years ago, in the peripheral blood of pregnant women, we discovered that you can actually find fetal DNA floating around. And that was an early discovery of cell free DNA coming from the baby into the mother's bloodstream. But in some of those young, otherwise healthy women, we also discovered that there's another clonal signal, unfortunately not coming from the fetus, but coming from an undiagnosed tumor. And that led to the entire field of circulating tumor DNA and all of its applications. Of course, scientists in the last six or seven years have harnessed the fact that DNA and the methylation patterns on the circulating tumor DNA, as well as other analytes like glycosaminoglycans, proteins, and other analytes, are secreted by tumors into the peripheral blood in order to try and screen for tumors, hopefully at early stages, when there are still curative, definitive interventions that are available. There's several different tests now that are providing the ability to detect cancers at many stages, including early stages. They're in different phases of preclinical to clinical development, and one is even commercialized and available by prescription in the United States. Dr. Davide Soldato: Okay. So I think that in most of these tests, they really look at the tumor DNA, so they identify mutations or, for example, methylation patterns. But do we also have some tests that integrate some other type of biomarkers that we can identify in the blood? Like, are they integrated all with the others, or are we just relying on circulating tumor DNA? Dr. Sana Raoof: It's a great question. There's a lot of really fascinating biology that different companies predominantly are using in order to find signs of early cancer. One of the analytes that I find really interesting, other than looking for small variants in circulating tumor DNA and looking at methylation patterns, as you mentioned, is looking at fragment length. So, for example, the company DELFI looks at the different patterns of the length of DNA fragments that are floating around in the peripheral blood. And not only is fragment length tissue specific, so in theory, a fragmentomics based multi-cancer early detection test could tell us what is the tissue that this aberrant signal is coming from, but they can also tell you if there's likely a cancer present, because there's a difference in fragment length patterns in cancer versus non cancer. There are also other analytes. I mentioned glycosaminoglycan. There's another company that doesn't yet have prospective data, to my knowledge, that is making a test that looks at these analytes instead. There are other companies, again, without prospective data yet, that are looking at circulating tumor cells. And I'm sure that in the next few years, we're going to start getting prospective data from all of these players and also hear about other analytes that scientists have found can predict cancer from non cancer and maybe even protect tissue of origin based on artificial intelligence. Dr. Davide Soldato: So you mentioned artificial intelligence. So, basically what you're suggesting, but correct me if I'm wrong, is that when we use this test, we are actually measuring something in the bloodstream, but at the same time, we are actually applying some type of artificial intelligence to actually interpret these results and then give us the definitive results, or what we would call like a positive and a negative of the tests,

In this episode of JCO Article Insights, Rohit Singh interviews Dr. Ticiana Leal on the editorial, "Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade." TRANSCRIPT The guests' disclosures can be found in the transcript. Dr. Rohit Singh: Hello and welcome to JCO's Article Insights. I am your host Rohit Singh and today we will be discussing the JCO article, "Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade." And we are joined by the senior author of the article, Dr. Ticiana Leal. Dr. Leal is an Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and she serves as director of Thoracic Medical Thoracic Oncology Medical Program and Multidisciplinary Thoracic Oncology Leader at the Winship Cancer Institute. She also served as a member of the Board of Directors at the Georgia Society of Clinical Oncology. Dr. Leal, welcome to our podcast and thank you for joining us. Dr. Ticiana Leal: Thank you, Rohit. Thank you for this interesting opportunity to discuss our editorial. My co-authors and I are very glad to be here today. So, Dr. Jennifer Carlisle and Dr. Liu were co-authors with me on this editorial. Dr. Rohit Singh: It's a really good article. And just for our audiences, the article again, titled "Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade," it discusses the challenges and the potential strategies for overcoming resistance to immune checkbox inhibitors in patients with non-small cell lung cancer. In this article, Dr. Leal and colleagues talk about the second line of drug when the patient developed disease progression while immunotherapy and they develop resistance and their definitions and what to do. So, to Dr. Leal, can you please explain the mechanisms of primary and acquired resistance to immune check prohibitors in non-small cell lung cancer? I also saw in your article you proposed the definition of immunotherapy resistance in solid tumors, distinguishing between primary resistance and acquired resistance. So, if you can please share your thoughts and explain their mechanism. Dr. Ticiana Leal: So primary resistance and acquired resistance are related to tumor intrinsic and tumor extrinsic factors. And this is mainly clinically defined as of now according to previous response patterns and timing of occurrence, and these definitions can be heterogeneous, and we certainly think that biologically they can be very different. And it can be different according to prior therapy, whether patients got immunotherapy as PD-1, PD-L1 inhibitor alone or combination strategy with CTLA-4, or the combination with chemotherapy. But the patterns of resistance can be very different and can be based on defects and antigen presentation. It can also be due to tumor microenvironment immunosuppressive effects, and there are also additional inhibitory checkpoints that can be involved. The definition in terms of when to call it primary or acquired resistance at this point has really been based on consensus guidelines by SITC, by Esmo, as well as our group Lung-MAP has developed clinical trials in this space. Specifically, through Lung-MAP, we've defined and incorporated the definition of acquired resistance as patients who have had prior exposure of 84 days or greater and then have had progression of their disease. Dr. Rohit Singh: I can see why it is so challenging to come up with a standard definition for immune checkpoint resistance and I think incorporating these definitions and predictive biomarkers for clinical trial design is going to be more important going forward. Your article talks about CONTACT-01 study, so can you please discuss the CONTACT-01 study and how the shifting treatment paradigm in the first-time study impacted it and at the same time also discuss the potential implication of the differential outcome observed between the men and women in the CONTACT-01 study. Dr. Ticiana Leal: CONTACT-01 was a much-awaited study. The authors, Dr. Neal et al, looked at a very important question in the area of immunotherapy resistance. So, CONTACT-01 was a randomized phase three global study that investigated the combination of cabozantinib plus atezolizumab versus docetaxel in patients previously treated with chemotherapy and immunotherapy. And as background, cabozantinib is an inhibitor of multiple receptor tyrosine kinases including VEGFR-2, MET, RET and TAM family kinases. Preclinically, cabozantinib could lead to immuno permissive tumor microenvironment and so it was rational to combine it with a PD-1 inhibitor. In early results of a phase 1B expanded cohort of COSMIC-021 showed really promising results of this combination which led to the rationale of CONTACT-01. In this study, however, patients that were included had different prior treatment sequences. They could have had prior immunotherapy alone followed by chemo or the opposite, or they could have had prior immunotherapy and then upon progression gotten a c

Dr. Shannon Westin and her guest, Dr. Chao Cao, discuss the paper "Prevalence and Cancer-Specific Patterns of Functional Disability Among US Cancer Survivors, 2017-2022" recently published in the JCO. 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 with authors and manuscripts that have been published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, gynecologic oncologist by trade and Social Media Editor for the JCO. And it is my pleasure to welcome Dr. Cao, a research fellow in medicine, Department of Medical Oncology, Dana Farber, Cancer Institute, Boston, Massachusetts. Welcome. Dr. Cao: Thanks for having me. Dr. Shannon Westin: Of course. And we're going to be discussing your very important work, "The Prevalence and Cancer Specific Patterns of Functional Disability Among US Cancer Survivors, 2017-2022," which was published in the Journal of Clinical Oncology on April 4, 2024. And Dr. Cao has no conflicts of interest in regards to this podcast. So let's get right into it. I'd love to level set. Can you speak a little bit about the definition of cancer survivorship and the number of cancer survivors currently in the United States? Dr. Cao: I think this is an important question because everyone somewhat has confusion about the definition of cancer survivorship. So based on the definition by the National Cancer Institute, cancer survivorship refers to the phase of life following the diagnosed cancer. And nowadays, it's estimated about 80 million American individuals are living after being diagnosed with cancer. And this number is projected to rise to 26 million by 2040. Dr. Shannon Westin: Wow. So obviously, any research that we can do in this population is going to be so important as that number absolutely continues to grow. And before we get into the specifics of your work, I'd love for you to speak a little bit about the importance of functional disability, which is what we studied in this work and why it might be observed in cancer survivors. Dr. Cao: Yeah, sure. So, maintaining physical function is fundamental to perform life tasks and engage in fruitful jobs. In terms of cancer survivors, many cancer survivors experience side effects from cancer and its treatment. These side effects, include the pain, fatigue, and musculoskeletal dysfunction, which can induce physical limitation and eventually physical disability. And specifically, this is such a burden for the US, social, societal and economic burden. Here I have the specific number: so in 2019, an estimate of over 100,000 people living with and beyond cancer were unable to work and they received a Social Security Administration disability benefit with the resulting cost of US$1.8 billion in disability claims. Dr. Shannon Westin: Wow. We always think about the impact on the survivor, on their family, but I think it's also really important to look at those other objective data about the impact on society as a whole. Thank you, that was great detail. Do we know anything about who might be proportionately more affected by cancer induced physical impairments and disabilities? Dr. Cao: Actually, this is our key question for our manuscript, but before we developed our hypothesis, we also looked at the data from the general population. So we observed that visual minorities and underserved populations, such as people with lower socioeconomic status and living in the rural area, and also those with unhealthy types of behavior, for example, smoking, obesity, and physical inactivity, are more likely to have physical limitations and disabilities. And also the comorbidity in cancer survival, such as diabetes, cardiovascular disease, also increase the likelihood of physical disability. We also have cancer survivors, particularly for cancer patients who are currently receiving cancer treatment, for example, chemotherapy and radiation therapy, they also are more likely to report side effects from the treatment, also have the reduced physical function. So we also think the cancer patients during the treatment also have a higher likely chance to have physical disability. Dr. Shannon Westin: Absolutely. That makes sense, and that really dovetails nicely into the objective of your study. We'd love for you to briefly summarize your objective and the methods you employed to achieve that goal. Dr. Cao: Yeah, sure. We used the six-year data, 2017 to 2022 from the Behavioral Risk Factor Surveillance System to investigate problems and factors of functional disability in over 47,000 cancer survivors and 2.4 million adults without cancer diagnosis aged 80 years and older. And we specifically focused on two types of functional disability. The first one is mobility disability, which is defined as self reported severe difficulty walking or climbing stairs. And also another one is self care disability, which is defi

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

Dr. Shannon Westin and her guest, Dr. Bryan Schneider discuss the article "ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer" recently published in the JCO and presented at the 2024 ASCO Annual Meeting. 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 am your host, Shannon Westin, GYN Oncology Extraordinaire and also the Social Media Editor of the Journal of Clinical Oncology. And it is my great pleasure to present some really incredible work today that is going to be a dual publication in the Journal Clinical Oncology and a presentation at the American Society of Clinical Oncology Annual Meeting on Monday, June 3. And this is the "ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer." And I am joined today by the senior author on the presentation and the primary author on the manuscript, Dr. Bryan Schneider. He is the Vera Bradley Professor of Oncology, the Professor of Medicine and Medical Molecular Genetics at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center in Indianapolis. Welcome, Dr. Schneider. Dr. Bryan Schneider: Dr. Westin, thank you for having me on today. Shannon Westin: We're so excited and we're really excited to really summarize this incredible work that's being presented today. So, first, let's just levelset. Can you speak a little bit about peripheral neuropathy and the most common causes in patients with cancer? Dr. Bryan Schneider: Yeah, I mean, I think for those of us who treat patients using the taxanes, we recognize probably one of the most important and common side effects that we deal with is peripheral neuropathy, and one that can, I think, impact both quality of life, but also impacts the ability to maintain dose intensity. When we think about risk factors for neuropathy, historically, I think obesity has been reported as a potential risk factor, as has diabetes and other conditions which put people at risk for neuropathy. Shannon Westin: And prior to your work that you'll discuss with us today, what do we know about the incidence of peripheral neuropathy in patients that identify as black? Dr. Bryan Schneider: Yeah. So, interestingly, I think we've recognized that patients who self identify as black have disparate outcomes in terms of inferior survival and more aggressive subtypes of breast cancer, like triple negative breast cancer. But I think the idea of toxicity being a disparate factor as well is probably a more recent one. Interestingly, as we set out to identify biomarkers to predict outcomes in the large adjuvant trial E5103, we weren't really setting out to look at this by race. We were using at that time, genome-wide approaches to identify biomarkers for toxicity and also efficacy. But what was interesting as we did that one of the most important predictors, as we looked across a number of important toxicities, was ancestry. And really the science spoke to us, it was very clear that patients of African ancestry had higher rates of bev-induced hypertension, anthracycline-induced cardiomyopathies and also peripheral neuropathy. Shannon Westin: That's so interesting. We have so much overlap in gynecologic oncology and breast cancer. And I don't know that I've ever seen work like this. And now it's making me very intrigued and making me want to move forward to that. Can you talk a little bit more about this ECOG-ACRIN E5103, like briefly about the study and what it demonstrated specifically? Dr. Bryan Schneider: Yeah. So E5103 was an adjuvant breast cancer trial that really set out to look at the impact of bevacizumab in the curative setting. This was a 5000 patient trial that randomized patients the standard backbone of chemotherapy. So everyone received four cycles of doxorubicin and cyclophosphamide, followed by weekly paclitaxel, and then with or without the addition of bevacizumab. So the parent clinical trial showed, as we know now, bevacizumab didn't add benefit, but certainly this was a fertile ground for us to use genomic markers to try to identify a number of other important factors and predictors. Shannon Westin: And what did you find genomically in that study that led to kind of where we are now? Dr. Bryan Schneider: Initially, what we found is that ancestry was a major predictor of neuropathy. And in that trial we saw essentially a doubling of the risk of grade 2 and above and a doubling of the risk of grade 3 and above neuropathy. When we then looked comprehensively across the genome for common variants that might put patients at risk for neuropathy, we had enough patients in the black population to identify some markers that

In this JCO Article Insights episode, Alexandra Rojek provides a summary on "Romidepsin Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Versus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Final Analysis of the Ro-CHOP Trial" by Camus et al published February 16th, 2024 and the associated editorial written by Dr. Mehta-Shah and Dr. Horwitz. 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 a clinical trial update published in the May 10th issue of JCO addressing the long term follow up of the addition of romidepsin to CHOP chemotherapy for previously untreated peripheral T-cell lymphoma, or PTCL. This report by Camus et al discusses a five-year follow up of the original Ro-CHOP trial, which did not meet its primary endpoint of progression free survival. The original Ro-CHOP study, conducted by the LYSA group, was published in 2021 in JCO and was conducted as a one-to-one randomized phase III study of Ro-CHOP versus CHOP for patients aged 18 to 80 years with PTCL. 98 international centers were included, and the study enrolled patients between 2013 and '17. Nodal follicular helper T-cell, or TFH lymphoma was defined in this study follow-up as a PTCL expressing at least two of five TFH markers according to the latest classifications. The study's primary endpoint was PFS with secondary endpoints of OS and duration of response, or DOR. Five year follow up was reached in December 2022. In the original study report, the addition of romidepsin to CHOP did result in a reduction of dose intensity of chemotherapy. However, in this updated follow up, there were no new safety signals reported. A total of 421 patients were enrolled in the trial with a median age of 65 years. Notably, those who were randomized to the Ro-CHOP arm had a higher proportion of IPI 4-5 scores at 33%, versus 24% of those who were assigned to CHOP alone despite randomization. Nearly half of patients carried a histologic diagnosis of angioimmunoblastic T-cell lymphoma. 30% were characterized as PTCL NOS, not otherwise specified, 10% ALK negative anaplastic large cell lymphoma, leaving 13% reported as other. Over 60% of patients had stage four disease at enrollment, with nearly half having more than two sites of extranodal involvement. Median follow up was six years with a median PFS of 12 months for Ro-CHOP and 10.2 months for CHOP, which did not reach statistical significance as reported in the original study publication. Estimated five year OS available as a part of this clinical trial update was 50% for Ro-CHOP and 43% for CHOP alone, and also did not reach significance. There was, however, a longer duration of response observed in the Ro-CHOP arm at 52 months versus 24 months for CHOP, which is a new finding in this extended follow up of the study. In an effort to better understand whether there are subgroups which may benefit from romidepsin despite the overall negative outcome of this study, the authors are able to provide new insights from this Ro-CHOP study in line with our current and updated understanding of PTCL. When the authors evaluated the study population for subgroups which may benefit from addition of romidepsin, TFH lymphomas, which included angioimmunoblastic, follicular, and NOS subtypes, were noted to have an improved response to the addition of this HDAC inhibitor. This subgroup, numbering 201 patients, experienced a mean PFS of over 19 months with Ro-CHOP versus over 10 months for those who received CHOP, and this difference achieved statistical significance. Similarly, there was a higher complete response rate and longer duration of response for those in the TFH subgroup who received romidepsin. The authors also make note that those patients in this subgroup with high IPI appeared to particularly benefit. However, those in the PTCL NOS group who did not fit the TFH subtype experienced poor outcomes with shorter PFS and OS as compared to other histologic subtypes, which is in line with other reported data in the field. The authors in this update also report on treatments and outcomes after first progression or relapse of disease, which includes a total of 274 patients, of whom 251 received second line therapy. The median PFS in OS after progression or relapse was only 3.3 months and 11.5 months, respectively, and again, patients with the TFH subtype experienced a longer median OS than other included histologies. Only 8% of patients proceeded to undergo autologous stem cell transplantation overall, and 5% underwent allogeneic stem cell transplantation. While the authors note that they did not observe any notable outcome differences between various included second line therapies, they do note of a possible benefit of the antibody drug conjugate brentuximab vedotin or BV in combination

Dr. Shannon Westin and her guest, Dr. Patrick Stone, discuss the article, Methylphenidate Versus Placebo for Treating Fatigue in People with Advanced Cancer, a Randomized, Double-Blind, Multicenter Placebo-Controlled Trial, recently published in 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 go in depth on manuscripts and research published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for JCO and a Gynecologic Oncologist by trade. I am thrilled today to present Methylphenidate Versus Placebo for Treating Fatigue in People with Advanced Cancer, a Randomized, Double-Blind, Multicenter Placebo-Controlled Trial. This manuscript is a dual publication in the Journal of Clinical Oncology and presentation at the European Association of Palliative Care Congress here on May 17, 2024. And to review this incredible research with us will be Professor Patrick Stone, the Head of Department of Marie Curie Palliative Care Research Department, Division of Psychiatry at University College London. Welcome, Dr. Stone. Dr. Patrick Stone: Thank you very much. Thank you. Shannon Westin: Let's get right to it, we'll level set. Can you speak a bit about the definition of cancer-related fatigue and how common it is in people with advanced cancer? Dr. Patrick Stone: Sure. I think fatigue is a difficult thing to nail down really and define it clearly, and there are lots of definitions out there. In many ways, the simplest definition is the EAPC, the European Association of Palliative Care's definition of just a subjective sensation of weakness, feeling tired, and exhaustion. The reality is that that symptom is very common in the general population. And so if you really want to get a handle on it, I think a good way to do it is to think about taking an operational definition and say, "Look, if fatigue is normally distributed approximately in the general population, then we should consider severe fatigue or pathological fatigue could be defined as fatigue that is worse than 95% of the general population. And if you think that definition, then prevalence of fatigue in patients with newly diagnosed breast or prostate cancer, for instance, is around 15%, so three times as common as the most severe fatigue in the general population. If you come to patients with newly diagnosed non-small cell lung cancer, it's up to about 50%. And if you come to my area, which is palliative care and you go to a hospice and you ask people to complete a fatigue questionnaire, 78-80% of people complain of fatigue that is more severe than 95% of the general population. So that I think gives us a good handle on sort of the severity of this problem in cancer patients and how it progresses as disease progresses. Shannon Westin: I love this because I think we always struggle with exactly how to nail down the definition and exactly how to treat it. So I think that it's a really nice transition to existing treatment options for this issue and exactly how they might work. Dr. Patrick Stone: The first thing to say is in medicine if you can find a cause then you give a treatment directed at the cause and obviously that applies to fatigue as well. So the first thing is to do a thorough assessment of your patient, and if you can find an easily remediable cause such as anemia, hypocalcemia, or hypomagnesemia, or maybe other things like depression, which might manifest as fatigue, then you should try and give a treatment directed at that cause. But, for many patients, there won't be a single clearly identifiable cause you can target. And then people use more broad spectrum approaches if you like. The most well-studied I think is exercise. And exercise, there have been lots of randomized controlled trials in different types of exercise and it's a well attested treatment, which I think has good evidence of effectiveness, certainly in patients who are on treatment and in disease-free survivors. There is less evidence in advanced cancer because the trials are fewer. I would still say that there's moderate quality evidence that exercise is effective in advanced cancer. The other group of treatments, broadly speaking, would be psychological therapies, cognitive behavioral therapy and psychoeducational approaches, mindfulness based stress reduction, that sort of thing. And again, in earlier stage disease and in patients on treatment and in survivors, there's more quality evidence that that sort of approach can help, if not alleviate fatigue, allow people to cope better with fatigue. But the evidence in advanced cancer is weaker than for exercise. So I think the evidence for the effectiveness of those psychological therapies is not so strong. And then you come on to pharmacological therapies and there have been lots of trials of different agents. I won't list them all because most of them are negative an

