Journal of Clinical Oncology (JCO) Podcast

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 to say who it is going to have optimal outcomes for compared to other kinds of survivorship care models.  Shannon Westin: And that makes sense. I mean, I think we're seeing this over and over again in all aspects of cancer care that one broad stroke or one broad plan isn't right for everybody, whether that's therapeutic or surgical or prevention, so it makes sense to me that that's what we're seeing here in survivorship as well. So I see this manuscript as a call to action about what are we missing, what data do we need to generate to really be able to move this care forward. So that makes total sense to me. And I guess in line with that, another belief, and I've heard this all the time from my patients, too, is this idea that primary care providers feel unable to provide survivorship care. They're not comfortable. “Oh, you have a diagnosis of cancer. You have to be seen there at the cancer center.” What does our evidence demonstrate here? Dr. Emily Tonorezos: This is another belief that was found to be a presumption. So that means that this is a belief that we think was true, but which convincing evidence does not confirm or disprove. So what the available evidence tells us is that primary care providers do have challenges in taking care of cancer survivors, particularly with regards to certain cancer-related care needs. But at the same time, we found lots of evidence that primary care providers are more than willing and able to take care of cancer survivors. They express confidence in their skills. They think that they are capable of taking care of cancer survivors. And especially for survivors of more common cancers, primary care providers, in general, express a lot of confidence in their ability to take care of those patients. What they might lack could be things along the lines of survivorship-specific knowledge. So that is a gap that we identified. But this idea that primary care feels unable to take care of survivors really was not supported by the evidence. Shannon Westin: I mean, and that makes sense, right? If we're seeing more and more cancer survivors, primary care is going to adapt to that. We adapt to the things we see commonly in our clinics, and that goes across all specialties. So that certainly makes sense. I guess you've already kind of said this, and I'll just highlight it for the listeners. You know, clear guidelines seem to be a clear, nice option to potentially improve this situation.  So let's discuss this next myth that you all identified, that oncology providers are hesitant to transition survivors to primary care. Now, I understand this one because I definitely, we get this a lot, and I'm a center medical director in GYN, and we've definitely tried to put patients that are free of disease out back in the community to be able to free up space for other patients. And we definitely get pushback because seeing patients that are in this state of being free of disease and they're living their life, it's inspiring. We remember why it is we're doing the things we do. What did the data show us about this myth? And are we creating barriers to this transition to survivorship care outside of the oncology centers? Dr. Emily Tonorezos: Exactly. So this belief is a myth. We found evidence that this belief is not true, and it seems to be one of those things that feels true, that oncologists want to take care of cancer survivors, that it contributes to the joy of medicine. But that evidence really does not suggest that that's the case. In fact, the opposite is true in the evidence. We found when we looked at the available research Oncologists want to take care of people who are diagnosed with cancer and need treatment. That is really what they think their role is. That's what they feel they're contributing. And so, even though there is a pleasure in seeing a person who has finished treatment, most oncologists say that the amount of time that they spend taking care of people who are done with treatment is appropriate - meaning they're not looking to expand their panel of post-treatment patients. They really want to take care of people who need treatment currently and then perhaps have a little bit mixed in of people who are done with treatment or who are in that survivorship phase. We found a lot of evidence, also hard evidence, that oncologists are, in fact, transitioning survivors to primary care. There is a lot of evidence that people who have been diagnosed with cancer are being seen in primary care and that that proportion increases over time. So if oncologists were really creating these insurmountable barriers to transition to primary care, we would not be seeing so many survivors in the primary care setting. But the fact is they're there, and they are being moved there by their providers. Shannon Westin: I love hard evidence. I do have a few patients that have said, "Can I just come see you every once in a while?" And I love seeing them, but I agree, we can't fill our p

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 transplantation for patients with mantle cell lymphoma. Although the extended follow-up was conducted prior to the COVID-19 pandemic, during which increased risk of infection was shown for those undergoing B-cell depletion with agents such as rituximab, this extended follow-up of the LYMA study continues to show that the optimal therapy for mantle cell lymphoma should include maintenance rituximab after transplant. Studies since the design of the LYMA trial have sought to address whether consolidative transplants are necessary when BTK inhibitors are added to induction therapy, and ongoing studies in this era of newer treatment agents will continue to challenge and potentially redefine this now well-established standard of care. The second article by Kahl et al. is titled "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." The RESORT study, conducted by the Eastern Cooperative Oncology Group, was designed to address whether rituximab-responsive low tumor burden follicular lymphoma patients benefit from maintenance rituximab until progression versus a rituximab retreatment approach at the time of progression. The primary analysis of the RESORT study, published in 2014, did not show a difference in the primary endpoint, which was defined as time to treatment failure. The five-year risk of treatment failure for those on a maintenance strategy was 53% compared to 50% for those on a retreatment dosing strategy. At the time of the primary analysis, letters were sent to participants and providers, and thus the data was locked for further primary endpoint analysis in late 2011. The data lock for long-term follow-up presented in this paper was continued through 2021.  The authors looked at several endpoints in this long-term follow-up. They found that freedom from first cytotoxic therapy, at a median follow-up of almost nine years, favored the maintenance group over the retreatment group, with 83% versus 63% of patients free from chemotherapy or radiation at year seven. When looking at response duration, the analysis also favored a maintenance over retreatment approach, of 66% versus 30% for 10-year response duration, with a median follow-up of 12 years. However, when looking at overall survival at 10 years, there was no difference between rituximab dosing strategies, with a 10 -year overall survival of 83% for those receiving maintenance versus 84% for those receiving retreatment. While this extended follow-up of the RESORT study was not able to assess the long-term follow-up of the primary endpoint, the secondary endpoints suggest that while a maintenance dosing strategy was superior for prolonging time to first cytotoxic therapy and response duration, this again did not translate to an overall survival benefit. The authors conclude that they continue to recommend a rituximab retreatment strategy for these patients instead of a maintenance strategy, in the absence of a survival benefit, particularly with the high response rates observed with next-line treatment strategies for follicular lymphoma patients.  