JCO Editor in Chief, Dr. Jonathan Friedberg interviews Dr. Pamela Kunz, Editor in Chief of the new premier open access journal, JCO Oncology Advances. Dr. Friedberg and Dr. Kunz discuss what is to come from the journal and the benefits of an open access journal. TRANSCRIPT Dr. Jonathan Friedberg: Hello and welcome to another episode of JCO After Hours. I'm your guest host, Jonathan Friedberg, Editor in Chief of JCO, and today we have a very special episode with Pamela Kunz, Associate Professor of Medicine in the Division of Oncology at Yale School of Medicine and Yale Cancer Center. As the new editor in chief of JCO Oncology Advances, she is with us today to share a new opportunity for authors to submit to ASCO's new online open access journal. Pam, welcome. Dr. Pamela Kunz: Thank you. Dr. Jonathan Friedberg: I guess my first question to you is, why did you take this role of editor in chief? People have asked me the same question, and I'm still, I think, trying to figure out the answer. So how did you decide to do this? Dr. Pamela Kunz: That's a great question, and I might ask you the same thing. I think as I've gone on in my career, I really like saying I think about what I say yes and no to, and like saying yes to things that I think can make a difference and have real impact. And as a clinical trialist and someone who really hopes to advance the field scientifically, I think it was really exciting to think about helping to craft the future of the science of oncology and to also do it in a way, as we will later talk about open access, but do it in a way that really thinks about a broad audience, because open access really requires us to think about meeting the needs of our audience, as the articles will likely have broader reach. Dr. Jonathan Friedberg: So, I mean, I can say I'm very excited about this journal. We do have a number of outstanding papers that we're not able to accept at JCO and knowing that there'll be a good home for these papers is heartwarming for me. Can you tell me a little bit about your vision and goals for this journal? You're really starting with a blank palette. It must be exciting to try to craft what this is going to be about. Dr. Pamela Kunz: It is really exciting. It's a little scary, I'll be honest, to have a blank slate, but I'm appreciative of you and the other editors in chief and staff for helping to provide some guidance. I think that in the beginning, as you were speaking to, there's an opportunity for us to really keep some great science in the JCO family. And so at least early on, we're hoping to really attract and think about publishing some earlier phase trials that may not quite meet the bar of getting published in JCO. So, phase I, phase II trials, even secondary analyses that yield important data from some of the larger phase III trials. This will be an evolution, I think, also. I think that what we may look like this year may look a little bit different in future years, but at least initially, we'll be focusing on some of the earlier phase clinical trials. I'm now framing this around beyond the clinical trial of secondary analyses quality of life, PROs. One thing that's exciting, a new article type will be plain language summaries. So really interpreting the clinical trial for patients and the lay public, I think that's an initial way that we're going to be thinking about it. Dr. Jonathan Friedberg: And who do you see as the audience for this journal? Dr. Pamela Kunz: Well, the opportunity that we have with open access is that we really have a much broader audience than we will have had historically with some of the non-open access journals. And I think that means that we have an obligation to be thinking about who that audience is. So, it's a great question. I think our audience will certainly be some of our typical readers, really, the oncology scientific community, but it will likely also be other physicians, primary care physicians, community oncologists, global oncology, and even patients, patient advocacy groups. So, I think that we have to be, as we're crafting and thinking about new article types, those article types, and the content that we create really has to meet the needs of the audience. Dr. Jonathan Friedberg: And to that end, I know we've discussed, you had some discussions with your group about brief reports as another article type that is somewhat differentiating for the journal. Dr. Pamela Kunz: Yes, exactly. And I think this also speaks to really trying to attract science that may be earlier in its development. And maybe an author, a team has an idea or a smaller scientific report that they'd like to publish. It may not quite meet the bar for JCO, but maybe we think that this is something that's exciting, that will lead to future studies, and that's exactly what we're hoping to attract. Dr. Jonathan Friedberg: And I guess folding into maybe some of the input from your new editor team and editorial board, what features do you look for when rev

In this JCO Article Insights episode, Rohit Singh provides summary on two articles published in the April 10th issue of the Journal of Clinical Oncology. The first article, "Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)" describes a randomized, open-label, multicenter, phase III study evaluating the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. The second is the accompanying Oncology Grand Rounds. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Rohit Singh: Hello and welcome to JCO Article Insights. I'm your host, Dr. Rohit Singh. Today I will provide a summary of a Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04), by Dr. Park and colleagues from Seoul, Korea. The purpose of this study was to evaluate the efficacy and safety of the ABCP regimen based on IMpower150 in patients with EGFR or ALK mutated non-small cell lung cancer who had progressed on prior targeted treatment. I will also discuss an Oncology Grand Round case titled "Management of Treatment Resistance in Patients with Advanced EGFR Lung Cancer: Personalization, Parsimony, and Partnership", by Dr. Vallillo and colleagues from Lahey Hospital Medical Center and Tufts University School of Medicine, Boston, Massachusetts. Oncology Grand Round cases help us to give a clinical context to the clinical trial. While TKIs are the established standard of care for non-small cell lung cancer harboring driver mutations, most patients will develop resistance to these treatments. Immune checkpoint inhibitors, with or without chemo, have shown clinical benefits of immune checkpoint monotherapy in patients with EGFR-mutated non-small cell lung cancer. Consequently, platinum-based chemo is the standard of care for patients with EGFR TKI failure. This was a phase III, multicenter, open-label, randomized trial conducted at 16 hospitals across the Republic of Korea. Patients diagnosed with stage four non-small cell lung cancer with sensitizing EGFR mutation or ALK translocation were included in the study. Patients were randomly assigned to the ABCP arm or chemo-only arm in a 2:1 ratio. Eligible patients were stratified on the mutation type (EGFR mutation vs. ALK translocation) and the presence of brain metastasis. No crossover to atezolizumab was permitted. The recruitment with T790M mutation was capped at 30%. Patients who responded continued to receive maintenance with atezolizumab until disease progression or unacceptable toxicities occurred. If a patient was identified to have an acquired T790M mutation after the failure of a first or second-generation EGFR TKI, the patient had to be treated with a third-generation EGFR TKI before enrollment. The primary endpoint was investigator-assessed objective response rate according to research criteria. The secondary endpoints included overall survival and progression-free survival at one and two years, and the duration of response, along with a safety analysis. Investigators also did an exploratory biomarker analysis based on PD-L1 expression and its correlation with the response. They also analyzed the distribution of tumor-infiltrating lymphocytes, and a cut-off of 20% inflamed score was used to compare the two arms. Overall, 228 patients were enrolled, 154 in the ABCP arm and 74 in the chemo-only arm. Most patients were female at 56.1% and never smokers at 62.7%. Brain metastasis was present in 42.7% of patients. Most patients had previously received EGFR TKI therapy, however, only 8% and 30% received third-generation TKI as first-line therapy in the ABCP arm and chemo-only arm, respectively. The majority of the patients were EGFR at 90%. The median duration of follow-up for the study population was 26 months. The objective response rate in the ABCP arm was significantly higher at 69.5% compared to 42% in the chemotherapy alone arm. The median PFS was significantly longer in the ABCP arm at 8.48 months versus 5.6 months, and the duration of response was similar at around seven months in both arms. The median overall survival was also similar at around 20 months in both arms, with a hazard ratio of 1.01. In the subgroup of patients with brain metastasis at the time of study enrollment, PFS was significantly longer in the ABCP arm at 8.4 months compared to 4.4 months in the chemotherapy-only arm. In contrast, no difference in PFS was observed in the subgroup without brain metastasis. Regarding EGFR mutation status, there was no difference in PFS or OS between the two arms in the EGFR deletion 19 subgroup. However, a favorable PFS was observed in the EGFR L858R subgroup. For those with acquired EGFR T790M mutation, there was no difference in PFS between groups,

Dr. Shannon Westin and her guests, Dr. Emily S. Tonorezos and Dr. Michael Halpern, discuss their article, "Myths and Presumptions About Cancer Survivorship" recently published in the JCO. TRANSCRIPT The guests on this podcast episode have no disclosures to declare. Shannon Westin:Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Social Media Editor of the JCO, Shannon Westin, and also a GYN Oncologist by trade. I'm thrilled to bring a topic that is very close to my heart. We're going to be talking about a Comments and Controversies article published in the JCO on November 16, 2023, entitled "Myths and Presumptions about Cancer Survivorship." I know you all will find this topic as enthralling as I have, and the authors do not have any conflicts of interest. I'm joined by two of the authors on this important work. The first is Dr. Michael Halpern, he's the Medical Officer in the Health Assessment Research Branch of the Health Care Delivery Research Program. Welcome, Dr. Halpern. Dr. Michael Halpern: Thank you for having us on. Shannon Westin: We're also accompanied by Dr. Emily Tonorezos, the Director of the Office of Cancer Survivorship, and both of them work in the Division of Cancer Control and Population Sciences at the National Cancer Institute, National Institutes of Health. Welcome. Dr. Emily Tonorezos: Thank you for having us. Shannon Westin: So, let's get right into it. I want to level set first. I would love for one or both of you to speak a little bit about the state of cancer survivorship currently. What's the prevalence of cancer survivors here in the US? Globally? What do we expect as time passes? Dr. Emily Tonorezos: Thank you for starting with this question. In the Office of Cancer Survivorship, we use a definition of cancer survivor that we got from the advocacy community many years ago. We use a definition that says "a person is a cancer survivor from the time of diagnosis through the balance of life." That means in the United States, we estimate that we have a little over 18 million cancer survivors, and globally, it's a little more difficult to estimate those numbers. Not every country has a cancer registry to count the number of cases, but we think there are upwards of 53 million cancer survivors diagnosed within the last five years in the world. Shannon Westin: Wow. And so this is why it's so important, such a large number, and that's just an estimate. And we know this is only going to be growing. I personally learned so much from your manuscript, which is critically based on the understanding that our beliefs as practitioners truly impact the way we care for our cancer survivors. I admit, I definitely held or hold some of these beliefs, and I'm certainly grateful that you're providing that objective evidence to support or refute these claims. So, with that being said, let's tackle the first one that you all approached: Shared care results in the best outcomes for cancer survivors. I think first I'd love to hear about what your definition of shared care is. What does that really mean in the context of cancer survivorship? Dr. Michael Halpern: Shared care is a deliberate process to coordinate and integrate components of survivorship care between specialty, in this case, oncology providers, and primary care providers. And part of the issues with this belief about shared care being the best have to do with the broad practice experience of survivorship care. While the ideal definition is this integrated and coordinated care, shared care can range from one extreme to being essentially oncologist-led care - where the oncologist also sends information to the primary care providers; and to the other extreme - care led by primary care providers and an oncologist is available to answer questions as needed. So part of the issue with the available literature is that there is a tremendous range in terms of the definition of shared care that's being used in studies. Shannon Westin: So, understanding those limitations, obviously, based on what you just said, what have we seen in some of the studies that have been exploring shared care and what it might mean for cancer survivors? Dr. Michael Halpern: So there have been some wonderful studies and some very well-done research in shared care. The majority of it indicates essentially no benefits, not any worse, but definitely not any better than other survivorship care models among multiple domains, quality of life, patient preference, clinical outcomes, in some cases, costs. So there isn't at this point a rationale for believing that shared care leads to better outcomes than does other types of models of care. And that's not to say that we don't think that shared care is a valuable model, that it's potentially very useful and beneficial for certain groups of cancer survivors. It's just that at this point, we don't have evidence t

In this JCO Article Insights episode, Alexandra Rojek provides a summary on two long term follow studies: "Long-Term Follow-Up of Rituximab Maintenance in Young Patients With Mantle-Cell Lymphoma Included in the LYMA Trial: A LYSA Study" by Sarkozy, et al published on December 18th, 2023 and "Long Term Follow Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma," by Kahl, et al, published January 9, 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 two clinical trial updates published in the March 1st issue of JCO, focusing on the long-term outcomes of rituximab therapy for patients with lymphoma. The first paper discusses the use of maintenance rituximab for mantle cell lymphoma patients in the LYMA trial, and the second paper addresses rituximab dosing strategies for low tumor burden follicular lymphoma in the RESORT study. The first article by Sarkozy et al. for the LYSA group is titled "Long-Term Follow-Up of Rituximab Maintenance in Young Patients with Mantle Cell Lymphoma Included in the LYMA Trial: A LYSA Study." The LYMA trial was designed to answer whether the addition of the CD20-targeting monoclonal antibody rituximab provided additional benefit for patients with mantle cell lymphoma who achieved a response to induction chemoimmunotherapy, followed by consolidative autologous stem cell transplant in randomized patients, maintenance rituximab for three years versus observation alone. The primary analysis of the LYMA trial was published in 2017 and showed that the primary endpoint of four-year event-free survival or EFS was met at 79% in the maintenance rituximab arm compared to 61% in the observation alone arm. Additionally, there was a four-year overall survival or OS benefit of 89% versus 80% in favor of maintenance rituximab. Thus, on the basis of the LYMA trial primary analysis, the use of maintenance rituximab after consolidative autologous stem cell transplantation has become the standard of care in the field for these patients. The long-term safety and efficacy data presented in this clinical trial update for the LYMA study continue to demonstrate ongoing EFS and OS benefit for patients randomized to maintenance rituximab. Patients were initially enrolled between 2008 and 2012, and 240 patients were randomized to either arm. EFS in this study was defined as absence of disease progression, relapse, or death, severe infection, or allergy to rituximab. The data cutoff for this updated analysis was April 2019, with a median follow-up from randomization of seven years for living patients with a note that this is prior to the COVID-19 pandemic. For those in the maintenance rituximab arm, the seven-year EFS was 76% compared to 46% for those under observation. For those on the rituximab arm, the majority of relapses occurred within three years of randomization and thus while on maintenance rituximab, which the authors suggest does not show an increase in incidence of relapse after the end of maintenance therapy. The seven-year overall survival was 83% for those on the rituximab arm compared to 72% for those on the observation, with a log-rank p-value of 0.08. There was no difference in causes of death between the treatment arms noted. Notably, the patients who received maintenance rituximab after induction and transplant experienced a shorter second OS after relapse therapy, with a median OS2 of 1.1 years compared to 4.6 years favoring those on the observation arm, without impact of the type of salvage therapy received. Although this study was conducted before BTK inhibitors were approved in France and thus used at a low rate for patients who relapsed after initial therapy. This suggests that those who relapse after maintenance rituximab were those with the most aggressive disease biology. The authors also identified a group of patients who experienced progression of disease within 24 months of initial therapy or POD24 and showed that a Ki-67 score greater than 30% and high MIPI score were prognostic of POD24 events. For those who experienced POD24 within the rituximab arm, they also experienced a shorter OS2 compared to those on observation, again suggesting that those whose disease relapses after maintenance rituximab tend to have more aggressive and difficult-to-treat. While the interpretation of post-relapse outcomes and therapies needs to be interpreted in the light of a different era of available therapeutic options in more recent years, particularly the newest generation of BTK inhibitors, this updated follow-up of the LYMA study provides additional strength to the standard of care established through the trial's primary analysis of the benefit of maintenance rituximab after induction therapy and consolidative autologous stem cell transplant

Dr. Shannon Westin and her guests, Dr. Herbert Duvivier and Dr. Richard Schilsky, discuss the paper "Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study" 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 into articles published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. As always, it is my pleasure to serve and bring this information to you. Today, we will be discussing, "Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study." And this was published in the JCO on August 10th, 2023. None of the authors have any conflicts of interest to disclose. Joining me today are two of the authors, Dr. Herbert Duvivier, the principal investigator of this arm of the TAPUR trial. Welcome. Dr. Herbert Duvivier: Thank you. Shannon Westin: And then, of course, many of you know Dr. Richard Schilsky, who is the former CMO and Executive Vice President of ASCO and a principal investigator on the TAPUR study. Dr. Richard Schilsky: Thank you, Shannon. Shannon Westin: So, let's get going. I think the first thing would be great is to level set and make sure everyone knows exactly what this TAPUR basket trial is, the Targeted Agent and Profiling Utilization Registry study. Can you guys give the audience a brief description of the objective of TAPUR and maybe how it came to fruition? Dr. Richard Schilsky: Sure. This is Richard Schilsky. Maybe I can start with that. The TAPUR study is a prospective, phase II, multi-basket, multi-center genomic-matching trial. Its primary objective is to identify signals of drug activity for targeted agents that are already marketed. But in the TAPUR study they are being used outside of their FDA-approved indication. The study, as you may know, was conceived in 2014, launched in 2016, and is still enrolling patients across the country. Really, the genesis of the study came from the fact that it began at the time where genomic profiling of patients with advanced cancer was becoming more commonplace. Genomic alterations that could be targeted by already marketed drugs were being identified. However, patients and doctors were having difficulty accessing these drugs because they were not used on label and were unlikely to be covered by insurance. And moreover, even if they could access the drugs, there was no organized mechanism to collect outcome data and report on the results of the patient experience receiving that treatment. So those factors led to the development of TAPUR, which attempts to solve both the drug access problem by having collaborating pharmaceutical companies donate their drugs to the trial so they're available to patients at no cost, but also implements a structured data collection mechanism so all of the relevant clinical outcomes with the patients can be collected and ultimately reported. And that's how TAPUR came about. Shannon Westin: Well, it was so necessary, and I think we do so much of our oncology treatments off-label, but as we get more and more expensive drugs when we move away from chemotherapies and more targeted immunotherapies, it's very hard to get those drugs off label. So this was such a relevant and necessary trial that had to happen, and it's a great example of leadership that you had the vision to put this together through ASCO. I think the natural next question for me is having not put patients on the TAPUR study, how does a patient join this study? How do they get started? Walk us through that. Dr. Herbert Duvivier: At our institution, normally, all the physicians are aware of the TAPUR trial through internal conversations. When they have patients who have been treated with multiple lines of standard therapy, usually the next step for them is to get NGS testing. We have a research team that reviews all NGS testing for these patients and knows the open arms of the TAPUR trial. And if there happens to be a particular patient who may match with one, they will inform the physician. It is then up to the physician to speak to the patient about that option. Shannon Westin: Do you have people come looking for the TAPUR trial or are these generally more established patients? Dr. Herbert Duvivier: From my perspective, I think it is usually established patients. Shannon Westin: I think what I love about this trial, and I have spoken about this trial in lectures around baskets, it's such a pragmatic design making it as straightforward as possible to really implement across different centers, whether academic or community, or wherever they are. I guess one of the questions always around these targeted therapies is the molecular selection. How do you make sur