Similarly to the LYMA study discussed in the first paper, the treatment arms of the RESORT study were completed prior to the COVID-19 pandemic. B-cell depletion, such as with prolonged rituximab therapy, is known to negatively impact the ability to combat viral infections such as SARS-CoV-2. Thus, the authors conclude that, in light of current and future infectious concerns, the extended follow-up of the RESORT study does not support the use of maintenance rituximab for patients with low tumor burden follicular lymphoma. Other studies have also evaluated modified and abbreviated maintenance rituximab dosing strategies for this same population and have also not shown a survival benefit, thus further strengthening this recommendation of favoring a retreatment approach over maintenance therapy. Together, the extended follow-ups of the LYMA and RESORT studies, while addressing different questions regarding the use of maintenance rituximab in mantle cell lymphoma and follicular lymphoma, support the primary endpoints of each respective study. There is a clear role for the use of maintenance rituximab therapy to promote improved event-free and overall survival, as the LYMA study has shown for mantle cell lymphoma patients. However, this does not extend to low tumor burden follicular lymphoma patients in the RESORT study. The updated analyses of these two studies provide additional strength to the nuanced and targeted application of this stalwart of lymphoma therapy that is rituximab, in the modern treatment era. While ongoing studies will aim to address how we optimize therapies with new agents for each subtype of lymphoma patients, the LYMA and RESORT studies continue to guide best practice and standards of care.  This is Alexandra Rojek, thank you for listening to JCO Article Insights. Don't forget to gi

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 sure that people are being appropriately molecularly selected and how do you decide which testing to utilize?  Dr. Richard Schilsky: As you pointed out, Dr. Westin, the goal of the study from the beginning was to have a very pragmatic design, in a sense to have this study attempt to replicate the way oncologists were deploying precision medicine in their practice. The study has broad eligibility criteria, it has minimum necessary data collection, it uses conventional clinical evaluations, there are no additional clinical evaluations required that are not part of routine clinical care. And it just makes it easy to embed the study into the clinical workflow. The study is based largely at community sites, about 85% of the 268 participating sites are located in smaller communities. The study has a set of genomic matching rules that are listed in the protocol and baked into the IT platform for the study as a rules engine. For every treatment available in TAPUR, there is a set of genomic inclusion and exclusion criteria.  So in essence the way it works, the physician determines that NGS testing is appropriate for their patient and can use any NGS test they want, as long as the test is performed in a CLIA certified, CAP, or New York State-accredited laboratory. They select the test, they select the biospecimen to be tested, they get the results, they look at the results, and they determine if there is a genomic alteration in the patient's tumor that is targeted by one of the study treatments in the TAPUR study. They can enter that into the rules engine, the rules engine will confirm or not that the appropriate alteration of treatment has been selected. If it is confirmed, then the patient can immediately be enrolled in the study if they meet the clinical inclusion and exclusion criteria.  If the rules engine does not confirm the treatment match is appropriate, or in some cases there are multiple possible treatment matches, if there are multiple alterations that can be targeted, or another case is the doctor is simply uncertain about which alteration is best to target, then the clinical site can send that patient case to the TAPUR molecular tumor board. A group of experts convenes weekly that reviews the clinical history, the pathology report, genomic test report, the prior therapy the patient has received, and they make a determination as to whether or not there is an appropriate therapy that’s available on TAPUR for the patient. And if not, then are there other potential therapies  that are available that could be considered. That information is sent back to the treating physician who determines whether or not here she feels that treatment option is appropriate for their patient, and if so, the patient can then be enrolled and receive the therapy. Shannon Westin: So awesome. I love the idea. If we don’t have an arm for you on our trial, we can help assist you potentially determine an option for your patient outside of that. That’s so clever.  Okay. So let’s get into this particular arm. Obviously, our audience is quite savvy and are aware of the role of immune checkpoint inhibition across a number of solid tumors. Could you describe what you sought to determine in this particular arm of the TAPUR study?  Dr. Herbert Duvivier: I think one of the most important things to remember about this study is that this study was opened and accruing prior to pembrolizumab becoming FDA approved in, I think, June of 2020. So prior to June of 2020, there was no indication for pembrolizumab in high TMB tumor types and the goal of the study was to determine if pembrolizumab had any overall response rate, duration of responses, progression-free survival, or overall survival advantage over what would be considered standard chemotherapy at that time in patients with high TMB. Dr. Richard Schilsky: Yeah, that's exactly right. And in this paper that we're discussing, we're reporting on two different groups of patients. So there's a group of 28 patients, all with colorectal cancer, all of whom had high tumor mutation burden, as defined by the protocol. And that's one group. Then there's a second, larger group of patients, which is a very heterogeneous group of solid tumor patients. And the reason that that group is reported is there were patients who were being enrolled with multiple different tumor types with high tumor mutation burden. Each tumor type determined a specific, tumor-specific cohort in the study, and they were enrolling at different rates depending upon how common the particular tumor type was. But once the FDA approval for pembrolizumab, for any tumor with a high tumor mutation burden, was granted, then all of those cohorts essentially had to close to new enrollments because there was no longer an off-label use for pembrolizumab in that setting - everything was now on the label.  The result was that we then basically collapsed all of the open cohorts that were not then going to be able to compl

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 a 10% rate, and the group with lymph node positivity with extracapsular extension and axillary soft tissue involvement had a 14% rate. The 10-year axillary failure rates were only 1.6% and 0.8% for the groups with no axillary soft tissue involvement but rose to 4.6% and 4.5% for the groups which did have axillary soft tissue involvement. In multivariable analysis, including tumor size, grade, number of positive nodes, and receptor status, axillary soft tissue involvement remained significantly associated with distant failure with a hazard ratio of 1.6, local-regional failure with a hazard ratio of 2.3, and axillary failure with a hazard ratio of 3.3. Of note, the number of axillary failures was overall low, only 4.6% in the group with both lymph node and axillary soft tissue involvement. Delivery of regional lymph node irradiation, defined as treatment of axillary, supraclavicular, and internal mammary nodes, was associated with improved local-regional outcomes in patients with extracapsular extension or axillary soft tissue involvement with a hazard ratio of 0.5 and a p-value of 0.03 but was not associated with any improvement in distant failure. The authors described the main limitations of this study as the retrospective nature and the absence of genomic marker results. In summary, although current guidelines do not emphasize axillary soft tissue examination, this study shows the importance of reporting axillary soft tissue involvement beyond the number of positive lymph nodes and the presence of extracapsular extension, as there is an increase in local-regional, and axillary failure rates for patients with axillary soft tissue involvement even without extracapsular extension. Therefore, both extracapsular extension and axillary soft tissue involvement should be consistently reported in large randomized trials as we continue to work to tailor local therapy to individual patient risk. This is Giselle Carvalho. Thank you for your attention and stay tuned for the next episode of JCO Article Insights. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.        

Dr. 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 tolerate that. So can we find a population in whom the risk is low enough that at least some of those women say, "Look, I want to go without radiation." And of course, the balance of where that number should be changes as we get better and better at delivering radiation. So you mentioned, radiation comes with toxicity, comes with burden and yet, there have been some tremendous advances, and particularly in recent years, to shorten the course of radiation. We have evidence that we can treat partial breast radiation safely in five treatment fractions. We have five-year data that we can treat the whole breast in five-treatment fraction. We certainly have long term evidence that we can the whole breast with 15 fractions from many patients diagnosed with breast cancer. So the burden has decreased. We’ve also found that with hypo fractionated shorter courses of radiation, the toxicities are much lower, patients tend to tolerate radiation treatment both in terms of acute side effects and long term side effects extremely well.  So that balance of what is low enough is changing with time.  But the trials that were started in the 1990s included the CALGB 9343 trial, a landmark trial published in the New England Journal of Medicine, with its five-year results showing only a 4% risk of recurrence at five years in patients who were 70 or older with clinical stage one disease that was hormone receptor-positive if they received a lumpectomy and tamoxifen alone, not receiving radiation - that risk, if we added radiation in this randomized trial, was only 1%. So there was still a substantial relative risk reduction with radiation treatment. This was published in 2004 in the New England Journal of Medicine.  At the same time, there was a Canadian trial that was published, and in that trial that included women who were 50 years of age and older, there were more concerning results with, even in a very favorable prespecified subgroup of patients who had node-negative breast cancer and T1 hormone receptor-positive tumors, the risk of ipsilateral breast tumor recurrence was 15% at eight years. So that started to feel excessive for women 50 and older.  Meanwhile, we went on to get the update of the CALGB trial, and the 10 -year results showed that the risk was, in the women 70 and older, was only about 10% without radiation. It was 2% with radiation. So again, there was a benefit from radiation, and it's up to each individual woman to decide whether they'd prefer to proceed and minimize their risk, or would be willing to tolerate something like a 10% risk. More recently, just this past year in the New England Journal, the PRIME 2 study from the United Kingdom, looking at women 65 and older, again, early-stage node-negative hormone receptor-positive tumors, and very similar results - 10% versus 1% local control at 10 years.   So you get an improvement with radiation. But there are some women who are 65 or 70 and older who say, I'm willing to tolerate the 10% risk. And so the question was, could we identify some patients who are younger than 65 to 70, but still postmenopausal, like in that Canadian trial, who might actually have similar outcomes - low risks at five and ten years - such that they might want to entertain the option of omitting radiation therapy, which right now is not standard or in any guidelines? So we have some promising information from some retrospective analysis of that Canadian trial that suggested that looking at biology might help. And in fact, the LUMINA trial, published just this year from Canada, did a prospective cohort study selecting patients based on immunohistochemistry, and suggested very low risks, five years in patients who were somewhat younger, although it ended up that the median age of the patients in that study was 67. So we still sort of had this question of what about the younger postmenopausal patients? And that's what took us to IDEA.  Shannon Westin: And just for my education and for the education of the listeners, when you have an in-breast recurrence, how likely are you to be able to cure that? Is that tough to cure, or can you usually get control again? Dr. Reshma Jagsi: It's an excellent question. And so often these recurrences are caught early and are still completely curable with additional intervention. Now, there can be an impact, of course. You can talk to any survivor about the devastating impact of being diagnosed with breast cancer recurrence, and no one wants to go through that. And so there are reasons that people will want to reduce that, and there are implications for breast conservation because it may be that the remaining breast tissue is insufficient to allow a second breast conserving surgical procedure. It may also be that when one experiences recurrence, one decides, "I'm done with this. I'm having a mastectomy at this point." So, in-breast recurrences are very meaningful to patients and something that we should not take lightly. Shannon Westin: It se

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 surgery around that. We have the same thing when we talk about risk-reducing surgeries for endometrial and ovarian cancers. This seems more like what we do in Lynch syndrome, where patients are at risk for endometrial cancer. Removal of the uterus is almost definitive in its ability to reduce that risk, but it's obviously a very large surgery. Jeremy, can you review the gastrectomy in general? What are the most common short-term and long-term adverse events? What did you have to discuss with Kathryn and her five family members around what they could expect from this surgery? Dr. Jeremy Davis: Yeah, I think this is a great question because it's the thing at the top of most patients' minds. When I sit down to talk to somebody about gastrectomy, usually a lot of the conversation initially centers around ‘how long does the operation take, how long am I at the hospital, and what are the most likely risks of the operation?’ The good news is that as operations go, it can be done in two to three hours, and most people are in the hospital for maybe five to seven days. The risks of this operation, however, at least during the operation or immediately afterward have to do with how we have to reconnect everything and reconnecting the intestine to the esophagus so that people can continue to eat. Because I think a lot of people wonder, "Well, how am I going to eat?” The stomach's gone, but we recreate intestinal continuity. We put things back together in a way that people can eat and absorb their food.  But that connection we make between the esophagus and intestine is almost like the Achilles heel of this operation. It's the one thing that keeps surgeons up at night, and it's probably the one thing that causes the most trouble in terms of immediate risks, like leaking. If that connection leaks, it can lead to infection. There are other aspects of the operation that relate to any kind of intestinal surgery, such as leakage, blockage, or narrowing or something like that. So these are the things you need to worry about in the short term. But you mentioned the long-term consequences, and that was really one of the reasons why we wrote the paper. If you look in the literature, the focus is on the acute problems, things that happen within 30, 60, or 90 days of the operation. Which, yes, those are very, very important. But since we're talking about an operation that's supposed to prevent cancer and therefore allow the patient to live a long and happy life, I think it's important for us to think about what happens well beyond the time that the patient essentially heals from the operation.  Shannon Westin: It's so critical. And I think before we go into the work that you did and what you all found, Kathryn, I would love to get your perspective. Having gone through the procedure, what was your experience? Give us as little or as much detail as you want, whatever you're comfortable with. But also, what did you wish you had known? What surprises kind of came up during the course?  