In this JCO Article Insights episode, Giselle de Souza Carvalho provides a summary on "Pathologic Exploration of the Axillary Soft Tissue Microenvironment and Its Impact on Axillary Management and Breast Cancer Outcomes" by Naoum, et al and "Optimization of Breast Cancer Regional Nodal Management" by Braunstein et al published in the January 10, 2024 issue in Journal of Clinical Oncology. The original report discusses how the examination of axillary soft tissue beyond lymph nodes is often omitted and it predicts breast cancer outcomes and need for nodal radiation. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Giselle Carvalho: Welcome to the JCO Article Insights episode for the February issue of the Journal of Clinical Oncology. This is Giselle Carvalho, your host, one of the ASCO editorial fellows at JCO this year. Today, I'll be providing a summary of an article focused on "The Association of Axillary Soft Tissue Involvement on Outcomes for Breast Cancer Patients." It was published in November 2023 and was partially presented at the 64th Annual ASCO in October 2022. Although lymph node involvement in breast cancer patients is correlated with a worse prognosis, the impact of extracapsular involvement is still a matter of debate, and the implications of axillary soft tissue involvement are still not fully understood. There is some evidence indicating a decrease in disease-free survival for patients with less than four lymph nodes and with extracapsular extension, while other studies show that extracapsular involvement has no prognostic role in these patients and that the number of positive lymph nodes might matter more. Patients with node-positive disease may present with only lymph node involvement or lymph node involvement plus extracapsular extension and/or axillary soft tissue involvement. The axillary soft tissue involvement can result from either direct lymph node extension through the capsule or direct microscopic spread from the primary tumor. It is pathologically defined in this article as axillary lymphatic channel invasion, axillary soft tissue deposits, axillary blood vessel invasion, or any combination of these. This was a retrospective study of patients with invasive breast cancer who received treatment at Massachusetts General Hospital in Boston, Massachusetts, from 2000 to 2020. Lymph nodes and surrounding adipose tissue were submitted in their entirety for histopathologic evaluation using hematoxylin and eosin stain, and immunohistochemical stains could be added at the pathologist's discretion. Eligibility criteria included primary breast cancer and positive lymph nodes without prior or contralateral breast cancer. 2,162 patients were included. They were divided into four groups according to their axillary pathology: the first group was composed of patients with positive lymph nodes with no additional axillary involvement; the second group of patients with positive lymph nodes and extracapsular involvement; the third group of patients with positive lymph nodes and axillary soft tissue involvement but with no extracapsular extension; and the fourth group of patients with positive lymph node and both extracapsular extension and axillary soft tissue involvement. Primary endpoints were 10-year rates of local-regional failure, which was defined as recurrence in the breast or chest wall or ipsilateral axilla, axillary failure, and distant metastasis. Among 2,162 patients, 58% had lymph node involvement only, 25% had lymph nodes with extracapsular extension, 3.5% had lymph node involvement with axillary soft tissue involvement, and 14% had lymph node involvement with both extracapsular and axillary soft tissue involvement. 51% of cases of axillary soft tissue involvement were in the form of axillary lymphatic channel invasion. The median follow-up was 9.4 years, and 74% of the cohort had hormone receptor-positive breast cancer, 10% had triple-negative disease, and 16% had HER2-positive disease. The groups with axillary soft tissue involvement, extracapsular extension, or both had more advanced tumor pathologic features when compared to the lymph node-only group, including a higher median size of breast tumors, a higher number of malignant lymph nodes, and an increased likelihood of breast lymphovascular invasion. Additionally, more patients in these three groups received mastectomy, axillary lymph node dissection, regional lymph node radiation, and systemic therapy. The lymph node-only group had the lowest 10-year incidence of distant failure, 13%, while the group with extracapsular extension and the group with axillary soft tissue involvement both had a 23% rate of distant failure at 10 years. The risk of distant failure reached an impressively high rate of 42% for the group with both extracapsular extension and axillary soft tissue involvement. Considering 10-year local-regional failure, the first group had a 6.2% rate, the second group a 5.7% rate, the third group

Dr. Shannon Westin and her guest, Dr. Reshma Jagsi, discuss the paper "Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA" 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 with manuscripts that were published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the JCO. It is my pleasure to speak with Dr. Reshma Jagsi. Hello, Dr. Jagsi. Dr. Reshma Jagsi: Hello. Thanks for having me. Shannon Westin: I am so excited that you're here. Dr. Jagsi is the Lawrence W. Davis Professor and Chair of the Department of Radiation Oncology at Emory University School of Medicine, Winship Cancer Institute. She is going to be talking about her incredible work, "The Omission of Radiotherapy After Breast Conserving Surgery for Women with Breast Cancer with Low Clinical and Genomic Risk: Five-year Outcomes of IDEA," which was published in JCO in February 2024. All right, let's get right to it. First, I want to levelset. Can you run us through some brief facts and figures about breast cancer just to make sure that all the listeners are on the same page? Dr. Reshma Jagsi: Breast cancer is the most common cancer in the world. It's 12.5% of all new annual cancer cases worldwide and is the most commonly diagnosed cancer among US women. About a third of all newly diagnosed cancers in women are breast cancer, and about 13% of US women develop invasive breast cancer over their lifetime. In 2023, there were nearly 300,000 new cases of invasive breast cancer. The median age of breast cancer diagnosis is 62, meaning an awful lot of people are getting diagnosed with breast cancer in the population that we specifically chose to study. Shannon Westin: Wow, you're really good at this. That's like the perfect transition to move to the next piece. So, first, I think I'd love to hear about the standard of care for the population that you were studying and how we got to this point. Dr. Reshma Jagsi: We offer women who are diagnosed with early-stage invasive breast cancer the option of breast conservation, and we encourage breast conservation because, of course, it is a better-tolerated surgery than mastectomy. Many women are eligible for breast-conserving therapy. And years ago, we as radiation oncologists encouraged our surgical colleagues to refer to breast-conserving therapy as lumpectomy plus radiation, just as one set. Because the studies that have been done in the 1970s and 1980s to establish that breast conversation was equally safe and effective in treating breast cancer relied on radiation therapy to minimize in-breast tumor recurrence rate, which one of those trials independently showed that there was no difference in survival. But the ones that compared lumpectomy surgery alone to lumpectomy followed by radiation therapy did show a pretty substantial improvement in local control with the addition of radiation treatment. And so radiation treatment became a part of a parcel of breast conservation in the early 1990s when consensus statements came out favoring breast conservation as a treatment approach. And so the net analysis has combined all of these studies together and showed that overall, without radiation treatment, a patient treatment with a lumpectomy had a 30% risk of in-breast tumor occurrence in those historical studies. And it was reduced by about two thirds to about 10% when that lumpectomy was followed by radiation in those historical randomized trials. But of course, we've made many advances in our understanding since that time, and so that's what this study is seeking to build on. Shannon Westin: It makes sense. We all know that radiotherapy can lead to other issues, acute and chronic morbidities, as well as cost and having to do the treatment itself. So we're all interested in de-escalation of therapy. Tell me, prior to your study, what data were out there potentially supporting the de-escalation and avoiding radiotherapy in that specific population? Dr. Reshma Jagsi: In the '90s, after those landmark foundational historical trials have been completed, there was a lot of interest in seeing if we could identify a population of patients in whom the risk of local recurrence was sufficiently low that they might safely choose to omit radiation therapy. All of these randomized trials have shown very consistently that there is a relative risk reduction. Whatever your risk is without radiation, radiation reduces that risk. The overall disease recurrence risk is cut in half with the addition of radiation treatment. But, if I told you that your overall risk was 1%, and I could cut that in half with radiation, you might say, "I might be willing to tolerate the 1%." At least some women might be willing to tole

Dr. Shannon Westin and her guests, Dr. Jeremy Davis and patient advocate Kathryn Carr, discuss the paper "Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy" recently published and printed in the JCO. TRANSCRIPT Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, a professor of GYN Oncology at MD Anderson, and the JCO social media editor. I am so thrilled to have wonderful authors here today who do not have any conflicts of interest. We are going to be discussing the "Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy." This was published in the Journal of Clinical Oncology online on October 30, 2023, and in print on February 1st, 2024. And I am excited. I am accompanied by the lead author, Dr. Jeremy Davis, who is an Associate Professor and Surgical Oncologist at the NIH, National Cancer Institute Intramural Research Program. Welcome, Dr. Davis. Dr. Jeremy Davis: Thank you. Shannon Westin: If it is okay with you, I'll call you Jeremy. Dr. Jeremy Davis: Yes, please. Shannon Westin: Fabulous. We also have patient advocate Kathryn Carr, who is a board member for No Stomach for Cancer. Welcome, Kathryn. Kathryn Carr: Thank you so much. Shannon Westin: So let's get right into it. I think this is really thought-provoking work. First, I'd love to level set. So this was work around hereditary diffuse gastric cancer syndrome. Can we get a little bit of information about what causes this and how common it is? Dr. Jeremy Davis: So, hereditary diffuse gastric cancer syndrome, also referred to as the diffuse gastric cancer and lobular breast cancer syndrome, is basically early-onset diffuse gastric cancer and in women, lobular type breast cancer attributed to germline mutations in the CDH1 gene. If we look at all cases of gastric cancer in the United States, only about 1-3% may be considered hereditary in nature. But when we do study hereditary causes of cancer, it is by far the most common one that we are aware of. Shannon Westin: What is the likelihood that someone who is a carrier of a germline CDH1 variant will develop gastric cancer? Dr. Jeremy Davis: That's a good question. Early on, when the syndrome was first described, the estimates of cancer risk were quite high, probably upwards of 70-80%. The good news is that more current estimates published in the last few years suggest that that risk in a lifetime is probably in the 25-40% range. It's interesting, we do have our own data that are under review right now, where in some families where there's no history of stomach cancer, that risk of stomach cancer in a lifetime getting a CDH1 mutation might be as low as 10%. So I think the takeaway is that there's clearly a spectrum and that spectrum of risk is probably based on factors that we don't quite yet understand. Shannon Westin: What are the options for management of this hereditary syndrome, really focusing on the gastric cancer syndrome portion today? How good does it do to reduce the risk? Dr. Jeremy Davis: The options are really two. One is probably the prevailing recommendation that most people would be aware of, is to prophylactically remove the stomach, and we choose to use the term most often 'risk-reducing gastrectomy', but to remove the entire stomach and really eliminate the risk of cancer from ever developing. The other option is enhanced surveillance, and people might think of this as akin to other high risk cancer syndromes. But for this we would do yearly or annual endoscopic surveillance. Many people think that that may not be the best option, but it is certainly an option. We discussed some of that in the paper about what are the risks and benefits of gastrectomy, and then what may be the benefit of enhanced surveillance for some people. Shannon Westin: Well, I would love to hear Kathryn. I think this is a perfect opportunity to hear a little bit about your journey with carrying this variant, as much as you are willing to share with our listeners. Kathryn Carr: Yeah, absolutely. So I found out that I have this spicy little gene back in 2019. My whole family got tested so the gene comes down from my paternal great grandmother. There are five of us who actually all had our stomachs removed by Dr. Davis. Within a year, he had five Carr stomachs. For me when I found out, I was extremely overwhelmed. I mean, "You want to take my stomach out? Like, what do you mean?" But after talking to Dr. Davis and his entire care team, I knew for me, having the total gastrectomy was the only option simply because I know my personality type enough that I was not going to be able to move forward with life unless I got rid of this overwhelming worry. Shannon Westin: Yeah, I think that makes sense. I'm a GYN oncologist by trade, so I often reference all things

In this JCO Article Insights episode, Subodh Selukar summarized findings from the original article published in the January 2024 JCO issue: "The Importance of Low and Moderate Grade Adverse Events on Patients' Treatment Experience and Treatment Discontinuation" and accompanying editorial "Patient Experience, Adverse Event Reporting, and Clinical Trial Design". The summary provides information regarding low and moderate grade adverse events and the patient experience in clinical trials. TRANSCRIPT Welcome to the JCO Article Insights episode for the January 2024 issue of Journal of Clinical Oncology. This is Subodh Selukar, your host, and today I will be providing a summary on 2 articles focused on low and moderate grade adverse events. The first article, titled "The Importance of Low and Moderate Grade Adverse Events on Patients' Treatment Experience and Treatment Discontinuation" by Dr. O'Connell and colleagues, investigated low and moderate grade adverse events and the patient experience in clinical trials. Their article is accompanied by an editorial entitled "Patient Experience, Adverse Event Reporting, and Clinical Trial Design" by Dr. Neuman. In clinical trials, a standardized system for reporting adverse events is the Common Terminology Criteria for Adverse Events (or "CTCAE") established by the NCI, the United States National Cancer Institute. The CTCAE categorizes adverse events at 5 severity grades across 26 system organ classes. However, some clinical trials may only report adverse events at grade 3 or higher, with one possible rationale being that low and moderate grades are unlikely to affect patient safety or key trial endpoints. In Dr. O'Connell's article, the team investigated how the numbers of grade 1 and 2 adverse events related to patient self-reported side-effect burden and treatment discontinuation. To do this, they analyzed data from the Phase 3 trial E1912 conducted by ECOG-ACRIN comparing two treatments for chronic lymphocytic leukemia. They chose this trial as an example because the study data included all adverse event grades throughout the duration of treatment for each patient. The authors studied side-effect burden based on GP5, which is the fifth item in the FACT-G subscale in the Functional Assessment of Cancer Therapy. GP5 rates the patient's agreement with the statement "I am bothered by side effects of treatment" in the past 7 days, and it has previously been connected with adverse event grade and treatment discontinuation. For treatment discontinuation, the authors focused on those discontinuations that were recorded as being due to "adverse events, side effects or complications." They found that, for each adverse event grade, there were, on average, more adverse events in cycles that ended with a patient discontinuing treatment compared to other cycles. Next, they used Bayesian models to assess how the numbers of grade 1 and grade 2 adverse events in a treatment cycle were associated with the odds of higher side-effect bother and odds of treatment discontinuation, after adjusting for cycle number, treatment and occurrence of grade 3 or higher adverse events within the cycle. Baseline GP5 was also included in the models, and these models also accounted for the inclusion of multiple cycles for each patient. When adjusting for baseline GP5, treatment, cycle and presence of grade 3 or 4 adverse events, both the number of grade 1 and the number of grade 2 adverse events were each strongly associated with increasing side-effect bother. The adjusted odds of treatment discontinuation were also higher with more grade 2 adverse events. However, with the same adjustment variables, the odds of treatment discontinuation were actually lower with larger numbers of grade 1 adverse events. In their primary analysis, they focused on adverse events that were attributed to treatment, so they excluded non-treatment-related adverse events from the counts. Sensitivity analyses including these adverse events have similar conclusions but with a weaker magnitude of effect. They attributed this to issues like existing adverse events not causing new bother. Next, the authors analyzed whether symptomatic versus asymptomatic adverse events affected these results by re-fitting the models and separating the predictors into numbers of asymptomatic and symptomatic grade 1 or 2 adverse events. In these results, they found no evidence for associations between numbers of asymptomatic adverse events at any grade and side-effect bother. On the other hand, they found strong evidence for associations with symptomatic adverse events of grade 2 and 3 or higher both for side-effect bother as an outcome and with treatment discontinuation. Asymptomatic grade 2 adverse events were associated with treatment discontinuation but not side-effect bother, and symptomatic grade 1 adverse events were associated with side-effect bother but not treatment discontinuation. · The authors conclude that adverse events of all grades,

Dr. Shannon Westin and her guest, Dr. Ash Alpert and Spencer Adams, discuss the paper "Debunking Sex and Disentangling Gender From Oncology" recently published in the JCO. TRANSCRIPT The guests on this podcast episode have no disclosures to declare. Shannon Westin: Hello and welcome to 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 and GYN oncologist by trade. I'm so excited to be discussing a very important manuscript. This is "Debunking Sex and Disentangling Gender from Oncology," which was published in the JCO Online on May 26, 2023. So I'm joined by two of the authors here today on the podcast. First is Dr. Ash Alpert. They are an instructor of medicine and hematology at Yale Cancer Center. Welcome. Dr. Ash Alpert: Thank you. Shannon Westin: And we also have Spencer Adams. They have a bachelor's in public health, are a certified health education specialist, and are currently pursuing a master's in public health at Western Michigan University. Welcome, Spencer. Spencer Adams: Thank you for having me. Shannon Westin: So let's get into it. I'm so excited. First off, I just want to say thank you because I learned a ton from this paper, and I'm hoping to be able to implement some of these changes that we're going to discuss over the next few minutes at my own institution. So I wanted to just make sure we kind of level set and everyone's on the same page. So let's start off by discussing ontological oppression. Can you explain to the listeners what this means and how it relates to sex and gender and oncology? Dr. Ash Alpert: Sure. So, ontological oppression is actually a concept from one of my colleagues at Yale, Robin Demroff, who's a philosopher. Ontology is a way of thinking about what exists and how we categorize what exists. And so ontological oppression is discrimination or stigma that happens because of the ways people imagine us fitting or not fitting into social categories. For example, if we think that people are women or men based on their sex assigned at birth, then it makes sense that we would think of transgender people and nonbinary people as abnormal, weird, or pathologic. In oncology, if we think of ovarian cancer as something that happens to women and a man with ovarian cancer comes into our clinic, we may be confused or uncomfortable. We may respond to those feelings by denying his identity, for example, thinking he's actually a woman or using the wrong pronouns or name for him or even potentially denying him care. And we have some data to suggest that clinicians respond to lack of knowledge about transgender people by treating them as abnormal, weird, or bad in some way. Spencer Adams: Yeah. And to add to that, when we consider how we classify people, first, there's a problem within that. There's an ethical problem within that, but it's an idea or a construct that society has created and wants people to fit into these nice little boxes just because it's easier to digest, or you make the person more palatable if they're able to do these things. And life is not like that. We have differences, and we have things that make people fit outside the box. And I believe that when we keep reminding people that a box exists or a social construct exists, you're stifling who they are, their personality, their guiding light. You're stifling a lot of things about that person and ignoring something that's incredibly important to them. Shannon Westin: I think that along those lines, kind of taking that to the next step, it would be really helpful to discuss a little bit more around this interaction between sex assigned at birth and gender and what assumptions are made. And I think you kind of started along this, like, how that impacts oncology care. But in your paper, you did, I think, a really great job of really laying out a lot of the problems that happen in this space, and I'd love to explore that more right now. Dr. Ash Alpert: So sex is a designation made when a baby is born by somebody viewing that baby's external genitalia. And so I think we all, as doctors, know that that designation doesn't necessarily tell us what that person's karyotype is, what their later hormonal milieu will be, what their internal anatomy is, and it certainly can't tell us anything about their gender, which is how someone sees themselves as a man, woman, nonbinary, or something else, and usually develops around the age of four. And even though I think that we all know that, we're so used to sex and gender being used interchangeably, not just in the ways that we talk to each other, but in everything about the way that we do our work. And so it becomes very difficult to disentangle these concepts for ourselves. And we have used sex in particular as a proxy for so many other factors where it doesn't necessarily function. And parts of medicine are based on that. So it's very hard to start to unpack and disentangle

Dr. Shannon Westin and her guests, Dr. Judy Garber and Dr. Geoffrey Oxnard, discuss the paper "Germline EGFR Mutations and Familial Lung Cancer" recently published in the JCO. TRANCRIPT The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello, and welcome to JCO After Hours, the podcast where we get in-depth on articles that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for the JCO and Gynecologic Oncologist by trade. And it is my great pleasure to speak today with you about an amazing manuscript entitled, "Germline EGFR Mutations and Familial Lung Cancer." It was published in the JCO on August 14, 2023. The authors have no conflicts of interest, and they are Dr. Geoffrey Oxnard, he's a Thoracic Oncologist and Associate Professor, Hematology and Medical Oncology at Boston Medical Center. Welcome, Geoff. Dr. Geoffrey Oxnard: Hi, Shannon. Thanks. Shannon Westin: And Dr. Judy Garber, the chief of the Division of Cancer Genetics and prevention at the Dana-Farber Cancer institute in Boston. Welcome, Judy. Dr. Judy Garber: Thank you. Hi, Shannon. Hi, Geoff. Shannon Westin: So excited you both could be here. Let's get started. So first I just want to levelset for our audience. Can you speak just a little briefly about the incidence and mortality of lung cancer and how that's been changing over time? Dr. Geoffrey Oxnard: Sure. Lung cancer is common and it's deadly, more than 200,000 cases a year in the United States, more than 100,000 deaths a year in the United States. But I think importantly, it's evolving. Its biology is evolving as smoking incidence goes down. We've identified these genomic subtypes of lung cancer that are sort of increasingly apparent and important as we think about its treatment. Outcomes are changing with emerging therapies, presentation is changing with lung cancer screening and with a growing ability to now find cancers early and prevent them. And so it's in that setting of a very dynamic disease that we chose to study a really unique little slice of it, which is germline risk. Shannon Westin: So let's take that one step further because I think that's really interesting. You mentioned the genomic aberrations and kind of how you're using that to target. Can you expand upon that a little bit more for me? Dr. Geoffrey Oxnard: Lung cancer that I've long studied is different than breast cancer when Judy has long studied because we think about its somatic alterations, we've always thought about KRAS mutations, EGFR mutations, and smaller and smaller splice limit. ALK, RAS, RET HER2, etc. And so tumor testing in lung cancer has one of the first to be standard across on solid tumor oncology. And the germline genetics was kind of an afterthought and is the flip, I think, of how genetic testing evolved in the breast cancer space for example. Dr. Judy Garber: I might argue a little bit if breast cancer was earlier and it was subtyped some molecularly it doesn't have as many molecular subtypes yet perhaps as lung cancer. But we've all been studying the somatic space to look for targets for therapy. And the germline space, certainly in breast cancer, came much earlier. And everybody knows about BRCA1 and 2. Now, we hope everybody knows about Lynch Syndrome, but certainly not everybody's thinking about inherited lung cancer risk. Dr. Geoffrey Oxnard: Yeah, these have converged. I think 10 years ago when this kicked off, I felt like a super outlier for thinking about, wait a second, what about the genetics behind all this that is leading to this strange variable presentation of lung cancer? For example, we know that in Asian populations, one type of lung cancer, EGFR mutant lung cancer, is more common. There must be some geneticness that leads to that. What explains the sort of pattern of presentation of these genetic subtypes in the populations we see in the US, that's pretty unclear? Dr. Judy Garber: So, I think, Shannon one of the clues about all this came from the fact that the EGFR mutations were being identified in the tumors. And then I really should let Geoff tell this story, but as the amateur thoracic person in the room here, to me, it was so interesting that there were the EGFR mutations, then there was treatment exploiting EGFR mutations, and the most common resistance mutation was this T790M variant. But when labs started testing EGFR, there was a small group of people who had that resistance variant without ever having been treated at all. So that was the obvious question, what was it doing there? And that's where Geoffrey came in. Dr. Geoffrey Oxnard: Yeah, this is a patient I met more than a decade ago at my fellowship in MSKCC. She'd been living with a T790M mutation in her tumor for years and years and years. I was like, "Well, I don't understand. Why is this sitting there?" And she had this sort of slightly mysterious history of lung cancer in her family. And we realized, wait a second, this T790M wa

In this episode of JCO Article Insights, host Dr. Soldato discussed with Dr. Knikman and Dr. Cats the findings of a study that assesses the influence of fluoropyrimidine dosing based on DYPD genotype on both progression-free and overall survival. The article, featured in the December edition of JCO, presents groundbreaking and reassuring data. Furthermore, it highlights emerging research challenges aimed at refining the prescription practices of one of the most widely utilized chemotherapy agents, striking a delicate balance between safety and efficacy. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Davide Soldato: Welcome to this JCO Article Insights episode for the December issues of the Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Knikman and Dr. Cats, respectively first and corresponding authors of the manuscript titled "Survival of Patients with Cancer with the DPYD Variant Alleles and Dose Individualized Fluoropyrimidine Therapy: A Matched-Pair Analysis." Dr. Knikman is a clinical pharmacologist and assistant professor at the UMC Utrecht, while Dr. Cats is a gastroenterologist specializing in gastrointestinal oncology at the NKI in the Netherlands. Welcome, Dr. Knikman and Dr. Cats, and thank you for accepting our invitation today. Dr. Annemieke Cats: Thank you so much for the invitation. Davide Soldato: So I just wanted to start by discussing the manuscript that you published. But before delving into the results of the manuscript that was published in the JCO, I just wanted to ask if you could give a brief overview of the DPD polymorphism and explain a little its relevance in the clinical practice. Dr. Annemieke Cats: The DPD polymorphism is very important in the metabolism of fluoropyrimidines. Fluoropyrimidines have been in practice for over seven decades now in the world and more than 2 million people received fluoropyrimidines in the beginning of this millennium. The indications for fluoropyrimidines have only been extended since then, so a lot of people are receiving this fluoropyrimidines. But with the good side of that there's also another side and that is that there are a lot of side effects encountered by this chemotherapeutic drug. In the 1990s, it became clear that DPD was a key enzyme in the metabolism of fluoropyrimidines. Dr. Jonathan Knikman: To better understand the toxicity associated which fluoropyrimidines are accompanied by, we have to take a closer look at the metabolism of fluoropyrimidines, and more specifically at the key metabolic enzyme which is dehydropyrimidin dehydrogenase, DPD in short. This enzyme breaks down the main active metabolite into inactive metabolites because 5-fluorouracil is the main active metabolite which is metabolized into inactive metabolites. However, if this enzyme does not function properly, this could lead to higher exposures of the active metabolites and subsequently more toxicity. This can be caused by mutations in the gene encoding for the DPD enzyme, which is the DPYD gene, and single nucleotide polymorphisms, so mutations in this gene can lead to less functional DPYD enzymes, subsequently can lead to more toxicity. Davide Soldato: So basically, patients that are harboring these SNPs in the gene encoding for the enzyme have a higher risk of toxicities. I think what is really important about the manuscript you published is that, apart from looking at the toxicities, side effects and pseudo profile among these patients who harbor these SNPs you also wanted to check whether this was associated with some reduction or at least with inferior clinical outcomes. The endpoints you selected were progression-free survival and overall survival. But I was really interested, and I think our readers and listeners would be interested in understanding a little bit the methods of the study. What was the cohort of patients that was selected? Was this a cohort composed only of patients with gastrointestinal malignancy or also different types of malignancies? And in this second case, if you included the patients with different types of malignancies, did you have any methods to be sure that there was not any differences among these patients at the very beginning? So basically, how you handled all the confounding factors that could potentially impact the analysis of clinical outcomes. Dr. Annemieke Cats: To start your question, we have to go back to a previous study we performed, which was a prospective, multicenter study we performed in the Netherlands in 17 centers in which 1100 patients that had an indication for fluoropyrimidine therapy were included. In these 1100 patients, there were about 85 patients that were heterozygous carriers of a DPYD variant. What we did, we compared these two groups with each other, but before the DPYD carriers started, they had a reduced dose. The *2A variant carriers and the *13 carriers, they received a 50% dose, and the 1236 and 2846 they r

Dr. Shannon Westin and her guest, Dr. Michael Anne Kyle and Dr. Nancy L. Keating, discuss the paper "Prior Authorization and Association With Delayed or Discontinued Prescription Fills" 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 that goes in depth on articles and manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the Journal of Clinical Oncology. And as always, I'm so excited that you've joined us, and none of the authors have any conflict of interest today. We are going to be discussing a very exciting piece of work, "Prior Authorization and Association with Delayed or Discontinued Prescription Fills," recently published in the Journal of Clinical Oncology. And I'm thrilled to be joined by the two authors of this important work. The first is Michael Anne Kyle. She's a PhD research fellow in the Department of Healthcare Policy at Harvard Medical School. Welcome, Michael Anne. Dr. Michael Anne Kyle: Hi. Thanks for having me. Shannon Westin: We're so excited. And the second is Dr. Nancy Keating. She's Professor of Healthcare Policy at Harvard Medical School and Professor of Medicine at Brigham and Women's Hospital in Boston. Welcome. Dr. Nancy Keating: Thank you. It's great to be here. Shannon Westin: So, we'll get right to it. First, I always like to level set because we have such an interesting and diverse audience. Can one of you describe the process and goals of prior authorization? What does this mean for our groups that maybe haven't experienced this? Lucky them. Dr. Michael Anne Kyle: Prior authorization is- the process can take many forms. Basically, what we're describing is before you can be prescribed a treatment, in this case, we're looking at medications, you have to submit a request to the payer, to the insurance company, asking for approval to receive that treatment, or in this case, that drug. The doctor's office does have to do a ton of work, but very often, the patient also receives a lot of the communication. So, there's a lot of work for everybody in prior auth often. And the uses of it- in principle, the purpose of prior authorization is to confirm that the reason this medication or this treatment is being prescribed is because the patient meets the criteria for need. So that can mean, you want to confirm that you have the right tumor markers for the drug that's being prescribed. You want to confirm that you are aligned with guidelines. And then I think the thing that's often on many people's minds is that in the US, we don't have a lot of controls on drug pricing, but drug prices are very high. And so, I think we often think about prior auth as being a mechanism to try and contain costs. Shannon Westin: And this isn't new, right? So, this is a process that's been going on for a while. I'd love to hear you speak a little bit about, maybe, some of the changes, like how have the requirements for prior authorization been changing over time, especially for patients with cancer? Dr. Michael Anne Kyle: That's a great question. And that was the first step we took in this work because we've heard from oncologists, from patients, from researchers, that prior auth has been increasing. And we did find, looking at Medicare data, that that is true, that the use of prior authorizations for oral oncology drugs, so that will be Part D outpatient drugs you get at the pharmacy, has been rising over the past decade. And I think what's really interesting to point out here is we found the use of prior authorization increasing both for branded drugs and for generic drugs, and for specialty drugs, which are high cost, as well as non-specialty drugs, which are typically lower cost. So, across the board, prior auth is increasing. And why is this happening really is the million-dollar question. Some of it is surely like we have accelerated approvals happening predominantly in oncology. So, you could imagine that you do need to verify some evidence of these newer treatments, but some of it is a little bit harder to interpret. And that was one of the things in our paper that we were very interested in because we also see a lot of prior auth on drugs that have a very well-established record of efficacy. And we know our first-line therapies often now include some generics, and yet we still see that they have prior auth. And the reason for that is less clear. Shannon Westin: Yeah. Just as a gynecologic oncologist, coming from this standpoint of PARP inhibitors, which have long been established as a standard of care and for years now have been a frontline treatment, we're getting so much pushback around that, and it's a huge issue because that impact of delays and things, and I know that's your work. So, I think that's one of the reasons I was very enthusiastic about this because I

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 b

In this JCO Article Insights episode, Davide Soldato provides summary on two articles published in the November issues of the Journal of Clinical Oncology. The first article provides data on the prognostic effect of physical exercise on overall mortality and cancer-related mortality in a pan-cancer analysis of the PLCO study. The second article provides data regarding the impact of BMI on treatment-related adverse events and adherence to Palbociclib in the PALLAS trial. Overall, results of these study support the need to conduct studies investigating lifestyle behavioral factors and their impact on outcomes in survivors of and patients diagnosed with cancer. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Davide Soldato: Welcome to the JCO Article Insights episode for the November issue of the Journal of Clinical Oncology. This is Davide Soldato, your host, and today, I will be providing a summary on two articles focused on the impact of exercise on cancer prognosis and of BMI on treatment side effects. In the first article titled Pan-Cancer Analysis of Postdiagnosis, Exercise, and Mortality, Lavery and colleagues investigated whether higher exercise was associated with a reduced risk of mortality among individuals diagnosed with cancer. The authors conducted a pan-cancer analysis using data from the Prostate, Lung, Colorectal, and Ovarian cancer screening study or PLCO, using data from a questionnaire that was administered to participants in the study at a median of nine years after initial randomization. The questionnaire including 12 questions related to physical activity, both occupational and non-occupational. Of these 12 questions, four were used to assess the prognostic impact of moderate and strenuous exercise evaluated both in terms of frequency, so a number of sessions per week, and duration of exercise sessions. The exposure to exercise was defined according to international guidelines, and patients were so divided among those who had a moderate intensity exercise defined as at least four days per week with each session on average for 30 minutes in duration, and strenuous intensity exercise equal or more to two days per week with each session on average of at least 20 minutes in duration. So, based on this definition, the patients were categorized as either exerciser, if they were meeting the recommendation or non-exercisers. Additionally, to assess the existence over those response relationship between exercise and mortality, the authors further categorize patients on a four level scale as reporting no exercise, exercise, not meeting recommendation, meeting recommendation, or exceeding recommendation. The primary endpoint of the study was all-cause mortality, and secondary endpoints included cancer mortality and mortality from other causes. This study included more than 11,000 patients diagnosed with cancer. 38% of them reported meeting guidelines recommendation with a median of 44 and 19 minutes spent in moderate and strenuous exercise respectively. Individuals belonging to the group of exerciser were more frequently male, non-smokers, and with a lower prevalence of cardiovascular diseases. The most common cancer diagnosis were prostate cancer, breast cancer, and colon cancer observed respectively in 37%, 20%, and 7% of the participants. Patients who died within six months from the completion of the questionnaire were excluded from this study. A median follow-up time between this landmark point and the last follow-up was 11 years. More than 4,500 deaths were observed in this period, and less than half were related to cancer meeting. Meeting exercise recommendation was associated with a 25% risk reduction in all-cause mortality, a 21% risk reduction in cancer mortality, and a 28% risk reduction in mortality from other causes. In particular, five-year cancer mortality rate was 12% among exerciser and 16% among non-exerciser. Interestingly, the positive prognostic effect of exercise was observed starting within the first five years of observation, but persisted up to 20 years afterwards. An inverse to those response relationship between exercise and mortality was observed, so increasing exercise was overall associated with incremental reduction in the risk of death. The authors compared patients reporting no exercise with those reporting exercise under at the recommendation or over the recommendation. For all-cause mortality, the risk reduction was equal to 25% among those reporting exercise below the recommendation, and increased to 35 and 36% among those meeting and exceeding recommendation respectively. Similar results were observed for cancer mortality, risk reduction ranged from 19% in those reporting exercise below recommendation, up to 33% for those exceeding recommendation. Finally, the authors investigated the effect of exercise on mortality by cancer type, and observed a significant reduction in cancer mortality only for head and neck cancer and renal cancer.

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 historic

In this JCO Article Insights episode, Davide Soldato interviews Dr. Jacob Sands, medical oncologist at Dana Farber Cancer Institute (Boston, MA) and Assistant Professor at Harvard Medical School, on their paper "First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01". The interview offers a deep dive into the safety and efficacy data of this novel drug and puts these data in the context of the current treatment landscape of NSCLC and of the revolution that ADC are bringing into the oncology world. TRANSCRIPT Davide Soldato: Welcome to this JCO Article Insights episode for the October issue of Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Jacob Sands, co-author of the manuscript titled, "First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01." Dr. Sands is a Medical Oncologist working at Dana-Farber Cancer Institute in Boston and Assistant Professor at Harvard Medical School. His main field of research and clinical interests revolve around improving screening and diagnosis of lung cancer and also on developing novel therapeutic agents for this disease. So, welcome Dr. Sans, and thank you very much for accepting our invitation today. Dr. Jacob Sands: Happy to join. Thanks for having me. Davide Soldato: I just wanted to start with a very general question because I think that we are going to discuss a very important study and the manuscript that you co-authored is going to look at the safety and the efficacy of this novel ADC datopotamab-deruxtecan that is targeting TROP2. But I just wanted to have a little bit of context before starting to discuss the safety and efficacy data. So the population that was included in the study included more or less 60% of patients that received three or more lines of therapy and also 20% of patients who received five or more lines of therapy. So I think that this is a very particular population, especially considering that we are speaking about non-small cell lung cancer. And so I wanted to get from you like a general context, like what are the therapeutic options for these patients normally in clinical practice and what do we expect in terms of outcomes and in terms of toxicity? Dr. Jacob Sands: Yeah, so as you point out, this is a highly pretreated population in general, which is to say that they've really gotten the most effective lines of treatment up to this point. Now, we certainly do see some efficacy from some of the later lines of therapies in some patients, but inherently there is a decreasing response rate and decreasing durability of these responses as patients get further along in their treatment courses as far as lines of therapy. So it's generally considered to be a challenging clinical scenario, which is part of what makes the data that we're going to discuss, I think, so meaningful. Davide Soldato: Yeah, I think that especially if we look at the population that was included first, I think that the very particular thing is that included both oncogene-addicted and non-oncogenic addicted patients, and also the great majority of these patients received the most effective treatments that are available because they all received more or less immunotherapy and platinum-based chemotherapy, if I'm not mistaken. Dr. Jacob Sands: That's right. And that's an important distinction that you're drawing in the patients with oncogenic drivers and, of course, there's plenty of data with this compound with Dato-DXD in that population as well. But broadly speaking, in the non-oncogenic actionable alterations where they've gotten chemo-immunotherapy, those really are the most meaningful. Of course, docetaxel has been a long-standing second line that I'd say there is less and less enthusiasm about that as a line of treatment as we've seen some of these other more novel therapies that have just a better toxicity profile in particular, but also some with really durability that we don't quite see with docetaxel as well. And so once you're getting past that, you're really now reaching a bit deeper to then have something that is well tolerated and has efficacy. That's a setting where we really need it even more. Davide Soldato: So, going back to the results of the study, as we kind of pointed out, this was a very standard classic with a Bayesian design, phase I dose escalation and dose expansion study of this novel ADC datopotamab-deruxtecan. So I just wanted to go over with you and to provide our listeners a little bit with some data regarding the doses that were explored and then what were the doses that were selected for the expansion. And also to discuss a little bit the safety data. We were discussing the tradeoff betwee

Dr. Shannon Westin, Dr. Stephanie Wheeler, and Dr. Caitlin Biddell discuss the paper "Economic Evaluation of a Non-Medical Financial Assistance Program on Missed Treatment Appointments Among Adults With Cancer," a simultaneous publication, podcast, and presentation at the ASCO Quality Care Symposium. 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'm your host, Shannon Westin, Social Media Editor of the JCO and GYN Oncologist. And I am so excited that today we have a simultaneous publication in JCO and presentation at the 2023 ASCO Quality Care Symposium here on 10/28/2023. And this is going to be the manuscript "Economic Evaluation of a Nonmedical Financial Assistance Program on Missed Treatment Appointments Among Adults With Cancer." Very exciting work. And I'm thrilled to tell you I have two of the authors here with me today. First is Dr. Caitlin Biddell. She's a Health Services Researcher at Mathematica Policy Research. Welcome, Caitlin. Dr. Caitlin Biddell: Thank you. Happy to be here. Dr. Shannon Westin: And we also have Dr. Stephanie Wheeler. She is the Michael S. O'Malley Distinguished Professor in the Department of Health Policy and Management at the University of North Carolina, Chapel Hill, as well as being the Associate Director of Community Outreach and Engagement at UNC Lineberger Comprehensive Cancer Center. Welcome. Dr. Stephanie Wheeler: Thank you. Happy to be here as well. Dr. Shannon Westin: Please note that our authors and participants have no conflicts of interest. Let's get started. So first I would love to level set. Can you speak a little bit about what financial toxicity is and how common it is among patients with cancer? Dr. Stephanie Wheeler: Sure, Shannon. I'm happy to take that one. This is Stephanie. So we know that financial hardship is often reported by patients and survivors who've experienced cancer. And as many as 50% of people with cancer have trouble with financial toxicity. There has been prior work that has conceptualized financial toxicity in three domains. So there's the material hardship, kind of the out-of-pocket material costs associated with cancer, which include both medical and nonmedical expenses. There is the stress and the psychosocial effects of that material hardship. And then there's coping behaviors that patients and their caregivers may employ to help deal with the high cost of cancer care. And as we've seen, cancer care increases in cost over time, and these expenditures really have very burdensome effects on patients and their families. We've been interested in looking at ways that we can try to mitigate that harm and really thinking about interventions in addition to the health policy changes that are needed to really ensure that this doesn't become a barrier to patients seeking and receiving the best quality care that they can. Dr. Shannon Westin: I think that kind of leads pretty nicely into my next question, which is really: How does this toxicity potentially impact equitable cancer care delivery? Dr. Stephanie Wheeler: Yeah, I'm happy to talk about that a little bit as well. So we know from prior research, including some of our own, that patients of color, those from rural areas, and those who are uninsured or underinsured face the largest financial burdens associated with their cancer care. So to the extent that those financial hardships influence people's ability to seek and continue with and complete their cancer care that's been recommended, this actually is directly in the pathway and a mechanism through which patients are not able to get recommended treatment and therefore can contribute to differences in cancer outcomes. So there's direct health impacts in terms of their ability to receive and respond to cancer treatment. In addition to that, we know that this financial hardship contributes to household-level harms both economic and psychosocial in nature. And in some other work, this financial hardship has translated to worse quality of life, worse economic outcomes, things like being able to stay employed and seeking changes in employment or remaining within a particular position because you don't want to lose your insurance—this is referred to as "job lock"—or can also contribute to higher mortality. So there's been some really important work showing that financial toxicity is directly linked with cancer mortality. And so, as we think about ways that we need to address this, it's really key to ensuring cancer health equity that we are thoughtful about multiple solutions implemented at multiple levels that can deal with not only the contributors to high cancer costs but that can also start to affect both the nonmedical and the medical components of this cost burden. And by nonmedical, I mean things like the cost associated with