Kathryn Carr: I'm going to quote Rachel, who works with Dr. Davis at the NIH. She's the clinical dietitian. And my question to her was, "Seeing all the patients you've seen and knowing all that you know, what would be the advice that you would give me?" She told me to have the patience to get through the first year. I think that really set my expectation of, "Okay, this is not just a surgery where in a week or two weeks I’m going to be up skipping along." It is a marathon. I really worked hard with Dr. Davis in the hospital. I'm allergic to everything. I was convinced that my spleen was erupting. I think I scared many fellows, and they were like, "That's actually not where your spleen is. It's fine. You're okay. Stop getting on WebMD." But once I got home, those first eight weeks, they’re hard. There were several moments where I would just sit and stare off into space and think, "Oh my gosh, what have I done?" But for me when Dr. Davis called to tell me the pathology report and that they did find some signet cells, I was 100% sure that I made the right decision. I would have been worried every second of every day that my body was going to turn on me. So once I kind of had that relief, it was like, "Okay, my body can do this. We're built to do hard things." Then it was just getting through the first six months, learning what I could eat, what I couldn't eat, working with Rachel on different strategies of, “Okay, I’m going to maximize my protein in the morning and then maybe get a little more adventurous as the day goes on.” But what I wish I had known before surgery, because I'm a planner, I want everything scheduled and figured out. I was in the hospital, I had a different outfit for every day, and I just wanted it to go perfectly. I think taking away the expectations of what your journey is going to look like would be the best advice I could go back and give myself. Because I am very competitive, and my dad and I were separated by

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, especially symptomatic adverse events, should be recorded regularly in cancer clinical trials. Formal patient reported outcomes are not typically collected as frequently as adverse events are recorded, so identifying patients with a high number of lower grade adverse events could be used to facilitate early supportive care to improve patient quality of life and reduce the likelihood for treatment discontinuation. ·       They also highlight their result identifying lower odds of treatment discontinuation with larger numbers of grade 1 adverse events. They provide one explanation that patients may perceive grade 1 adverse events being associated with treatment efficacy, but this perception changes with higher grades.  In their call to collect more lower grade adverse events, the authors acknowledge that recording more adverse events may be time-consuming and burdensome for sites and recommend cost-benefit analyses to develop future guidelines. ·       This balance between the benefits and costs of increased adverse event data collection is the focus of Dr. Neuman’s editorial. Dr. Neuman acknowledges that Dr. O’Connell’s article provides a convincing argument for how low grade adverse event information is valuable, but notes the clinical trial context that current efforts at the NCI are to more efficiently conduct cancer research, which could be supported by streamlining data collection. ·       Requiring the collection of low grade adverse events could have important impacts to trial logistics. Due to the high volume of low grade adverse events, reporting all low grade events could delay reporting higher grade and more serious adverse events; and it would require an increase in the effort of clinical trial research staff, which would be difficult if not accompanied by an increase in reimbursement to sites. ·       Dr. Neuman suggests 3 approaches to balance the costs and benefits of collecting low and moderate grade adverse events. First, investigators could consider limiting low-grade adverse event reporting to the experimental arm. The standard of care regimens may not always have low-grade adverse event data available, but this may still be justified when there is extensive clinical experience with the standard of care. However, this approach is only practical when the experimental arm is not blinded. ·       A second approach for moderating the effort in collecting low-grade adverse events is to limit collection to symptomatic adverse events, connecting with Dr. O’Connell’s example E1912 dataset. This approach could be addressed by prespecifying types of symptomatic adverse events that would be most impactful during the trial design phase. ·       Dr. Neuman’s third suggestion is to plan for a follow-up study after the phase 3 trial to collect low-grade adverse event data and their impact on patients’ experiences and treatment discontinuation. This would be beneficial by only requiring low-grade adverse events in an experimental regimen that has successfully passed phase 3. However, a new study would require funding and site enthusiasm, which could prove challenging. ·       Overall, Dr. Neuman emphasizes that investigators should develop trial-specific considerations and engage with the relevant stakeholders during study design. Because of the complexity of adverse events in these patient populations, the best uses of grade 1-2 adverse events will likely continue to develop in the future. In their article, Dr. O’Connell’s team studied grade 1 and 2 adverse events as separate predictors, but I would be curious to know how the accumulation and trajectory of these adverse events affect the patient experience. For example, even if the severity does not rise to grade 3, an increasing trend in a patient’s adverse event severities could signal the treating physician to modify study dose or to discontinue the treatment. I’m not sure if that type of information was available in their trial E1912, but perhaps that could be a factor to consider for the future. And, of course, it will be important to assess how these grade 1-2 adverse events relate to the patient experience in different studies, especially across different cancer patient populations, acknowledging that this is inherently challenging to study because the data to inform this research is not universally available. As Dr. Neuman indicates, trial-specific goals and expertise will remain critical when considering the data collection for a given trial.  That concludes this episode of JCO Article Insights regarding a summary of the article “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” by Dr. O’Connell and colleagues and the editorial entitled “Patient Experience, Adverse Event Reporting, and Clinical Trial Design” by Dr. Neuman. This is Subodh Selukar. Thank you for your attention and stay tuned for the next episode of JCO Article Insi

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 those things. For example, the ways that we talk about certain types of cancer can be linked with gender, like we were talking about earlier, women with ovarian cancer, men with prostate cancer. And that's the way that we talk to each other. But it's also in our clinical trial eligibility criteria, sometimes, it's in our patient facing materials, it's in the ways that we name our clinics, the ways that we talk about our work. So then even just sometimes occupying space to get oncology care can be a form of being misgendered.  Spencer Adams: Yeah, I think it's dangerous to conflate the two, sex and gender. As Ash was saying, that one is a visual inspection, the other is who the person is. And if we claim to be an institution that does patient-centered care, how can we be patient-centered if we are not properly respecting the patient? And to do that, you have to respect their gender as well. I see also one of the things that I want to add to the list is clothing that the patient is offered, especially going to a "women's clinic." We can change that to "reproductive health clinic," but usually the clothing is pink and that may be dysphoria-causing for some of our transgender and gender nonconforming friends. So it truly is in everything that is client facing, that is how the structural building is made. It truly is not just how we talk to each other, but how society runs.  Shannon Westin: Yeah, let's talk a little bit more about training because I think that will be pretty important as we try to change these things. So the way we're trained in medicine and oncology, regarding sex, regarding gender, how does this negatively impact the health? We've talked a lot about the mental health, definitely impacts, but also, I think, overall physical health. Dr. Ash Alpert: Well, I think something that we started to talk about, but didn't talk about in detail is not just the conflation of sex and gender, but the ways that this concept of sex is used as a proxy for a number of other factors, including anatomy, hormonal milieu, karyotype, and body size. One of the ways that this becomes problematic is in our laboratory values for example. Laboratory values are developed, as far as I understand it, based on looking at large studies of people that are categorized as women or men and looking at averages. So, averages are helpful, but they can't necessarily tell us about disease or no disease. So, for example, if a large number of cisgender women have iron deficiency that is undiagnosed, and we use their averages, then we're going to continue to underdiagnose iron deficiency anemia going forward.  So, the ways that we've tried to use sex as a proxy for a number of things doesn't just hurt trans people, but potentially leads to very imprecise data in general. Specifically for trans people, we know that many trans people have negative experiences with care, that this leads to people avoiding care and likely leads to decreased screening for cancer and delayed cancer diagnoses. So we don't have a lot of data about this, but we do have some data to suggest that transgender people may present later with later stage cancers, be less likely to be treated, and have poorer outcomes than cisgender people. Spencer Adams: And I think it's important to add that there are physicians who will - we call it like, “the trans illness" - but they will blame everything that you're experiencing on the fact that you're transgender or the fact that you're on hormones or the fact that you had the surgery, and say that you need a specialist. So you can't just go to your primary care physician anymore for the flu because they'll just blame it on your medical transition. When we take that into consideration, I think there's a whole host of physical ailments that come from just being denied care. I don't know if that is from the physician's own personal stigma around trans people or just them not being trained in trans healthcare to where they feel confident in going into that room. So it's a twofold attack. First, we need to make doctors who are competent in trans healthcare, and then second, we need to have more inviting spaces for trans and gender nonconforming people. Shannon Westin: I think the next step is really better understanding this idea around degendering care, specifically in oncology, but I could really talk about medical care as a whole, but let's focus on what you all brought forward in the paper. I would love to hear how we think this idea of degendering care will promote better healthcare. And then, I think, some practical actions. What can we do on a day-to-day basis? And you've already started peppering this through this discussion but I’d love to like bullet point it out for the listener.  Dr. Ash Alpert: Yeah. So the way we described it on our paper was: “disentangling oncology is a conscious and explicit disentanglement of gender, anatomy, hormonal milieu, karyotype, and other biological factors. In oncology, di

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 was behind her cancer from the beginning, and in fact, might have been the basis of why she developed lung cancer. And so that actually motivated a career development award I submitted to the Conquer Cancer Foundation of ASCO, a grant I received, and that then led to a program that I led at Dana-Farber under Judy's mentorship, where over the past decade, we sort of focused in and studied this strange, rare syndrome, really to dig into inheritedness as a kind of different flavor of lung cancer genetics.  Dr. Judy Garber: Well, and now it's really a good time to think about this because we're recognizing there are younger cancers, colon cancer, like an epidemic, and lung cancers, and we're not sure how many of them are genetic or come from other exposures. Geoff talked about the differences in Asia, some of which are certainly genetic, some which may be environmental, especially in the lung, where that's such an issue. But trying to sort these things out, you have to be willing to think a little bit differently. And that was fun when Geoff came from the lung program, interested in the germline, we said, “Oh, we have to do this.”   Shannon Westin: Well, let's talk about what you did. I would love to hear and I know the audience would as well about the design of this study, so called INHERIT study. Very good name. I love a good name. This is a good one.   Dr. Geoffrey Oxnard: Yeah. So that stands for Investigating Hereditary Risk of T790M, INHERIT. I forget where we coined that. Let me give you a case example. A patient presents in his 40s. I remember this man. He has an EGFR mutation in his tumor. He has a T790M in his tumor as well. He had routine tumor testing that lung cancer patients were getting. And he says, “Oh, also, my brother had lung cancer in his 40s just a couple of years ago. He was a smoker, though. He never had genetic testing.” And so this patient we test on the study, we hypothesized that when patients present with T790M at diagnosis, that it would be a representation of an underlying germline EGFR mutation. Our hypothesis was that about 50% of the time T790M at diagnosis would be explained by a germline behind the doll. And that that could then empower families like this one to understand the kinds of lung cancer they're getting in their family, the kinds of treatment they should be getting, and the kinds of testing they should be getting to look for lung cancer at risk early on.   It really saddens me that in a family that doesn't know about this condition, the brother would never get testing and would never think that I might be getting or might never get testing, might not be disposed to getting testing, and might not realize there's a therapy available to target that EGFR mutation if he died young without even much treatment. But this individual, we tested his lung cancer, we found him a therapy, we put him on a pill therapy that could last a very long time. And so we set up a program with a consortium alchemy, the Addario Lung Cancer Medical Institute, where we enrolled at three sites, both at Dana-Farber in Boston, Vanderbilt, and Ohio State, with some motivated investigators there that we appreciate their collaboration.  But also, again, this is now more than 10 years ago, set up shop where people could enroll remotely, that if you found a T790M in your tumor, for whatever reason, you could reach out to the team at Dana-Farber centrally and get consented online and even get counseling. And this is one of the early ways of getting this remote participation. And you can imagine, over the course of the study, we quickly ran out of individuals at any given site, but that remote enrollment accelerated and really allowed us to get to the large population of remote study. Dr. Judy Garber: We were lucky that things were happening. The things you don’t expect. So EGFR testing was not routine at that time. And the EGFR testing that had developed in Dana-Farber and NGH became standard of care at Dana-Farber so we were finding those patients, and then grew outside as well, at institutions and testing labs. And these people would somehow emerge so we were very lucky that we were able to set up remote testing. We could send and get a saliva sample and be able to test. Or these were people who got tested through their own doctors, found out they had this mutation and then went online and said, “Who knows anything about this?”  I would say that we and our amazing genetic counselors who spoke to all these patients, took their detailed family histories, got their other information, and were able then to really build out these cohorts so we can understand them. And to look at, for example, Geoff’s question, it was really his question, “Why did we have such clusters in certain parts of the country? Could it be that there were the so-called founder mutations that somebody had this mutation and they spread their genes around so that they’re around the country and that turned out to