Shannon Westin speaks with Holly Prigerson and Alfred Neugut about their thought-provoking editorial, "You Get (Offered) What You (Can) Pay For: Explaining Disparities in End-of-Life Cancer Care." TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast. And this is where we get in-depth on manuscripts and editorials that have been published in the Journal of Clinical Oncology. As always, I am your host, Shannon Westin, Gynecologic Oncologist and Social Media Editor for the Journal of Clinical Oncology, and I'm so excited to be here today. We are going to be talking about a very compelling editorial that is called "You Get (offered) What You (can) Pay for: Explaining Disparities in End-of-Life Cancer Care." And this was published on June 20th, 2023, in the Journal of Clinical Oncology as an editorial on an article entitled the "End-of-Life Systemic Oncologic Treatment in the Immunotherapy Era: The Role of Race, Insurance, and Practice Setting." So a very timely topic and very exciting for us to discuss today. I'm joined by two of the authors of the editorial, Dr. Holly Prigerson, Professor of Sociology and Medicine, the Irving Sherwood Wright Professor in Geriatrics Medicine at the Weill Cornell Medical College and the Director of Cornell Center for Research on End-of-Life Care. Welcome, Dr. Prigerson. Dr. Holly Prigerson: Great to be here. Dr. Shannon Westin: And also accompanied by Dr. Alfred Neugut, the Myron M. Studner Professor of Cancer Research and Professor of Medicine and Epidemiology at Columbia University and the former Associate Director for Population Science and Racial Disparities Program for the Herbert Irving Comprehensive Cancer Center at Columbia. Welcome, Dr. Neugut. Dr. Alfred Neugut: Thank you very much. Dr. Shannon Westin: Very excited to talk about this topic today, and I like to always start with a little bit of level setting. So I'd love for one of you to discuss: How common is the use of systemic anticancer treatment at the end of life? Dr. Holly Prigerson: So, based on the article, it looks like the rates within the last 30 days of death, it was 34% on average overall. So that was sort of the—you say level setting—the base statistic. Within 14 days of death, it dropped to 13% overall. So all the associations that are described are really disparities from that level. Dr. Neugut: Speaking as an oncologist, I don't think any of my clinical colleagues will be surprised that it's that high. There is an effort made really to, in desperation, try to help. Patients want it. Families want it. So there really is efforts made to try to do that to prolong life or palliate or whatever. Dr. Holly Prigerson: The design also, which is probably going to be a question that's coming up, does raise a question for me that I'm wondering if Al could enlighten at least me on. They did select patients who were getting treatment for metastatic or advanced cancer starting in 2011 and then who died four years later. Does the selection for the fact that they were getting treatment initially—because everyone, that's how they sampled the study—does that increase the likelihood that they'll get treatment later on so that the rates are somewhat inflated is my question. Dr. Alfred Neugut: Yeah, no, for sure. People who start chemo tend to continue partially because there is a certain amount of those who do well do well. If you respond to chemo initially, you tend to respond to the second-line therapy, you tend to respond to third-line therapy. If you didn't do well on first-line chemo, you're not likely to respond to a second line or a third line, so you don't have the enthusiasm to continue with it, and the patient certainly tends to lose interest in it. So you're right; there is a certain, call it, momentum or inertia in going forward with chemo once you've started. Dr. Shannon Westin: I mean, I think this just always highlights some of the issues we have, right, with any kind of retrospective data is how well can we design a population without—because we can't always do randomized control trials, and certainly not in this kind of setting. That would not be acceptable, I think, to providers nor patients. And I do agree that it can be tricky. Any other kind of, maybe just to help the listeners if they haven't gotten a chance to read this Canavan study, about the design, exactly what they were looking at in this population? Dr. Holly Prigerson: Basically, they took these patients who were getting systemic therapy and had advanced metastatic cancer prior, and then who died. So there's always a question about the sampling on death issue, that they had to have died to be in the sample. So those are methodological issues, but there's really very little way around that. If you want to know what treatments people received in the last month of life, they have to die for there to be a last month of life. S

A variety of perspectives are explored as Dr. Westin speaks with Dr. Jennifer Mack, Dr. Chun Chao, and Mallory Casperson about end-of-life care planning in adolescent and young adult cancer. 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 down and dirty with manuscripts that are being published in the Journal Clinical Oncology. And I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the Journal of Clinical Oncology. I am so very excited to have a number of guests with us today to discuss a very important paper entitled "Discussions About Goals of Care and Advanced Care Planning Among Adolescents and Young Adults with Cancer Approaching the End of Life." And I'm joined by several of the authors of this important paper. The first is Dr. Jennifer Mack. She is the Associate Chief in the Division of Population Sciences, an Associate Professor at Harvard Medical School and Senior Physician in Pediatric Hematology Oncology at the Dana-Farber Cancer Institute. Welcome, Dr. Mack. Dr. Jennifer Mack: Thank you. Dr. Shannon Westin: We also have Mallory Casperson. She is the cofounder and CEO of the Cactus Cancer Society. They provide online support programs and resources to young adult cancer survivors and caregivers in the comfort of their own homes. Welcome. Mallory Casperson: Thanks for having me. Dr. Shannon Westin: And then, finally, last but not least, Dr. Chun Chao. She is a Senior Research Scientist in the Division of Epidemiologic Research in the Department of Research and Evaluation at Kaiser Permanente Southern California. Welcome. Dr. Chun Chao: Thank you. It's a pleasure being here. Dr. Shannon Westin: So I want to get right into this. I think that there certainly has been a lot of discussion, at least at our institution as well as at the ASCO level, around advanced care planning across all patients with cancer and anyone with a diagnosis of cancer. And I would love to just start and level set and make sure all of our listeners are all on the same baseline around the incidence and prevalence of cancer in adolescents and young adults. Like, first, define what are the age groups that we're looking at here? How common is cancer in this population? Dr. Jennifer Mack: Right. For this study, we defined adolescents and young adults as individuals aged 12 to 39. And right now, about 90,000 adolescents and young adults are diagnosed with cancer in the United States each year. Those numbers are also rising, so more and more are diagnosed each year, and because of that, we think it's increasingly important to pay attention to the needs of this population. This population really experiences a whole range of different cancer types, some of which are more common in children, some of which are more common in adults, but the most common ones include breast and gastrointestinal cancers, sarcomas, germ cell tumors, leukemias, lymphomas, and brain tumors. Dr. Shannon Westin: And your manuscript notes that adolescents and young adults seem to receive medically intensive measures at the end of life. Now, how common is this across this group? And do you all have a sense of some of the reasons that we see this increased use of these measures? Dr. Jennifer Mack: That's a great question. We and others—actually, the early work that led to this study was done with Chun. We had previously found that most adolescents and young adults receive at least some kind of medically intensive care at the end of life. And that includes things like being hospitalized, being in the intensive care unit, receiving chemotherapy, and spending time in the emergency room near the end of life. And so, if you take all of those together, about two-thirds of adolescents and young adults receive at least one of these near the end of life. And we don't know the reasons for this. There are probably complex reasons. Some adolescents and young adults may actually want to receive these kinds of measures, maybe because they're young and they want to do everything they can to live as long as they can. And some patients in this age group are parents to young children, and they may be making choices to prolong life and be there for their kids. But we also know that if we look at older adults, most people who know they're dying don't want to receive this type of care, which is also associated with more suffering and with poorer quality of life. So it's also possible they're making these choices because they don't fully recognize they're approaching the end of life or because they haven't had opportunity to plan for this time through conversations with their medical teams. Mallory Casperson: I think the conjecture, too, that a young adult is likely to focus on extending life, even in a situation where palliation is the stated goal, is a really great conjecture. This population is really burdened by these uniq

In this JCO Article Insights episode, Davide Soldato summarized finding from the original article published in the September JCO issue: "Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort". The summary provides information regarding the ability of a blood-based panel of 4 biomarkers in improving the identification of individuals at risk of developing lethal lung cancer and potential of combined screening strategies to improve trade-off between potential harms and benefit of the screening process. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Davide Soldato: Welcome to the JCO Article Insights episode for the September issue of the Journal of Clinical Oncology. This is Davide Soldato, your host, and today I will be providing a summary on one article focused on the refinement of screening strategies for lung cancer. The article, titled "Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort" by Dr. Irajizad and colleagues, investigated the ability of a panel of circulating blood biomarkers in improving the identification of individuals at risk of developing lethal lung cancer. We already know that lung cancer screening based on the use of low dose CT is associated with a reduction in mortality, as already demonstrated by the National Lung Cancer Screening Trial and the NELSON Trial. Furthermore, the US Preventive Task Force has recently recommended an expansion of screening criteria for lung cancer. Currently, based on this recommendation, screening strategies are recommended for individuals 50 years of age and older with a smoking history of at least 20 pack-years and who are current smokers at the moment of the screening time or have quit within the past 15 years. Despite this positive data and this recommendation, the uptake of lung cancer screening in the US is still low, with reported uptake rates below 15%. The risk of false positive results, the unnecessary follow-up procedures, uneven access to lung cancer screening programs, and fear of cancer diagnosis and treatment have all been identified as potential barriers to optimal implementation and uptake of lung cancer screening. And so, in order to overcome some of these barriers, several efforts have been made in the last years to develop lung cancer screening prediction models with the aim of selecting a higher risk population who would derive higher benefit from lung cancer screening. In the present manuscript, the author builds on their previous work where they developed and tested a clinical prediction model and a blood-based prediction model in the context of the PLCO cohort. The Prostate, Lung, Colon and Ovarian Cancer Screening Trial was a randomized, multicenter trial in the US which aimed to evaluate the impact of early detection procedures on disease-specific mortality for the aforementioned cancers. Two lung cancer screening prediction model had already been developed and tested in the cohort. The PLCOm2012 model is based on several clinical and demographic characteristics, including age, race and ethnicity group, education, BMI, chronic obstructive pulmonary disease, personal history of cancer, family history of lung cancer, smoking status and intensity, duration and quit time. In a previous study, this model demonstrated a higher sensitivity and positive predictive value with no loss in specificity for lung cancer diagnosis compared to the National Lung Screening Trial criteria. Additionally, in the same cohort, the 4MP was a blood-based panel that included the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment. In a previous study, a combination of this blood-based panel and the PLCOm2012 model was associated with a better identification of patients at high risk of developing lung cancer that would consequently benefit from lung cancer screening. In the manuscript that was published in the current issue of the JCO, the authors aim to expand on these previous results and test the ability of the combined 4MP and PLCO model to identify individuals at high risk of developing lung cancer death. The study used prediagnostic sera of 552 individuals that were diagnosed with lung cancer within one year from the blood draw and 2000 non-cases. In the study, the authors assessed the performance of this combined four 4MP and PLCO model at a risk threshold of 1% and 1.7% of developing lung cancer at six years. Among the more than 500 individuals who were diagnosed with lung cancer, 70% died from it and 18% died of other causes, and the median survival times for lung cancer cases was 2.7 years. The combined 4MP and PLCO model had an area under the curve (AUC) of 0.88 for the prediction of lung cancer-specific mortality. The performance of this combined model using both clinical demographic and also a blo

Dr. Mahdi Sheikh and Dr. David Zaridze join Dr. Shannon Westin to discuss how quitting smoking after diagnosis may impact survival in kidney cancer. 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. This is the podcast where we get in-depth on manuscripts that have been published in the Journal of Clinical Oncology. As always, I'm your host, Shannon Westin, Gynecologic Oncologist and Social Media Editor for the JCO. And I am so excited to be here today. We are going to be discussing the paper, "Smoking Cessation After Diagnosis of Kidney Cancer Is Associated With Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study," which was published in the JCO on March 29, 2023. And this very intriguing paper, I have two of the major authors from this paper. First is Mahdi Sheikh, who is a scientist and epidemiologist at the International Agency for Research on Cancer, the World Health Organization in Lyon, France. Welcome, Dr. Sheikh. Dr. Mahdi Sheikh: Thank you very much, Dr. Westin, and thanks for having us. Dr. Shannon Westin: And then with Dr. Sheikh is Dr. David Zaridze. He is the Director of the Department of Clinical Epidemiology at the N.N. Blokhin Russian Cancer Research Center in Moscow and also the President of the Russian Cancer Society. We are with greatness today. Dr. David Zaridze: Thank you. Thank you very much. Nice to be with you. Dr. Shannon Westin: Very nice to be with the two of you. So, let's get started. I first wanted to just level set. Could one of you review just the overall incidence of kidney cancer and what proportion of patients with kidney cancer are known to be smokers at diagnosis? Dr. David Zaridze: The figures I'm going to present are rates. They are adjusted to standard world population. Why am I saying that? Because in America you sometimes use adjustment to the US population. These figures will be different from what you are accustomed to see. Okay, incidence of kidney cancer in Russia, in men, 14.1 per 100,000. I compare this with the United States of America, men, 16.5. Very small difference. Women in Russia, 8 per 100,000. In the United States of America, 8.8 per 100,000 of population. Exactly the same. Very close. These rates are sort of high-ish, but there are very high rates, for example, in the Czech Republic, where rates are more than 20 and other Central European countries. In Russia, kidney cancer mortality in men is 6 per 100,000. In USA, 3 per 100,000. In women in Russia, 1.9. In the United States, 1.3. I would say that there is a difference in mortality in men, not much in women. The incidence of kidney cancer is increasing in Russia sharply, sharply. Since 1990 it has increased - it's tripled. It increased from 5 per 100,000 in 1990 to 14 per 100,000 in 2019. Mortality is stable or declining. This is suggesting that kidney cancer is overdiagnosed in Russia and probably elsewhere. But this is not a problem of our discussion now. The frequency of the prevalence of smoking in kidney cancer patients. It is estimated that 15% to 20% of patients with kidney cancer smoke. In Russia, we have results only from our study. 18% of patients smoked at admission to our cancer center. Dr. Shannon Westin: Got it. Okay, good. Well, that's really helpful, especially to those of us that don't take care of patients with kidney cancer every day. It helps us just understand. And I guess the next question is what do we know about the impact of tobacco cessation on the risk of kidney cancer? So you were talking about that increasing incidence. How does tobacco cessation impact that? Dr. Mahdi Sheikh: Tobacco smoking is a known risk factor for kidney cancer and an estimated 17% of the kidney cancer burden worldwide can be attributed to tobacco smoking. There is a recent meta-analysis of 56 studies that was published a few years ago that clearly showed a dose-response relationship between smoking and kidney cancer, meaning that the more cigarettes a day you smoke, the risk of kidney cancer will go up. For example, the risk that was shown for five cigarettes per day was 20%. It goes up until 70% for 30 cigarettes per day. And also with a duration, the more years you smoke, the risk for kidney cancer will go higher. However, the good news is that when you quit smoking, there is strong evidence that the risk for developing kidney cancer will be lower compared to if you continue smoking. And there is some evidence that shows again dose-response relationship, meaning that the more years you spend in quitting smoking, the lower your risk would be for developing kidney cancer compared to if you continue smoking. So this is not only about renal cancer or kidney cancer but also true about many other cancer sites as well. Dr. Shannon Westin: Okay, that's super helpful. And then I guess prior to your study that we're about to talk about, did we have any information on wh

Dr. Shannon Westin and her guest, Dr. Helena Yu discuss the paper "HERTHENA-Lung01, a Phase 2 Trial of Patritumab Deruxtecan (HER3-DXd) in EGFR-Mutated NSCLC Following EGFR TKI Therapy and Platinum-Based Chemotherapy" published in the JCO during the World Conference on Lung Cancer in Singapore. 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 that are published in the Journal of Clinical Oncology. I am your host, Dr. Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. And as always, it's my pleasure to review an incredibly exciting manuscript. Today, we're going to be talking about "HERTHENA-Lung01: A Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in EGFR-mutated NSCLC Following EGFR TKI Therapy and Platinum-based Chemotherapy." And this is exciting. This is a simultaneous publication in the JCO on September 10th, 2023 at the same time it's being presented at the World Conference on Lung Cancer in Singapore. I am joined today by the first author and overall outstanding physician, Helena Yu. She's an Associate Attending Physician, Thoracic Oncologist, and Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center in New York, New York. Welcome, Dr. Yu. Dr. Helena Yu: Thank you. I'm glad to be here, and thanks for having me. Dr. Shannon Westin: So we're so excited to have you, and we love doing these simultaneous podcasts because I think not everyone can go to Singapore and be with you today. So it's awesome that we'll be able to give people the data that they want to see as soon as possible. So first, let's just level set. Coming from the GYN Oncology standpoint, I always like to get down to the basics of the cancer. So, can you speak just a little bit about the incidence and mortality of lung cancer overall and what have been some recent trends in the treatment of this disease? Dr. Helena Yu: Everyone knows somebody that has been touched by lung cancer. It's the second most common cancer that is diagnosed in men and women in the US today. It is the leading cause of cancer-related deaths, with 25% of cancer deaths really being attributable to lung cancer. Historically, prognosis with lung cancer has been poor, with five-year survivals around 10%. What's really interesting is over the last couple of years, there have been some improvements in survival with lung cancer. And I think that that can largely be attributed to the advent of immunotherapies as standard of care, as well as targeted therapies for driver mutation-positive lung cancer. Dr. Shannon Westin: So that leads right into the next question: What is the role of the EGFR pathway in lung cancer? How common are these aberrations and how successful have prior treatments targeting this pathway been? Dr. Helena Yu: Yes. So we, in lung cancer, have this mutation pie, which really describes the different oncogenes that we see in lung cancer. And probably now two-thirds of patients actually have a detectable driver mutation when their tumors undergo next generation sequencing. EGFR is probably one of the first mutations that was identified. About 15% to 20% of patients diagnosed with lung cancer in the US have mutations in EGFR. It is both activating and sensitizing. So, obviously mutations in EGFR cause cancer and they are sensitizing to different EGFR targeted therapies we have. Right now, the standard of care for first-line treatment for EGFR mutant lung cancer are EGFR tyrosine kinase inhibitors. And those are oral therapies that actually are very successful at managing EGFR mutant lung cancer. They're not curative, but they do kind of control disease for a long period of time. But unfortunately for all patients, at some point their cancer does progress on these targeted therapies. And the most common one we use today is one called osimertinib, which is a third-generation EGFR TKI. And we do not have any approved targeted therapies after osimertinib. And so that kind of is the setting for this new drug, patritumab-deruxtecan. Dr. Shannon Westin: So tell us a little bit about HER3-DXd and why you prioritize targeting this particular part of the EGFR pathway in this population. Dr. Helena Yu: Yes. So HER3 is actually part of the HER EGFR family, and it is a protein that, when expressed, really portends a poor prognosis. It kind of tells us cancers that are more likely to recur and cancers where overall survival is shorter. So HER3-DXd is an antibody drug conjugate. There are a slew of new medicines in lung cancer that are ADCs. Historically, we looked at HER3 monoclonal antibodies in EGFR mutant lung cancer and they actually were not successful, not efficacious. And so it's really interesting that using these antibodies as part of an ADC construct has led to better efficacy. The HER3-DXd has that HER3 monoclonal antibody, there is a linker and then there is a