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 received a 75% dose. Those patients, a large amount of them consisted of patient with colorectal cancer, about 60%. And also breast cancer patients consist for a large amount of this group, it was about 20%. And then the rest were esophageal and gastric cancer mostly, and there was a group consisting of rare tumors as well like anal cancer.  The comparisons showed that toxicity in the variant carriers was higher in the wild-type patients that received 100% dose. So despite those reductions, toxicity was higher in the carriers. But when we compared the variant carriers with historical controls, we saw that, especially for *2A, there was a large reduction of toxicity to a lesser amount. This was also the case for the 2846 variant carrier. But to a much lesser extent, there was a reduction in the 1236 carriers which worried us and this was the basis for a Clinical Pharmacogenetics Implementation Consortium (CPIC) to give a recommendation for starting for all these variant carriers with a 50% dose when treatment with fluoropyrimidine was indicated. Davide Soldato: Thank you very much for the clarification. So basically, you started from one previous prospective study that was composed of a mix of different cancer types. And then in the study that you now published in the Journal of Clinical Oncology, you also added an additional part of patients who were carriers of this variants. I imagine that there was some variability between patients who were carrying the variants and those were not carrying a variant. So I wanted to understand a little bit, did you perform a matched analysis or did you try to be sure that there was not any confounding factors that could impact the results? Dr. Jonathan Knikman: Yes, we performed an exploratory retrospective matched-pair analysis and we used a matched-pair analysis to select patients which are comparable between the DPYD variant carriers and the DPYD wild-type patients to ensure that on the most important factors, they were comparable and outcome was also comparable. In this matched-pair analysis, we compared progression-free survival and overall survival between DPYD variant carriers treated with the reduced dose and DPYD wild-type patients treated with the full dose. We matched these patients on five matching variables which were primary tumor type, stage of cancer, age within a range of plus or minus 10 years, sex, and treatment regimen to ensure the these patients as comparable as possible.   Davide Soldato: And so now, moving on a little bit to the results, what were the results in brief regarding progression-free survival and overall survival for patients who were harboring a variant in the DPYD gene and those who were wild-type for this gene? Dr. Annemieke Cats:The results of our study showed that there was no significant difference in progression-free survival and overall survival between the DPYD variant carriers pooled as one group, treated with the reduced dose, compared to wild-type patients treated with the full dose. This suggests that DPYD-guided dosing can be performed safely without compromising treatment effectiveness. However, when we take a closer look at the individual variants, our study showed that progression-free survival and overall survival were not negatively impacted by DPYD-guided dosing in the 2846 and the DPYD *2A variant groups. However, in the group of 1236 variant carriers, we did find a significant difference in progression-free survival with a hazard ratio of 1.43, indicating that progression-free survival  was shorter compared to the matched wild-type patients treated with the full dose. However, no difference was found in overall survival.   So based on results on this study, we can conclude that DPYD-guided dosing can be used while treating patients with fluoropyrimidines without compromising effectiveness and improving safety. However, when patients do not experience toxicity or experience minimal toxicity, it is important to escalate the dose guided by toxicity to ensure maximum exposure to the treatment.  Davide Soldato: Thank you very much. That was a very comprehensive overview of the results. I was really wondering regarding the variants in the 1236. So the one that you said was associated with a shorter progression-free survival. At the very beginning, Dr. Cats very well explained that in the first prospective trial that was done, among these patients, toxicity was still higher or they experienced more severe toxicities, even with a 25% dose reduction compared to what was planned. So I was wondering if you could speculate a little bit. Do you think that this reduction in the progression-free survival might potentially be associated with these higher rates of severe adverse events, and that maybe this has created a little bit of a gap in the adherence to chemotherapy? Dr. Annemieke Cats: We looked into the mean dose that the 1236 variant carriers received, and this was about 75% of the dosage. So the dosage was what the pr

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 think it has such broad-based impact across all of our patient populations.   So, I think that kind of definitely transitions into this. What are the potential negative impacts in this process of patients? And I would say not only patients with cancer, but what do we know also in patients with other disease types that are facing this prior authorization issue as well? Dr. Michael Anne Kyle: What we were curious about is there's a sense that prior auth is increasing, the trends show it's increasing. And we were wondering, does that matter for patient care? And we could think about the benefits of prior authorization being like double-checking that you're getting the right treatment. But the negatives are that you can be delayed in getting treatment, and that can either be because you're going through the initial process or there can be some error or denial or dispute in a prior auth process that delays your access. And the clinical implications of that would vary by drug, how that would affect your treatment. In this case, in this paper, we're talking about drugs, but for any treatment, the implications would depend on what the treatment is and what the patient's condition is. But I really want to draw attention to this other piece, which is that it's stressful not to have your cancer medicine. And so even if you ultimately end up getting it, the time that you're on the phone trying to figure it out is time taking you away from other things. It's stressful. And very often, patients with cancer are taking multiple drugs and have complex health issues. So, they may be dealing with this for multiple parts of their care. And that can add up. Shannon Westin: Perfect. Thank you. So, I guess next is to talk about how you address this. Let's talk a little bit about the overall objectives of the study that you just published and maybe briefly kind of go through the design for our listeners. Dr. Michael Anne Kyle: What we were interested in doing, like I said, was trying to figure out what happens with prior authorization at the point of care. And our study looks at 11 oral anticancer drugs in Medicare Part D. And the reason for that is because data available to look at prior auth is fairly limited. And Medicare Part D for the outpatient formularies does have indicators for whether a drug has a prior auth. So, we were able to use that. The next piece is we're not inside the office understanding why these treatment decisions were made. So, what we decided to do was say, “Okay, let's look at patients who've been consistently taking this drug.” And we said, “Okay, let's say you've had to have at least three fills in the past four months.” And we sort of take that as an indicator that you're able to access this drug and it seems to be working for you. And then what we do is we look at who are patients in plans, same drug, same plan, where the plan introduced a new prior auth on this drug they're taking, as compared with patients in plans who did not have a change in their prior auth policy. And we said, “Okay, there's this new prior authorization introduced, does that affect whether you get that next fill or how long it takes to get it?” Dr. Nancy Keating: I want to emphasize Michael Anne's point about these are patients who are already successfully filling and regularly taking their drugs. And unfortunately, due to data limitations and the inability to see prescriptions that aren't filled, we would love to look at the same question with people that are starting on a new drug but weren't able to do so but would imagine that you might even see bigger impacts in those patients. We both recognize from a health policy standpoint that there could be benefits of prior authorization policies. But it's also very unlikely to think that for a patient that's regularly filling an anticancer drug over a long period of time, that there's a reason that that patient should not be on that drug. And so, this is an area where we think that there may be really limited benefits of prior authorization, but potential harms.  Shannon Westin: Yeah, it makes sense. And of course, it would be. There's always the ideal way to set research up, and then a practical way. So, I was struck by what you chose. I thought it was really very practical and rational and made a lot of sense. And certainly, there are inferences that we can make based on what you found. So, let's talk about that. Let's talk about your primary findings. What did you see as the impact of a new prior authorization policy on patient care? Dr. Michael Anne Kyle: We found that for the patients who had a new prior auth policy introduced in their plan, compared to patients who didn't have a prior auth change, their odds of discontinuation within the next 120 days increased by about 7.1 times higher odds of discontinuation. And then for delays, we found that people were delayed an average of 9.7 days from when we last saw that they were expected to run out of thei

Dr. Shannon Westin and her guest, Dr. Nanda Horeweg and Dr. Carien Creutzberg, discuss the paper "Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer" recently published in the JCO. TRANSCRIPT  The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. I'm your host Shannon Westin, Social Media Editor for the JCO and GYN Oncologist by trade. And I'm so excited about today's topic because it is a GYN Oncologist dream. Before I start, please note that none of the authors have any conflict of interest. We are going to be discussing molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early-stage endometrioid endometrial cancer. And this was published in the JCO on September 20th, 2023. And we're going to be speaking to two of the lead authors. First is Nanda Horeweg. She's a senior researcher in the Department of Radiation Oncology at the Leiden University Medical Center in the Netherlands. Welcome. Nanda Horeweg: Thank you. Happy to be here. Shannon Westin: And Dr. Carien Creutzberg. She's professor at the Department of Radiation Oncology at the Leiden Medical Center as well. Carien Creutzberg: Thank you. Shannon Westin: So, let's get into it. And I want to really level set because we have a mixed audience here. So, why don't you start by speaking about the incidents and mortality of endometrial cancer? Nanda Horeweg: Yes, of course. Endometrial cancer is the sixth most common cancer in women with around 400,000 new diagnoses made globally each year. And a woman's lifetime risk to get endometrial cancer is around 3%, and the median age, the diagnosis is 61 years. Most of the women who are diagnosed with endometrial cancer are diagnosed at an early stage, around two thirds, and they have an excellent prognosis. Actually, the five-year survival rates are around 92%. For stage 2 disease, this is actually already going down a bit to 74%. Therefore, stage 3 disease is only 48%. Women that are diagnosed with advanced disease have only a five-year survival, 15%. Shannon Westin: So, given that we know the majority of endometrial cancers are diagnosed at this early stage, prior to your evaluation, what was known about the optimal way to treat this early-stage patient population? Carien Creutzberg: Well, of course, the PORTEC trials were done … were started PORTEC-1 in the 19th of the last century, and PORTEC-2 in 2002. So, at that time, there were still many, many women treated adjuvantly with external beam radiation therapy. And we just developed risk factors to decide on their risk and the incidents for radiotherapy. And in PORTEC-2, because in PORTEC-1 we had seen that most of the recurrences in these early stage cancers were in the vaginal fold, we compared local vaginal brachytherapy only three sessions within full course of pelvic radiotherapy and showed that it had similar pelvic control and survival. Of course, this study, which Nanda conducted, was a long-term analysis with many new factors known from the translational research in the tissue samples of these patients who participate in PORTEC-1 and 2. And in the meantime, we've developed much more knowledge on the molecular factors and other important factors such as LVSI, which tell us much more about the individual prognosis to patients. So, the treatment has been developing greatly in the past 20 years. Shannon Westin: Yeah, and I think this is a great case of less is more, right? We were doing so much for so many people that really didn't need it. And so, really tailoring who needs less treatment, who doesn't need any treatment, and then also, conversely, who may need more treatment that would be missed by the traditional risk factors that you're speaking of. So, I think that brings us right into my next question, which is just bringing the audience up to date on the cancer genome atlas and how that's changed the way we classify endometrial cancer. Nanda Horeweg: Yes, I think the molecular classification of the TCGA has shaped the way we think about endometrial cancer, and has huge impact on decisions on adjuvant treatments in the years to come. The TCGA performed an extensive characterization of the endometrial cancers and found that in fact, this disease exists of four different groups. And the first of the groups I'd like to discuss is the ultra-mutated group, which is characterized by POLE mutations. And this group is shown to have an excellent prognosis in many independent studies. A second group that also has a high mutational burden is characterized by microsatellite instability, and mismatch repair deficiency and has shown to have an intermediate prognosis. Then there's another group that has a low mutational burden with high copy number alterations and frequent TP53 mutations, and these have a poor prognosis. And then lastly, there's a group that does not have any of the classifying features and is often called non-specific molecular profile or TP53 wild type. And this group also has an intermediate prognosis. And then finally, there's a small group of cancers that has more than one of these classifying features, the so-called multiple classifiers. And the WHO 2020 has developed an algorithm which can be used to classify them into the four groups. And that's first on the POLE status. And for the POLE wild type tumors, they are assigned according to mismatch repair deficiency status. And for those that are mismatch repair proficient than POLE wild type, they are classified according to the TP53 status into NSMP or p53 abnormal. Carien Creutzberg: Yeah, that is because of in the ultra-mutated and hyper mutated groups, many of the other mutations are secondary mutations in the context of the ultra-mutated stage, and they behave like the first molecular group. Shannon Westin: Yeah. So, that POLE mutation is going to trump anything else, and it's so important. And I will just say as a sidebar, it's been challenging with the price of next gen sequencing sometimes to get that for everyone. So, sometimes for us when we see a p53 mutation, we actually go back and do the