In this JCO Article Insights episode, Emily Zabor interviews Dr. Gregory H. Reaman, the Scientific Director of the Childhood Cancer Data Initiative at the National Cancer Institute, on their paper titled "The Childhood Cancer Data Initiative: Using the Power of Data to Learn From and Improve Outcomes for Every Child and Young Adult with Pediatric Cancer". Dr. Reaman introduces us to the initiative, its goals and structure, and what has already been achieved since its launch. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Emily Zabor: Welcome to this JCO Article Insights episode for the August issue of JCO. This is Emily Zabor, JCO's Biostatistics Editorial Fellow. And today I am interviewing Dr. Gregory Reaman, the Scientific Director of the Childhood Cancer Data Initiative at the National Cancer Institute, on their paper titled "The Childhood Cancer Data Initiative: Using the Power of Data to Learn from and Improve Outcomes for Every Child and Young Adult with Pediatric Cancer." Dr. Reaman, welcome to our podcast. Dr. Gregory Reaman: Thanks very much, Emily. Appreciate the invitation. Emily Zabor: Dr. Reaman, could you start by introducing yourself and describing your involvement in the Childhood Cancer Data Initiative? Dr. Gregory Reaman: I'm Gregory Reaman. I'm a Pediatric Oncologist. And I guess my involvement with the CCDI began shortly after the initiative was announced at the State of the Union media address in 2019, which was followed shortly thereafter by the formation of a working group by the NCI's National Cancer Advisory Board Board of Scientific Advisors. Given my role at the FDA at that time as Associate Director for Pediatric Oncology in the Oncology Center of Excellence, and the fact that I was the founding Chair of the Children's Oncology Group, I was an ex-officio member of this working group. So from very early on, I had involvement. I formally joined the NCI in November, left the FDA to assume the position as Scientific Director of CCDI. Emily Zabor: That's great. So you've really been involved from the start. I had not really been familiar with the initiative until I read this paper. And as a cancer biostatistician, I was really excited to learn about this initiative, which sounds like it will ultimately create a very valuable data resource to be used for research purposes, among other things. So I think it's a really interesting project. So for our listeners who may not be familiar, could you describe the motivation for and goals of the Childhood Cancer Data Initiative? Dr. Gregory Reaman: As I mentioned, this really is a very unique initiative, venture, if you will, on the part of the Cancer Institute and in large part driven by this fortunate infusion of funds to support childhood cancer research. And given the fact that pediatric oncology is very much a collaborative enterprise, it really does sort of follow that data sharing and using the power of data, its ability to be used by multiple investigators, irrespective of the source, aspirationally can improve outcomes for children cancer. The three primary objectives– actually, this working group that I mentioned earlier put together a white paper that had 24 specific recommendations to the NCI. But there were three foundational objectives or goals. One was to learn from every child diagnosed with cancer, irrespective of the institution where they were diagnosed to receive therapy, to develop an ecosystem that would enable the submission, aggregation of data, and harmonization in a federated system that could then be accessed and used by investigators and analyzed to ultimately improve outcomes. And then one objective, which was a little bit more specific, and that was to really focus on the opportunity to genomically classify tumors from newly diagnosed pediatric cancer patients, because this was something that obviously is much more widespread in the adult population, given the advent of targeted therapy and precision oncology and its more widespread use in medical oncology than pediatrics. And although many large academic institutions do have resources, the majority of smaller institutions do not. And when it's necessary and preferable to accurately and timely identify or diagnose a child's cancer that may actually provide information on treatment recommendations, the ability to do that and have it covered by insurance is sometimes problematic. So developing a program that would not cost patients or institutions anything and then make that data available to patients, families, and providers, as well as making it available for secondary research use, was a major goal and objective. Emily Zabor: Yeah, that sounds like such an important initiative. The Molecular Characterization Initiative, which I understand has already enrolled and characterized the genomics of 751 participants just in the first year, I think is what the paper reported? Dr. Gregory Reaman: That's correct. That was in the first year. We'

Dr. Shannon Westin, Dr. Abbas M. Hassan, and Dr. Leticia Nogueira discuss the impact of heatwaves on cancer care delivery and what can be done about it. TRANSCRIPT The guests on this podcast episode have 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 that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the Journal of Clinical Oncology. I'm so excited to be here today to discuss a very thought-provoking manuscript. This was published on June 10, 2023, in the Comments and Controversies section of JCO, and it's entitled "Impact of Heatwaves on Cancer Care Delivery: Potential Mechanisms, Health Equity Concerns, and Adaptation Strategies." And I am thrilled to tell you I am joined today by two of the authors of this very important manuscript. Dr. Abbas Hassan is an intern in the Division of Plastic Surgery, Indiana University School of Medicine. Already reaching for the stars, publishing in the JCO as an intern, that has to be a record. Congratulations and welcome, Dr. Hassan. Dr. Abbas Hassan: Thank you for having us. Appreciate it. Dr. Shannon Westin: And with Dr. Hassan is Dr. Leticia Nogueira. She is now the Scientific Director of Health Services Research at the American Cancer Society. Welcome, Dr. Nogueira. I'm so excited to have you. Dr. Leticia Nogueira: Excited to be here. Dr. Shannon Westin: Let's get right to it. This topic is very timely. We are currently enjoying several weeks of greater-than-100° weather here in Texas, where I am, and across the United States. Why don't we start by just defining heatwaves in general and what their global impact is on morbidity and mortality? Dr. Abbas Hassan: Yeah. So, I mean, it's the Texas heat, right? It's hard to ignore it when you're sweating buckets, right? So this kind of extreme heat isn't just a Texas problem. It's happening everywhere, so from Australia to Europe and across the US. And what we're experiencing, my friends, are heatwaves. They're like the unwanted guests at a barbecue, showing up uninvited, hanging around for at least two straight days. Now, defining a heatwave isn't straightforward as it might sound, with various different definitions across studies and policies. But one thing that is clear: heatwaves aren't just about discomfort. They're deadly. They're claiming more than 5 million lives globally every year. Now, let's just imagine for a moment the year 2020. Not exactly a walk in the park. And on top of that, everything else, heatwaves cost over $4.5 billion in damages in the US. And that's probably just the tip of the melting iceberg, considering the tricky task of identifying exact heatwave periods. Dr. Shannon Westin: And you said it's really hard to define, so I imagine that that makes it really difficult to study. Hopefully, I think we've already gotten our first call to action is coming up with some type of consistent definition so we can truly look at this in a scientific fashion. I guess I'm asking you to predict, but I'll do it anyway. What do we expect to happen over the next 30 years in regards to the climate change we're seeing and maybe overall temperatures across the globe? Dr. Abbas Hassan: The way things are going, we're probably going to need a lot more sunscreen and a lot more ice cream. In all seriousness, the outlook is pretty stark. By 2023, we're looking at 8.1 million of our fellow Americans facing temperatures hotter than 125°F. And fast-forward to 2053, the number skyrockets to like 100 million. So that's a 13-fold increase. Remember when we thought 2014 was hot? And then 2015 came in, then 2016, and now all the way to 2020. Each year seemed to outdo the last, making the past seven-year span the warmest we've ever experienced. So we're not just dealing with a few off years. We're in the midst of a trend that's heating up our planet and impacting our health at an alarming rate. Dr. Leticia Nogueira: Yes, I would like to add to that, exactly what Dr. Hassan said. We don't really need to worry about or focus on what temperatures are going to be in 30 years. It is here now. The threats of climate change are here now, threats of extreme heat, no matter how we define it, right? Because it could be number of days above a certain temperature threshold, and that threshold is usually established by the previous 30 years. And we've already seen these jumps in temperatures in the previous 30 years, especially in most recent years. So these hazards, these threats, are already here. No future projections necessary to understand the hazards and the detrimental consequences of exposure to extreme heat due to climate change. Dr. Shannon Westin: Well, let's talk a little bit about that. And specifically, I would love to hear kind of what we've been seeing as far as the impact of heatwaves on health outcomes. I think our group would be inte

In this JCO Article Insights episode, Davide Soldato interviews Dr. Naqash from University of Oklahoma. Dr. Naqash provides insight into the original article published in the July JCO issue: "Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium". The interview offers a deep dive into the manuscript results on efficacy and safety of Immune Checkpoint Inhibitors in this specific population and offers insights on future research direction in this space. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Davide Soldato: Welcome to this JCO Article Insights episode for the July issues of JCO. This is Davide Soldato and today I will have the pleasure of interviewing Dr. Abdul Rafeh Naqash, the author of the manuscript titled "Safety and Activity of Immune Checkpoint Inhibitors in People Living with HIV and Cancer: A Real World Report from the Cancer Therapy Using Checkpoint Inhibitors in People Living with HIV-International Consortium." Dr. Naqash is an Assistant Professor of Hematology-Oncology at the University of Oklahoma and a Medical Oncologist working at the Stephenson Cancer Center. His research interests revolve around early-phase clinical trials in solid tumors, lung cancer, and the study of immunotherapy, biomarkers, and resistance. Welcome, Dr. Naqash, and thank you for accepting our invitation today. Dr. Abdul Rafeh Naqash: Dr. Soldato, thanks so much for having me. I'm really excited to discuss this article with you today. Davide Soldato: So I just wanted to go a little bit over the manuscript with you. So basically, this is a retrospective multicenter study that was conducted across the US, Europe, and Australia by the CATCH-IT Consortium. And so the aim of the study was really to investigate the safety and the activity of immune checkpoint inhibitors among patients diagnosed with cancer and also living with HIV. The article examined two different cohorts, and I just wanted to start with a brief explanation of how the two cohorts were built so that our readers can get a little bit of understanding of what you did then. Dr. Abdul Rafeh Naqash: Sure. Before I take a deep dive into the cohorts, Dr. Soldato, I would definitely like to mention the premise and the background for this paper as to why we did what we did. And one of the primary reasons was that people living with HIV, historically, there have been very limited number of trials that have included these individuals. So it becomes a very important question from a disparity standpoint. And most often we end up, in the real world setting, we end up extrapolating data from clinical trials, but not necessarily know what is the outcome of these individuals in the real world setting. So there have been some very important studies in the last three years or so in people with HIV as far as clinical trials with checkpoint inhibitors go, but most of those trials have been limited by the number of patients, number of people that have been part of those trials. So we wanted to understand it from a broad perspective, whether it is from a broad geographic perspective or from a heterogeneous patient population perspective, which is why we built this consortium called the CATCH-IT Consortium, which basically stands for Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International Consortium. And this required a lot of effort from a lot of different centers, including those in the US, Europe, and Australia, as you mentioned. And then we ended up having data worth around 400 plus patients, close to 400 patients or so. And then we wanted to look at obviously outcomes, whether it's related to a certain tumor such as lung cancer, which we did in this case, or a pan tumor assessment of toxicities and safeties. So, to your question, the cohorts that we basically had, we had close to approximately 390 patients that we included in the safety analysis. So first we looked at the safety analysis, which was the entire cohort, and then out of those we excluded around 12 patients or so. Those were patients that were treated in the adjuvant setting. So in the metastatic advanced setting, we had close to 378 individuals that we assessed clinical outcomes for. So, response rates, progression-free survival, and overall survival. And then as far as a separate cohort, we looked at non-small cell lung cancer, which was the most commonly represented tumor type, with approximately 111 patients that had non-small cell lung cancer. We did exclude a certain proportion of those that were earlier stage, stage III. So in the stage IV, basically we ended up matching in this separate cohort, around 60 odd patients or so of non-small cell lung cancer to 110 stage four, non-small cell lung cancers. So basically it was a one-to-two matching and we chose the same site. So if a site

Dr. Shannon Westin and her guest, Dr. Andreana Holowatyj, discuss the paper "Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer," recently published in JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast, the podcast where we get in-depth on manuscripts and interesting papers that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, and it's my pleasure to serve not only as a GYN Oncologist but as an Associate Editor for Social Media for the JCO. And as always, I'm super excited about the paper that we're going to discuss today. This is "Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer." This has been published in the JCO. And I am so excited to be accompanied by the last author, Dr. Andreana Holowatyj, who is an Assistant Professor of Medicine and Cancer Biology at Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center. Welcome. Dr. Andreana Holowatyj: Thank you, Dr. Westin, for having me. I'm really excited to get to talk about this paper. Dr. Shannon Westin: So are we. And please note that we do not have any conflicts of interest with this work. So let's get started. First, early-onset colorectal cancer is any colorectal cancer diagnosed before age 50. So I just wanted to level set. Can you give us a bit of background on the incidence of early-onset colorectal cancer? Dr. Andreana Holowatyj: Sure. All of the attention recently has been drawn to the fact that in contrast to incidence of colorectal cancer decreasing among adults over age 50, we've seen over the last several decades, this uptick—alarming uptick, in fact, in colorectal cancers among individuals diagnosed younger than age 50 years, or, as you point out, we call early-onset colorectal cancer, largely with reasons that are unexplained overall, which has drawn a lot of concern and attention as to what are the factors driving this marked increase in early-onset colorectal cancer both in the United States and globally. Dr. Shannon Westin: And what do we know about the burden of early-onset colorectal cancer across different racial and ethnic groups? Are there disparities in survival like we've seen in some of the other cancer types? Dr. Andreana Holowatyj: Yeah. So recently, a paper published demonstrating this greater shift towards early-onset colorectal cancer, where now we're seeing approximately 1 in every 8 adults with colorectal cancer being diagnosed under age 50. Add to that prior studies have shown that the proportion of early-onset colorectal cancer cases or incidence is actually higher among individuals who identify as non-White compared to those who identify as non-Hispanic White. We previously published in JCO a paper that assessed disparities in survival among early-onset colorectal cancer patients and strikingly found that individuals who identify as non-Hispanic Black had poorer survival compared with non-Hispanic Whites, both in colon and rectal tumors, specifically for young individuals. However, and of striking interest, we did not see these survival disparities between Whites and individuals who identify as Hispanic, which further led us to question what may be some of the biological, environmental, and other factors that may actually be driving some of these disparities by race and ethnicity, both in incidence but also in outcomes. Dr. Shannon Westin: So that kind of brings us to this study. Will you walk us through what the objective of this study was? Dr. Andreana Holowatyj: Yeah. So the underlying question really is what could be the role of germline genetic features or germline predisposition in early-onset colorectal cancer disparities? We know from prior studies published in JCO and other journals that about 14%-25% of early-onset colorectal cancer cases have a germline predisposition. However, these populations have been of limited size and, more importantly, of limited diversity. So we really wanted to tackle that question to understand what is the prevalence and spectrum of germline genetic features in early-onset colorectal cancer by race and ethnicity. Are there differences? Where do these differences lie? And what can this information really tell us in better understanding the early-onset colorectal cancer burden? Dr. Shannon Westin: Well, now, well, just talk us through the design that you employed to achieve these objectives. Dr. Andreana Holowatyj: We were fortunate to partner with a nationwide clinical testing laboratory to identify individuals who were between the ages of 15 and 49 years when diagnosed with the first primary colorectal cancer over about a five-year study period. We were able to identify around 4,000, or specifica

In this JCO Article Insights episode, Emily Zabor summarizes two original articles from the June 1st, 2023 Journal of Clinical Oncology issue: "A Clinical Genetic Risk Score for Predicting Cancer-Associated Venous Thromboembolism: A Development and Validation Study Involving Two Independent Prospective Cohorts" by Muñoz et al, and "Derivation and Validation of Clinical Risk Assessment Model for Cancer Associated Thrombosis in Two Unique Healthcare Systems" by Li et al, as well as the accompanying editorial "Fine Tuning Venous Thromboembolism Risk Prediction in Patients with Cancer" by Jean Marie Connors. The original reports describe the development and validation of two new risk prediction models for venous thromboembolism in cancer patients and the editorial puts them into context of existing tools. TRANCRIPT The guest on this podcast episode has no disclosures to declare. Emily Zabor: Welcome to JCO Article Insights for the June 1st, 2023 issue of JCO. I'm your host, Emily Zabor, JCO Biostatistics Editorial Fellow. Today, I will be providing summaries of three articles. The first article, titled "A Clinical Genetic Risk Score for Predicting Cancer-Associated Venous Thromboembolism: A Development and Validation Study Involving Two Independent Prospective Cohorts" by Andres Muñoz and colleagues, describes the development and validation of a risk score for venous thromboembolism in oncology patients based on both clinical and genetic features, called the ONCOTHROMB score. In developing this model, the authors sought to address the fact that venous thromboembolism is among the leading causes of death among patients with cancer. Whereas hospitalized cancer patients are typically treated with thromboprophylaxis, outpatient treatment with thromboprophylaxis is only suggested for patients at high risk for venous thromboembolism identified according to the Khorana score. The authors sought to determine whether incorporation of known genetic risk factors along with clinical factors would result in improved predictive accuracy. The risk score was developed in a cohort of 364 patients and was validated in an external cohort of 263 patients. The primary outcome of interest was venous thromboembolism within six months of a cancer diagnosis. The authors used logistic regression with backward selection with a p-value threshold of 0.25 to first select the genetic variants to include in the genetic risk score and then to separately select the clinical features to incorporate. Then the genetic risk score and clinical features were combined into a single multivariable logistic regression model, and backward selection was performed again. The final model included nine genetic variants, tumor site, TNM stage, and a BMI of greater than 25. In the validation data, the ONCOTHROMB score using a threshold selected with the Youden index resulted in an AUC of 0.686 as compared to an AUC of 0.577 for the Khorana score with a threshold of 3. The ONCOTHROMB score had statistically significantly higher sensitivity, whereas the Khorana score had statistically significantly higher specificity. The authors conclude that the ONCOTHROMB score demonstrated improved predictive ability and should be investigated further in clinical trials. The second article, titled "Derivation and Validation of Clinical Risk Assessment Model for Cancer Associated Thrombosis in Two Unique Healthcare Systems" by Ang Li and colleagues, describes the development and validation of a risk assessment model for venous thromboembolism, pulmonary embolism, and lower-extremity deep vein thrombosis in oncology patients undergoing systemic therapy. The authors developed this model to address the increased morbidity and mortality associated with venous thromboembolism among cancer patients and the fact that risk reduction for use of thromboprophylaxis as well as the efficacy-safety trade-off, and cost-effectiveness have been shown to be higher among patients selected as high risk for venous thromboembolism. The primary outcome was venous thromboembolism within six months of treatment initiation. In the development data set, the authors used lasso-penalized logistic regression analysis to shrink some of the covariates to zero as a form of variable selection, then a multivariable logistic regression model was fit to the remaining covariates and those with an estimated odds ratio greater than 1.2 or less than 0.8 were retained in the final model. A linear risk score was created from the resulting beta coefficients. The risk assessment model was developed in a cohort of 9769 patients and validated in an external cohort of 79,517 patients. The final model included eleven factors: cancer subtype, pre-therapy BMI greater than or equal to 35, pre-therapy white blood cell count greater than 11, pre-therapy hemoglobin less than 10, pre-therapy platelet greater than or equal to 350, cancer staging 3 to 4, targeted or endocrine monotherapy, lifetime history of venous thromboembolism, h

Dr. Shannon Westin, Dr. Lakshmi Sandhya, and Dr. Prasanth Ganesan discuss the use of olanzapine to treat chemotherapy-related anorexia, as recently published in JCO. 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. As always, I'm your host, Dr. Shannon Westin, GYN Oncologist and Social Media Editor for JCO. I'm very excited to be here today. And please note that our participants do not have any conflict of interest. So we are going to discuss a really exciting paper today entitled the "Randomized, Double-Blind, Placebo-Controlled Study of Olanzapine for Chemotherapy-Related Anorexia in Patients with Locally Advanced or Metastatic Gastric, Hepatopancreaticobiliary, and Lung Cancer." And this was published in the JCO on March 28, 2023, and has gotten a lot of excitement. And so I'm very thrilled to have two of the authors with me today. First is Dr. Lakshmi Sandhya. She's a Junior Consultant at the SVICCAR Hospital in Tirupati, India. Welcome, Dr. Sandhya. Dr. Lakshmi Sandhya: Thank you so much for the opportunity to be here. Dr. Shannon Westin: And I also have the senior author here today, Dr. Prasanth Ganesan. He is a Professor in the Department of Medical Oncology at JIPMER, which is the Jawaharlal Institute of Postgraduate Medical Education and Research in Puducherry, India. Welcome, sir. Dr. Prasanth Ganesan: Thank you. Thank you very much, Dr. Westin. It's good to be here. Thank you very much. Dr. Shannon Westin: Great to have you both. So we're going to get right to it. I think this is an excellent paper and certainly something we see across many of our patients who are diagnosed with cancer and who are receiving treatment for cancer. But first, I want to level set. What is the true definition of chemotherapy-related anorexia, and really approximately how many patients do you think it impacts? Dr. Prasanth Ganesan: As you know, anorexia itself is very common in advanced cancers. Almost like maybe 80%, 90% of patients have some form of anorexia. But at diagnosis, it depends on the type of cancers. Very high in upper GI cancers, esophagus, stomach, pancreas, or lung cancer. But when we talk about chemotherapy-related anorexia, we specifically mean anorexia that is brought on or probably worsened by chemotherapy. So this depends a lot on the regimen that is used. So studies in lung cancer, upper GI cancer that have used something like platinum agents, maybe as high as 50% to 80%. Now, the challenge is how much of it is contributed by the underlying cancer itself and how much of it is worsened by the chemotherapy. It's tough to say, but I think we all have seen that chemotherapy does kind of really increase the anorexia in many of these patients. So I would say the problem is common. Depends on the type of cancer, the type of agent being used, and also sometimes on how intently we are looking for it. Dr. Shannon Westin: You bring up a great point in really kind of making sure that we're screening our patients for it and understanding who's actually experiencing those things. And I do think putting it on our list of things that we, on a day-to-day basis, discuss with our patients is really relevant, although I will say sometimes we haven't done that because we don't have a good treatment. So that's what makes your paper so exciting. But before we get into the results of the paper, why don't we talk a little bit more about some of the factors that contribute to anorexia? Dr. Sandhya, I don't know if you want to elaborate a little bit on some of those. Dr. Lakshmi Sandhya: Yeah. So most important would be the cancer type and the type of chemotherapy agent being used. So, as we mentioned, some cancer types have high anorexia incidence even at baseline. So the most important and prominent would be the upper gastric cancers and the pancreatic and lung cancer. Among the chemotherapy types, I think the platinum agents are known to cause anorexia more often and also associated with nausea or vomiting. So anorexia and weight loss is not very common in other cancers like breast, if you see, or ovarian cancer during the therapy. In fact, there has been weight gain in most of the patients with breast cancer, and most of the data which comes from breast cancer show that weight loss is experienced only by around 5% of the patients. So we would say the factors contributing most commonly would be the type of cancer and the chemotherapy that is being used. Dr. Shannon Westin: Yeah, I think it's a great point. As a gynecologic oncologist, we do a lot of platinum, but we balance it, especially in upfront with paclitaxel or taxanes and we're giving steroids as premeds for them. And so we definitely see patients expecting to lose weight and instead actually getting hungry with the steroid use and eating to some degree. D

Host Dr. Shannon Westin interviews guests Dr. Ethan Basch and Dr Deborah Schrag on their JCO simultaneous publication paper at ASCO's 2023 annual meeting: "Patient-reported outcomes during and after treatment for locally advanced rectal cancer (Alliance N1048). TRANSCRIPT The Disclosure for guests on this podcast can be found in the show notes Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on articles that are published in the Journal of Clinical Oncology. It is your host, Shannon Weston, GYN Oncologist and Social Media Editor for the JCO. And I'm so thrilled to bring you our first podcast that will be a simultaneous podcast JCO publication and ASCO presentation at ASCO 2023, dropping on June 4, 2023. And it is an exciting one. We'll be discussing "Patient-reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer: The PROSPECT Trial Alliance N1048" (10.1200/JCO.23.00903) And let me introduce both of these amazing people that are going to be with us today. First is Dr. Deborah Schrag. She's the chair in the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York City, New York. Welcome. Dr. Deborah Schrag: Thank you. Dr. Shannon Westin: And then I'm also accompanied by Dr. Ethan Basch, the Chief of the Division of Oncology and Physician in Chief at NC Cancer Hospital at the University of North Carolina, Chapel Hill, North Carolina, my alma mater. So welcome. Dr. Ethan Basch: Thanks, Shannon. Nice to be here. Dr. Shannon Westin: And this is a good one. I was really intrigued by this work and I can't wait to talk about this with the audience, and I think that you're going to get a lot of excitement around this. So let's dive right in. I think we should start, first, let's speak a little bit about the role of patient-reported outcomes, assessing patient experience, especially as it relates to the evaluation of new therapies. Dr. Ethan Basch: Yeah, I'm happy to take that question, and thanks for asking it. All of us who practice oncology or accrue to trials recognize that patients receiving cancer treatment are highly symptomatic, either from their disease or from the sequelae of treatment. And as such, assessing and managing symptoms is really a cornerstone of what we do as oncology providers or investigators. But unfortunately, there's now abundant evidence that we as clinicians or investigators miss many of the symptoms and side effects that our patients experience, in fact, up to half of them. And so over the years, there have been a number of strategies developed to try to bridge this gap to fill in the pieces. And patient-reported outcomes is the one that has emerged to fill this gap, by informing us about the experiences of our patients. And without patient-reported outcomes and trials, we really have an incomplete understanding of the properties of products, the experiences of patients. And so when we are trying to do a risk-benefit assessment, for example, from data in a clinical trial, if we don't have patient-reported outcomes, we actually have an inadequate assessment of what was happening on the ground in that trial, particularly when it comes to adverse event assessment. Dr. Shannon Westin: I think it's been great how we've been able to start incorporating these more. But before we go too far down that line, this study was particularly done in rectal cancer and we have a very diverse audience. And so just to level set, can one of you speak a little bit about the current standard of care for locally advanced rectal cancer? Dr. Deborah Schrag: So, rectal cancer has a nasty tendency to come back in the pelvis. And Shannon, you're an OBGYN, so you know how miserable that can be. These are called locally recurrent cancers and they are just miserable. They cause a great deal of symptoms and a great deal of suffering. And back in the 1970s and '80s, a strategy to treat pelvic or local recurrence of rectal cancer was developed and that strategy was radiation. And it used to be that 10%, 20%, even 30% of patients who had rectal cancer surgery would have a cancer come back. And these were people who couldn't sit down, constant pain, leaking, trouble urinating, trouble moving their bowels. Radiation was a tremendous innovation. Radiation has been part of the management of locally advanced rectal cancer since 1990. Since 2004, we've given that radiation before surgery in the neoadjuvant setting. So this has been the predominant way that we treat these cancers really for the last two decades. We give about five and a half weeks of chemotherapy and radiation. Patients then have surgery, recover from the surgery, and many, not all, go on to receive some postoperative chemotherapy. It depends a little bit on what's found at surgery. But those three phases, the chemoradiation phase first, followed by surgery, followed by chemotherapy has been the prevailing care standard. When we launched this trial, we wonde

In this JCO Article Insights episode, Davide Soldato summarizes three articles from the May 20th, 2023 Journal of Clinical Oncology issue: "Smoking Cessation After Diagnosis of Kidney Cancer Is Associated With Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study, "Efficacy of a Smoking Cessation Intervention for Survival of Cervical Intraepithelial Neoplasia or Cervical Cancer: A Randomized Control Trial" and "Integrating Tobacco Treatment into Oncology Care: Reach and Effectiveness of Evidence-Based Tobacco Treatment across National Cancer Institute Designated Cancer Centers." The articles discuss clinical outcomes in survivors of cancers who quit smoking, efficacy of a novel smoking intervention and implementation of tobacco treatment programs. TRANSCRIPT Davide Soldato: Welcome to this JCO After Hours issue summary for the May issues of the Journal of Clinical Oncology. This is Davide Soldato and today I will be reporting results from three articles published in the May issue of JCO. Today's episode is focused on smoking cessation, impact on clinical outcomes, efficacy of novel smoking interventions, and implementations of tobacco treatment programs. The first article by Dr. Sheikh and colleagues is titled "Smoking Cessation after Diagnosis of Kidney Cancer is Associated with Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study". We know that smoking is a relevant risk factor for development of renal cell carcinoma, and previous retrospective studies showed better survival among patients who quit smoking after diagnosis. However, prospective data on the topic were lacking up until this point. The study by Dr. Sheikh and colleagues included patients diagnosed with renal cell carcinoma who were current smokers at the moment of diagnosis and that were followed prospectively for an average of eight years. At study inclusion, patients responded to a structured questionnaire investigating smoking habits and other behavioral factors. Furthermore, clinical pathological data were extracted from medical records. Subsequently, after inclusion, patients provided yearly information regarding smoking status and if applicable, date of smoking cessation. Follow-up information on vital status, eventual disease recurrence, and treatments were collected both from patients and from medical records. The study reports results among 212 patients who were current smokers at diagnosis; the majority were diagnosed with stage I tumors and had a high-level education. Over the eight-year average follow-up, 40% of patients reported quitting smoking, more than half of them shortly after diagnosis. Demographic, social, and tumor characteristics were comparable between patients who quit and those who continued smoking. Smoking cessation was overall associated with improved outcomes. Five-year survival rates were significantly higher in patients who quit smoking compared to those who continued (85% versus 61%). This higher probability of survival was observed across all evaluated subgroups, including light versus moderate and heavy smokers, and patients with early and late-stage tumors. Similarly, five-year progression-free survival rates were significantly higher among patients who quit smoking (80% versus 57%). In multivariable, time-dependent regression models adjusted for age of diagnosis, presence of other chronic health conditions, number of pack years, alcohol drinking status, tumor stage, and treatment received during follow-up, smoking cessation was significantly associated with a lower risk of all-cause mortality, disease progression, and kidney cancer-specific death. The results were comparable when excluding from the analysis patients who quit smoking three and twelve months after diagnosis, and this is important because inclusion of these patients might have biased results considering that these patients might have survived longer and thus had more chance to quit smoking. So, in conclusion, smoking cessation among patients diagnosed with renal cell carcinoma was associated with a 50% lower risk of death, a 46% lower risk of cancer-specific death, and a 55% lower risk of disease progression. These results are extremely important and informative as they reinforce the need to promote smoking cessation among patients diagnosed with renal cell carcinoma since the observed clinical benefit was at least similar to that of currently employed or emerging targeted and immunotherapy treatments. The second article by Dr. Vidrine and colleagues is titled "Efficacy of a Smoking Cessation Intervention for Survival of Cervical Intraepithelial Neoplasia or Cervical Cancer: A Randomized Control Trial". As for many other cancers, we know that smoking is a significant risk factor for the development of cervical cancer. Furthermore, smoking after a diagnosis of cervical intraepithelial neoplasia or cervical cancer was associated with poor treatment response, increased risk of recurrence and develop

In this JCO Article Insights episode, Emily Zabor interviews Dr. Gulam Manji from Columbia University Irving Medical Center. Dr. Manji provides insight into his editorial published in the April 10, 2023 JCO issue: "Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?" (10.1200/JCO.23.00039). His editorial focuses on the JCO Original Report, "Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial" by Tempero, et al on the APACT Trial. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Emily Zabor: Welcome to this JCO Article Insights episode for the April issue of JCO. This is Emily Zabor, one of JCO's editorial fellows. And today I am interviewing Dr. Manji from Columbia University on their editorial titled "Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?" Dr. Manji, welcome to our podcast. You wrote this editorial to accompany the article, "Adjuvant Nab-Paclitaxel plus Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results from a Randomized Open-label Phase III Trial by Dr. Margaret Tempero and Colleagues." That trial, called the APACT Trial, investigated the efficacy and safety of adjuvant nab-paclitaxel plus gemcitabine compared to gemcitabine alone in patients who had undergone resection for pancreatic ductal adenocarcinoma. So I wanted to ask if you could start by giving listeners a quick overview of the study design and the main findings from that trial. Dr. Gulam Manji: Yeah, sure, Emily. So, as you pointed out, it was a randomized phase III study in patients who had resected pancreatic carcinoma. The primary endpoint was independently assessed disease-free survival. Additional endpoints included investigator-assessed disease-free survival, overall survival, and safety. And we'll get back later on as far as the importance of investigator-assessed versus independently-assessed disease with survival because I think that that's the main point of discussion for today. The enrollment criteria were fairly stringent and included patients with macroscopic complete resection, ECOG performance status of either 0 or 1, and the peripheral tumor markers of CA 19-9 being less than 100. And patients were required to initiate adjuvant chemotherapy within 12 weeks. Patients received standard gemcitabine at 1000 milligrams per meter square, either with or without nab-paclitaxel of 125 milligrams per meter square once weekly for three weeks during every four-week cycle. Emily Zabor: Great. So I think that the main thing that we wanted to talk about today, and one of the main points you discuss in your editorial is the difference between the primary endpoint of independently assessed disease-free survival and the secondary endpoint of investigator-assessed disease-free survival. So can you describe the difference between those endpoints, how they were defined, and how they differed? Dr. Gulam Manji: Sure. So, independently-assessed DFS was determined by a radiologist who was blinded to treatment assignment, and new lesions followed RECIST 1.1 criteria. In contrast, the investigator-assessed recurrence was determined by the treating physicians using all available clinical information. So that could be abdominal pain, anorexia, probably elevation of peripheral tumor markers. And the other important aspect to the study is that the independent review was not performed in real-time to confirm investigator assessments. So patients who started subsequent therapy after recurrence by treating investigators were censured for the independently-assessed DFS analysis. So in this trial, 866 patients were randomized. And patients who are randomized to the experimental arm had a median independently assessed DFS of 19.4 months, while patients randomized to the control arm, which was gemcitabine alone, had a median DFS of 18.8 months. Now, when we compare that to the investigator-assessed DFS, the data looks quite different. Where the DFS was 16.6 months in the experimental arm compared to 13.7 months in the control arm. That is consistent with the five-year follow-up looking at the median overall survival, which was 41.8 months for the combination arm compared to 37.7 months for the gemcitabine alone arm. Emily Zabor: Okay, so there's some really interesting differences there. And I noticed that there were only 439 events according to the independently-assessed DFS versus 571 according to the investigator-assessed DFS. So that's a big difference in the number of events that I guess is coming from that additional censoring that was occurring due to the delay in the independently assessed endpoint. Is that right? Dr. Gulam Manji: Exactly. So you could envision a scenario where patients received chemotherapy and then on t

Dr. Shannon Westin, Dr. Rajendra Badwe, and Dr. Alastair Thompson discuss the JCO paper "Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer." TRANSCRIPT The guests on this podcast episode have no disclosures to declare. Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, gynecological oncologist by trade, but serve as our JCO Social Media Editor. And I'm super excited to talk to you about a paper that was just published online, April 6, 2023, entitled "The Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer." Before we start, I just note that our guests have no conflicts of interest. And so I'm accompanied by two greats in the field. First is the principal investigator on this trial, Dr. Rajendra Badwe, who is the Director and Head of Surgical Oncology Division at the Tata Memorial Center in Mumbai. Welcome. Dr. Rajendra Badwe: Thank you. Dr. Shannon Westin: And then, of course, I'm joined by Dr. Alastair Thompson, Co-Director of the Lester and Sue Smith Breast Center and the Section Chief for Breast Surgery at Baylor College of Medicine here in Houston, Texas. We should have met in person. Dr. Alastair Thompson: Great to be with you today, both of you. Thank you. Dr. Shannon Westin: So this is an exciting topic, and of course, as a surgeon, I'm super intrigued. So let's get started. First, I would love for you all to tell me about the rationale for modulating events at the time of surgery to improve survival in any cancer, but specifically in breast cancer as it was in this study. Dr. Rajendra Badwe: So we have been working on events at the time of surgery for quite some time. And for the first time, when I walked through the gynae OPD in Guy's Hospital, there was this cartoon of the cell being extruded for ovulation, and I felt a cell moving from one organ to the other is actually metastasis. And that's how we started working on it. And in the past few years, we have been—a decade or so, we have been publishing changes induced by event of surgery. So what we did earlier before beginning this trial is picking up a core biopsy before I start surgery. So it's normoxic, well-ventilated as well as well-nutrition-provided tumor, and I do a core biopsy and send it for expression profile on next-generation sequencing. Then, when 50% of the tumor surface is denuded from the opposite side, which is not denuded, I do other core biopsy. And the third core biopsy is when the tumor is in my hand in breast conservation surgery. So first was normoxic, second was hypoxic, and the last was completely anoxic tumor. And we found that the middle sample, which has never been studied, all our understanding of biology of breast cancer is based on the first core biopsy or the whole tumor sample post-surgery. The middle sample had approximately 800 genes going up and down on the next-generation sequencing mRNA, and majority of these were epithelial-mesenchymal transition, proliferation, invasion, motility. You name the hallmark of metastases, and they were up in the middle of surgery at least in 30% of the tumor. Now, if the cell surface on one side in a three-centimeter tumor ring to the cell at the other end of the tumor as to some invasion has happened, how quickly can it happen? The difference between the two biopsies was just about five minutes. Obviously, it was some kind of an electrical stimulus that went across the tumor. That's what our assumption was. And if it was to happen through the voltage-gated channels, the downstream effect of voltage-gated channel being depolarized was the same channels that I mentioned, the hallmarks of metastases that I mentioned. And if we were to block it, it was easiest possible by local anesthetic. So that's how this trial was originated. And we did in 1600 patients local anesthetic, half of them randomly allocated to receive lidocaine 0.5% versus not. Dr. Shannon Westin: That is so intriguing. I have to look up this work. I definitely agree with you. We do a lot of pre-biopsies and post-biopsies, but the intra-tumor biopsy is so novel with being able to study the anoxic tissue. I'm so interested. And you kind of started to get into this. Can you dig in a little bit more around that role or how the mechanism of action of this peritumoral anesthetic infiltration might work in preventing metastasis and preventing some of the changes that you were able to see? Dr. Rajendra Badwe: So if adequate amount of local anesthetic injected would paralyze or block the voltage-gated channels, sodium channels, and if the sodium is not allowed to get inside the cell as a gush, the first depolarization does not happen. And the downstream effect of such voltage-gated channels being stimulated is induction of proliferation, induction of invasi

Dr. Shannon Westin and her guest, Dr. Harvey Max Chochinov, discuss his article "Intensive Caring: Reminding Patients They Matter." TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and thank you so much for joining us for another JCO After Hours podcast. This is the podcast that gets in depth in manuscripts published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, GI oncologist by trade and honored to serve as the Social Media Editor for the JCO. And today we're going to be discussing a really exciting paper in the Comments and Controversies section called "Intensive Caring: Reminding Patients They Matter." This has been recently published, and I'm so excited to have the author of this paper join us today, Dr. Harvey Max Chochinov, who is a distinguished professor in the Department of Psychiatry in the University of Manitoba, senior scientist with Cancer Care Manitoba Research Institute, and the cofounder of Canadian Virtual Hospice. Welcome. So great to have you today. Dr. Harvey Max Chochinov: Thanks, Shannon. Dr. Shannon Westin: And please note neither of us have any conflicts of interest, so we'll just get right started. So first, I just wanted to explore the title of your paper, "Intensive Caring." Can you describe a bit about what that means? Dr. Harvey Max Chochinov: Well, we know that in medicine there are occasions when patients find themselves in such medical dire straits that they require intensive care. They've reached the stage where they certainly can no longer help themselves, and they require this kind of intensive approach that medicine is capable of offering. But intensive caring is meant to acknowledge that there are times when patients can be in such dire emotional straits that we need a way of being able to address that degree of abject suffering. So the idea of intensive caring was to try and provide language to describe that approach and, within the paper, as we're going to discuss, also to describe the ways in which we can actually deliver that kind of caring. Dr. Shannon Westin: Can you tell me a little bit about kind of when and where your inspiration for this work arose? Dr. Harvey Max Chochinov: The inspiration actually came from Dame Cicely Saunders. Dame Saunders was the founder of the modern hospice movement. There's a famous quote or adage that she said: "You matter because you are you, and you matter to the last moment of your life." And this has really become kind of a central philosophical tenet of palliative care. But yet it struck me that although it describes this philosophical approach, implicit is also perhaps a clinical approach which says how do we, in fact, show patients—how do we demonstrate to patients or practice medicine in a way that actually affirms that patients matter? So that's where the title came from: "Intensive Caring: Reminding Patients They Matter." Dr. Shannon Westin: There are so many pieces to this. I was so struck by what you said about these emotional dire straits. That's the best way I've ever heard it described. I feel like one of the major areas is that loss of hope and that feeling that you don't matter anymore. So what can we do? How do we, as practitioners, act and intervene to change that feeling? Dr. Harvey Max Chochinov: That's a wonderful question. The paradigm of contemporary medicine is we examine, we diagnose, and we fix. And yet, when it comes to addressing many elements of human suffering, it doesn't lend itself well to that paradigm because, of course, we know that there are things that are beyond the realm of fixing. So what we need, then, is to understand a way of approaching patient care where fix really is beyond our reach. How do we do that? It's by understanding that by being with the patient, by things like non-abandonment, all of these things are ways of maintaining patient engagement. There was a wonderful study a number of years ago by Kelly Trevino in which she looked at the associations between suicidality and the intensity and the quality of the connectedness with the medical oncologist. And it turns out that that was the single most predictive factor regarding suicidality over psychological interventions or over psychotropic medication. So the way in which we start to address this kind of abject suffering, maintaining hope, is to understand that and acknowledge that there are things that we may not be capable of fixing. But the provision of intensive caring—and, again, the elements of intensive caring that I described in the article—give us ways of being able to be with patients that don't require fixing but require presence, require involvement, require ongoing commitment to the well-being of that individual. Dr. Shannon Westin: This is a perfect segue because I was struck by that tenet of non-abandonment, you know, really committing to ongoing care. I wonder about this because we do have patients that transition to hospice, and oft

What factors could be excluding transgender people from oncology clinical trials, and what can we do to make them more inclusive? Dr. Westin discusses this important issue with her guests, Dr. Ash Alpert and Dr. Lola Fashoyin-Aje. TRANSCRIPT Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast. This is when we get down and dirty into manuscripts that are published in the Journal of Clinical Oncology. And I am so excited about our topic today. We are going to be discussing a Comments and Controversies article that was published online in JCO October 27, 2022, and it's entitled "Addressing Barriers to Clinical Trial Participation for Transgender People With Cancer to Improve Access and Generate Data." And please note all authors do not have any conflicts of interest. It is my great honor to be accompanied today by two of the co-authors on this important manuscript. First is Dr. Ash Alpert, and they are an Agency for Healthcare Research and Quality T32 Postdoctoral Fellow in Health Services Research at Brown University. And I'm so excited to note that they will be joining Yale as an Instructor of Medicine quite soon. Welcome, Dr. Alpert. Dr. Ash Alpert: Thank you. Dr. Shannon Westin: And I'm also accompanied by Dr. Lola Fashoyin-Aje, and she's the Associate Director for the Oncology Center for Excellence at the Food and Drug Administration. Welcome. Dr. Lola Fashoyin-Aje: Thank you so much. It's my pleasure to be here. Dr. Shannon Westin: So we'll get right to it. I'm so excited. I think this is a topic that many of us, almost all of us, are needing a lot of support, needing a lot of education, and I think let's start by level setting. So what we're going to be speaking today is about transgender people. These are persons whose gender identity does not correspond with what is commonly expected for them based on the sex registered for them at birth. Do we have information about how many transgender people will be diagnosed with cancer and what are the most common cancers they face? Dr. Ash Alpert: So, given many barriers to data collection about transgender people, we actually have very little quality data about transgender people's health outcomes in general and specifically around cancer incidence and outcomes. But what we do know is that at least 0.7% of the US population is trans. And the limited data that we have suggests that transgender people don't have higher rates of cancer than anyone else. So if you look at the numbers for the US, that translates into there being about 2 million transgender people in the US and about 900,000 transgender people who are diagnosed with cancer in their lifetimes. The other data that we have is that it looks like transgender people who are on hormone therapy and have surgeries, therefore less of a chance of being diagnosed with prostate cancer. If people have had bilateral mastectomy, they have less of a chance of being diagnosed with breast cancer. And it does seem like from retrospective data that it's possible that people on estrogen therapy are more likely to be diagnosed with a breast cancer. So basically, all things that we would expect. And given that about one in 10 transgender people in the US are living with HIV, it's likely that trans people also have higher rates of HIV-associated malignancies. Dr. Shannon Westin: And I wonder, what about screening? I would think that this could be a real difficulty. If people are misgendered, they may not be offered the appropriate cancer screening. I know I'm getting a little bit away from the crux of your talk, but I think this is so important. Dr. Ash Alpert: Yeah. So there's a number of barriers to screening, and two of the ones that come to mind immediately are that trans people, in general, have negative experiences with physicians. So one study suggested that one in three transgender people had had a negative experience with a physician in the last year and that given this, about one in four trans people avoid necessary health care. So that automatically means that trans people aren't getting screened. And then I think the other important thing that you're bringing up is that because of the ways that certain types of health care are associated with gender—so, in other words, getting a cervical PAP smear is associated with being a woman in the ways that we talk about those tests—there are many other barriers to trans people getting cancer screenings. And we do have some data from the literature that suggest that trans people have lower rates of cancer screenings than the general population, likely because of these two, if not more, reasons. Dr. Shannon Westin: I would anticipate that this could potentially impact, obviously, diagnosis, but then also cancer-related outcomes. Do we have data on that? I know that a lot of this is a data-free zone, so I appreciate you kind of just reviewing what we do know. Dr. Ash Alpert: So Sarah Jackson published a paper that suggested that

In this JCO Article Insights episode, Davide Soldato interviews Dr Frederic Amant from UZ Gasthuisberg - Katholieke University Leuven. Dr. Amant discusses his clinical trial update published in the March 10, 2023 JCO issue, "Cognitive and Behavioral Development of 9-Year-Old Children After Maternal Cancer During Pregnancy: A Prospective Multicenter Cohort Study", by Van Assche, et al. From the International Network on Cancer, Infertility and Pregnancy, the article reports the cognitive development of 9-year-old children after maternal cancer during pregnancy. TRANSCRIPT The disclosures for the guest on this podcast can be found in the show notes. Davide Soldato: Welcome to this JCO Article Insights episode for the March issue of JCO. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Frédéric Amant, corresponding author of the manuscript titled 'Cognitive and Behavioral Development of 9-Year-Old Children After Maternal Cancer During Pregnancy: A Prospective Multicenter Cohort Study' (10.1200/JCO.22.02005). Dr. Amant is a professor at the Ku Leuven in Belgium and at the University of Amsterdam, and he is the head of the Department of Gynecological Oncology of the Netherlands Cancer Institute and the Amsterdam University Medical Centers. Welcome, Dr. Amant. Dr. Frédéric Amant: Hello, good evening. Thank you for the introduction. Davide Soldato: So, Dr. Amant, you published this manuscript that reports the updated results of an ongoing prospective multicenter study. And this study is actually investigating cognitive and health outcomes in nine-year-old children that were born from women who were diagnosed and treated for cancer during pregnancy. So I wanted to ask if you could give us just a quick overview of the study design. What are the main outcomes that are investigated in the study, and also if you could give us some information about the results that you recently published in the JCO? Dr. Frédéric Amant: Well, the study is a follow-up study of children that are now nine-year-olds. A large part of these children, we have been following up since birth. So the first paper on this cohort basically was in 2015. And at that stage, children were 18 to 30 months old. Well, what we have to say is that all these children, or the majority of these children, in fact, the mothers, were exposed to chemotherapy during pregnancy. So the results actually in children at 18 or 30 months were, in fact, reassuring. And at that time, that was actually a big novelty because it was the first study where children were prospectively followed up and when they were compared to a control group. This study was actually changed a bit; the idea that chemotherapy during pregnancy was not possible. From there, we started to further follow up to some extent the children, but also it increased the awareness that we can treat cancer during pregnancy, including chemotherapy during pregnancy. This was followed up by a study two years ago in six-year-old children that was, in fact, also reassuring. Today, we discuss then the cognitive and the behavioral development of nine-year-old children when the mother was exposed to chemotherapy but also, in fact, cancer; all the diagnostic investigations, many women also received surgery, and actually, the children were controlled by researchers, by psychologists, by medical doctors to look into their general health. There were questionnaires to the parents, and then we assessed the IQ, we assessed memory tasks, and attention tasks. Overall, the results are, in fact, reassuring for the several subtypes of treatments, including several subtypes of cytotoxic drugs, and there were no differences when we looked into the intelligence quotient, so the IQ between exposed and non-exposed children. We did see some interesting analysis, however. To some extent, we did see that, for example, the IQ score increased by 1.6 points for each week's increase in gestational age. There was no difference in the full-scale IQ between the treatment types. Actually, in children prenatally exposed to chemotherapy, there was no association between full-scale IQ and the chemotherapy drugs, exposure levels, or the timing of the chemotherapy during pregnancy. So overall, the results are reassuring and indicate that during a critical maturation period of the child, when complex functions start to develop already and rely on the integrity of early brain development, this is actually reassuring. Especially, this critical maturation period means that when children are nine-years-old, we can test or do more complex tests when compared to children that are 18 months or 30 months, or even six years. So that is all reassuring news. Another finding, however, was if you look at the IQ, there are several components of the IQ, and there we see that the verbal IQ was, in fact, lower, and that was especially in children who lost their mother or for whom the mother was in a critical period. So the mother's health was

Dr. Shannon Westin and her guests, Jessica Star and Dr. Ahmedin Jemal, discuss how the COVID-19 pandemic affected cancer screening in the US in 2021. 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. I am your host, Shannon Westin, the social media editor for the JCO and Gynecological Oncologist at MD Anderson. And it's my pleasure to welcome you to our next episode, which is "Cancer Screening in the United States During the Second Year of the COVID-19 Pandemic." And please note the authors have no conflict of interest. I'm joined by two of the authors on this important work. First is Jessica Star, who has an MA and an MPH and is Associate Scientist II for Cancer Risk Factors and Screening Surveillance Research at the American Cancer Society. Welcome. Jessica Star: Thank you for having me. Dr. Shannon Westin: Of course. And we're also joined by Dr. Ahmedin Jemal, the Senior Vice President for Surveillance and Health Equity Science at the American Cancer Society. Welcome. We're so excited that you both are here, and I'm hoping that we'll have a really lively discussion about your important work. This paper was published online on February 23, 2023, in the Journal of Clinical Oncology. So let's level set. We'll start—Jessica, can you talk a little bit about how the COVID-19 pandemic initially impacted cancer screening in the United States? Jessica Star: So the COVID-19 pandemic disrupted the delivery and receipt of routine preventative services, and that included cancer screening. What we've seen from a lot of 2020 data that has been published is that cancer screening declined during that first year of the COVID-19 pandemic. One of those papers includes a paper by the American Cancer Society led by Stacey Fedewa. And many other studies also reported similar declines, including for breast, cervical, prostate, and colorectal cancer screening. However, some of these papers, by the end of 2020, it appeared that screening rates were starting to rebound back to pre-pandemic rates. And so that was sort of the interest in looking at that 2021 data now. Dr. Shannon Westin: And what did you hypothesize? Did you think that these data were correct? Like, did you think that we were going to start seeing an increase in screening in the second year of the COVID-19 pandemic, or what were your suppositions? Jessica Star: Yes, I think we kind of hypothesized or hoped, based off of what we were seeing from the 2020 data, that we would start seeing more substantial increases as we were getting into 2021. Based off of those declines during the first part of the pandemic, we were really wanting to see individuals coming back into screening now that stay-at-home orders had sort of been reduced and now that individuals were going back to screening more frequently. Dr. Ahmedin Jemal: I might add that the motivation for this screening, in addition to what Jessica said, is that the previous studies were based on representative US populations, either based on claims data or state-specific population-based studies. They were not based on nationwide population-based study. That's why we used the NHIS, National Health Interview Survey, which is a US population-based study, to look at whether screening in 2022 has returned to the pre-pandemic level. Dr. Shannon Westin: Yeah, why don't we get into a little bit more detail here? I would love—Jessica, can you talk a little bit more about the National Health Interview Survey? I get the idea of why you all used it, but can you tell our listeners just a little bit more about that database? Jessica Star: To go off of what Ahmedin mentioned, The National Health Interview Survey is a nationally representative cross-sectional household survey of the United States population that is generalizable. And that survey is housed by the National Center for Health Statistics in the Centers for Disease Control, and they report on cancer screening biyearly. So we have data from 2019, and we have data from 2021. And the next increment of the National Health Interview Survey that we'll have for cancer screening is in 2023. Dr. Shannon Westin: And then talk a little bit about which cancer types you all focused on when you're looking into this hypothesis, that potentially screening was being increased. Jessica Star: So we focused primarily on breast, cervical, colorectal, and prostate cancer screening. And some of the reason behind this was because of data availability. The NHIS only provided those four—receipt of those four screening types, as well as when we were looking at the data previously from that 2020 data, we were seeing a lot that were focusing on some combination of breast, cervical, colorectal, and prostate cancer screening. So we wanted to continue that work into the second year. Dr. Shannon Westin: And then let's cut to the chase. What did you find? Did you prove or disprove your hypothes

Dr. Shannon Westin and her guests, Dr. Michael Atkins, Dr. Adil Daud, and Dr. Gary Schwartz, discuss a definitive work: The DREAMseq Trial. TRANSCRIPT The guests on this podcast episode have no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast that gets in-depth on articles that have been published in the Journal of Clinical Oncology. And it is my great pleasure to be your host. I'm Shannon Westin, GYN oncology, and I serve as the social media editor for the Journal of Clinical Oncology. Today, we're going to be discussing a very exciting article describing "The DREAMseq Trial—ECOG-ACRIN EA6134, Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma." This article was published in the JCO on January 10th, 2023. And I am joined today by the lead author, Dr. Michael Atkins, who is Deputy Director, Georgetown Lombardi University Hospital, and Scholl Professor and Vice Chair of Oncology at Georgetown University Medical Center. Welcome. Dr. Michael Atkins: Thank you. Nice to be here. Dr. Shannon Westin: In addition, we are also accompanied by two experts in the field, Dr. Adil Daud, Professor in the Department of Medicine at the University of California San Francisco, and Director of Melanoma Clinical Research at UCSF Helen Diller Family Comprehensive Cancer Center. Welcome, Dr. Daud. Dr. Adil Daud: Hi, great to be here. Dr. Shannon Westin: And with Dr. Daud is Dr. Gary Schwartz, the Division Chief of Hematology Oncology and Deputy Director of the Herbert Irving Comprehensive Cancer Center in Columbia, New York. Thank you for being here. Dr. Gary Schwartz: Delighted to be here. Dr. Shannon Westin: So I'm surrounded by experts, and I'm very excited as a GYN oncologist to hear all of what you all have learned in melanoma because we're always excited to take that back into our field. So I think first, though, for those of us that aren't melanoma experts, Dr. Atkins, can you just level set for us and tell us what was the standard of care for melanoma when you began this study? Dr. Michael Atkins: Sure. Well, first of all, this was a study for patients with BRAF V600 driver mutations in their melanoma, which represents about 50% of the patients with metastatic melanoma. And at the time the study was launched in 2015, two BRAF/MEK inhibitor combinations were FDA approved and shown to produce significant progression-free survival and overall survival benefits relative to BRAF inhibitor monotherapy. In addition, combination checkpoint inhibitor therapy with nivolumab and ipilimumab was shown to be superior to ipilimumab and, in particular in patients with BRAF-mutant melanoma, also to nivolumab monotherapy based on the results of the CheckMate 067 study, leading to its FDA approval. So we had these two regimens there that were approved. Of note, despite the many debates and attempts to garner real-world evidence at the time—the study actually reported out in 2021—marketing data showed that half of all patients in the US with metastatic BRAF-mutant melanoma were receiving BRAF/MEK inhibitors, and only one-quarter received nivo-ipi as initial therapy. So there remained a confusion throughout the course of the study as to which regimen was best in the US and around the world. Dr. Shannon Westin: Tell me, what led to the current study? Was it really trying to drive at that very question? Dr. Michael Atkins: These were the best treatment available at the time. And they really had changed melanoma patient outcomes in ways that we could have only dreamed about just five to 10 years prior, when median survival for patients with metastatic melanoma was six to nine months. Hence, the DREAMseq trial, this doublet, randomized evaluation of advanced melanoma sequencing, was really an apt acronym for the trial. But we had these two regimens of BRAF/MEK inhibitors tending to display the overall survival curve, while immunotherapy tended to raise the tail. And at the time the study was launched, it was really unclear which treatment was preferred in general or for particular subsets of patients. And given that patients would likely have the option to receive both approaches, was there a preferred sequence? So the DREAMseq trial was a launch to address these questions. Dr. Gary Schwartz: I can echo Michael's statement about that. There was also—having been at the beginning of immunotherapy and targeted drug therapy, the transformation of cancer medicine in melanoma was extraordinary. Over a very short amount of time, we transformed a disease that's incurable to curable. And I don't think anybody, at least not in my lifetime, that ever think we'd ever see—or I'd see that type of transformation. But the debate in the community was what should be the first therapy. Should it be a targeted drug combination targeting RAF and MEK for BRAF-mutant melanoma, or should it be immunotherapy? And actual

In this JCO Article Insights episode, Emily Zabor summarizes two articles from the February 20th, 2023 Journal of Clinical Oncology issue: "Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study" by Johnson, et al and "The POSEIDON Trial: Will Secondary End Points Change Our Clinical Practice?" by Remon, et al. The Original Report by Johnson, et al describes results of the Phase III POSEIDON clinical trial. The accompanying editorial by Remon, et al discusses the findings of a significant progression-free survival and overall survival benefit for the combination of tremelimumab plus durvalumab plus chemotherapy as compared to chemotherapy alone, which were secondary endpoints in the trial. TRANSCRIPT Emily Zabor: Welcome to JCO Article Insights for the February 20, 2023, issue of JCO. I'm your host, Emily Zabor, JCO Biostatistics Editorial Fellow. Today, I will be providing summaries for two articles. The first article, titled 'Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study,' by Dr. Melissa Johnson and colleagues, describes the results of the Phase III POSEIDON clinical trial. POSEIDON was a randomized Phase III clinical trial in patients with metastatic non-small cell lung cancer. The trial had a three-arm design to evaluate the efficacy of tremelimumab plus durvalumab plus chemotherapy; durvalumab plus chemotherapy; and chemotherapy alone in a first-line treatment setting. The two immunotherapies were selected for study because of their complementary mechanisms of action. Tremelimumab is an anti-CTLA-4 antibody which can diversify T-cell responses and lead to increased tumor infiltration. Durvalumab is an anti-PDL1 antibody which can enhance T-cell function. Chemotherapy is still an important treatment option for early disease control and potential for immune priming. Patients in the POSEIDON trial were randomized to the three arms with equal allocation. The co-primary endpoints for the trial were progression-free survival and overall survival for the comparison of durvalumab plus chemotherapy vs. chemotherapy alone. Then, a hierarchical multiple-testing procedure with a gatekeeping strategy was used across the primary endpoints and key secondary endpoints. Gatekeeping procedures are a way of controlling the type I error rate across multiple groups of null hypotheses that have a hierarchical structure, meaning that some of the hypotheses are considered more important than others. In this case, the plan was to first test for differences in progression-free survival and overall survival between the durvalumab plus chemotherapy and chemotherapy alone arms. Then, if either of those tests had a significant p-value so that the null hypothesis of no difference between groups was rejected, tests for differences in progression-free survival and overall survival between the tremelimumab plus durvalumab plus chemotherapy and chemotherapy alone arms would be conducted. Additional levels of testing could be conducted for other secondary endpoints following significance at the previous level. These types of gatekeeping procedures are a rigorous way of controlling the type I error of the entire study at 5% while still allowing multiple tests to possibly be conducted. The efficacy analyses were conducted in the intention-to-treat population, which included 338 patients on the tremelimumab plus durvalumab plus chemotherapy arm, 338 patients on the durvalumab plus chemotherapy arm, and 337 patients on chemotherapy alone. The median follow-up among those without an event was 10.3 months for progression-free survival and 34.9 months for overall survival. The findings for the co-primary endpoints were that progression-free survival was significantly improved with durvalumab plus chemotherapy versus chemotherapy alone, with 12-month progression-free survival rates of 24.4% versus 13.1%. There was no statistically significant difference in overall survival, with 24-month overall survival rates of 29.6% versus 22.1%. Because progression-free survival was significantly different in the durvalumab plus chemotherapy versus chemotherapy alone arms comparison, according to the hierarchical testing procedure, the study proceeded to compare efficacy between the tremelimumab plus durvalumab plus chemotherapy and chemotherapy alone arms. Both progression-free survival and overall survival were significantly higher for the tremelimumab plus durvalumab plus chemotherapy arm, with 12-month progression-free survival rates of 26.6% versus 13.1% and 24-month overall survival rates of 32.9% versus 22.1%. The tremelimumab plus durvalumab plus chemotherapy arm had higher rates of grade III or IV treatment-related adverse events and immune-mediated adverse events as compared to the other two arms. The rates of grade III