full next gen sequencing to make sure that we're not going to act on that core prognostic feature when it really is in the setting of that more simplistic or that more positive prognostic place. So, this is great, we already kind of highlighted a little bit PORTEC-1 and 2, but if you don't mind, I would love to get the audience a little bit more information just maybe about the populations that were included as we were figuring out how aggressive to be with radiation just to remind people of that, or to teach them that if they haven't gotten a chance to look at those studies. Carien Creutzberg: Yeah, that's important to know because PORTEC-1 was still in the era that we also treated intermediate risk stage 1 endometrial cancer patients. So, deep invasion with grade 1 and 2 or superficial invasion with grade 2 and 3. That's what we defined at that point. Then we compared external beam radiation or no further treatment, showing no survival difference, but a higher risk of recurrence with higher risk being older age over 60, grade 3 for deep myometrial invasion. And we kept those high intermediate risk factors as also similarly found by GOG-99 at the time to do PORTEC-2. So, at the time, about 50% of patients did not have an indication for adjuvant therapy anymore, and with a high intermediate risk population for PORTEC-2, we compare external beam or vaginal brachytherapy and found the benefit of vaginal brachytherapy. A simple outpatient treatment, very short with almost no side effects ensuring local control. And nowadays, using the molecular classification of PORTEC-4a, we've compared achieving treatment with or without use of the molecular factors to designated treatment. So, the standard arm is vaginal brachytherapy and investigational arm is first, a molecular risk profile. And then we give no radiotherapy for those with a favorable profile, then a brachytherapy for the intermediate ones, and for the small group is either extensive LVSI or TP53 mutation or L1 chem overexpression external beam. And we hope to show that less overtreatment and less undertreatment will benefit these patients. Shannon Westin: Yeah, I'm very much looking forward to the results of PORTEC-4a. But let's circle back and talk a little bit about your amazing work here. So, how did you leverage those patient populations from PORTEC-1 and 2 for the current study? Nanda Horeweg: Yes. Well, the PORTEC-1 and 2 study provided a unique opportunity to look into differential treatment effects for radiotherapy. And that is because these are randomized trials, so the groups are comparable, and we have long-term follow-up data that's of very high-quality. In addition, as Carien said earlier, she had the vision already back in the nineties to directly ask the patients permission for the collection of the tissue. So, we have a broader complete biobank for both of these trials, which is quite unique. And our colleagues, Professor Smit and also Charlene Goseff from the pathology department, they have done extensive work on molecular classification, and have molecularly characterized all these cases. So, this allowed us to include 880 patients in this study, which is the largest so far. And besides like the very good starting point that we have of PORTEC-1 and 2 is that we also chose a design that was optimized to conduct like real causes, the causal effects of the molecular class on radiotherapy response. So, we tried to preserve this randomization effect, the exchangeability of the groups as much by working with the intention to treat population and not excluding any patients, except for when t

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. While reduction all-cause mortality and mortality from other causes were observed across a wide range of cancer, including breast, endometrial, and hematopoietic and prostate. The study confirms previous findings by showing an inverse relationship between higher level of exercise and lower risk of all-cause mortality, and provides novel insights on the topic by reporting that those response association, data on other causes of death, and edited analysis by cancer site diagnosis. All limitation of the study is related to the generalizability of the findings. The study included only patients that were alive at a median of 4.5 years after cancer diagnosis, which might have applied to selection of patients with good prognosis, and thus, reducing the number of cancer mortality events. Additionally, these patients were willing to complete an additional questionnaire in the context of the trial, which might be related to a higher motivation in engaging in healthy lifestyle behaviors. The study did not replicate previous findings observing a reduction in cancer mortality for breast, colon, and prostate cancer, among those reporting higher exercise. Although this might be related to the inclusion of long-term survivors in the study. In the second article titled Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial, Dr. Pfeiler and colleagues investigated the impact of BMI on side effects, adherence to treatment, and efficacy of palbociclib in the PALLAS trial. Just as a reminder, PALLAS is a randomized clinical trial that investigated whether the addition of two years of palbociclib to standard endocrine therapy in patients treated for stage two, three hormone receptor-positive HER2-negative breast cancer could improve invasive disease-free survival. Previous report of the trial showed that palbociclib did not improve invasive disease-free survival compared to endocrine therapy alone. More than 5,500 patients were included in this analysis, and among them, more than two third at a BMI equal or over 25 diagnoses with 32% being overweight and 30% obese. Overweight and obese patients were more frequently older and coming from North America rather than from Europe. In line with the age difference, normal weight patients were treated more frequently with Tamoxifen alone or in combination with ovarian function suppression or with aromatase inhibitors in combination with ovarian function suppression. No differences in tumor characteristics was observed according to BMI. However, there were some minor differences regarding the type of surgery and administration of chemotherapy. The authors observed that side effects of palbociclib were significantly different according to BMI and in particular, they observed a lower incidence of a hematological toxicity among overweight and obese patients. Conversely, higher rates of arthralgia, nausea and diarrhea were observed among overweight and obese patients, both in the palbociclib and in endocrine therapy alone. In particular, regarding hematological toxicity, the authors observed that overweight and obese patients experienced a significantly lower incidence of overall neutropenia, grade 3 and grade 4 episodes of neutropenia. For example, looking at grade 3 neutropenia, the incidence was equal 44% in the obese population versus 64% in the normal weight cohort. Differences in incidence of neutropenia remains significant even when adjusting for confounding factors, including previous administration of chemotherapy, age, ECOG performance status, and race ethnicity. Furthermore, a lower incidence of overall thrombocytopenia was observed in the overweight and obese cohort. The lower incidence of hematological toxicity led to significant differences in those reduction, early discontinuation, and relative dose intensity for palbociclib. At six months, only 29% of obese patients reduced to those of palbociclib compared to 50% in the normal weight cohort. Similarly, only 20% of obese patients permanently stopped palbociclib compared to 35% in a normal weight group. Finally, the risk of palbociclib early discontinuation was 25% lower for each additional 10 units of BMI, even when accounting for additional potential co-founders. As a consequence of a lower dose reduction and lower rates of early discontinuation, the relative dose intensity for palbociclib was significantly higher among overweight and obese patients compared to normal weight ones. Efficacy of palbociclib was not different according to BMI, neither in the palbociclib bar, nor when assessing patients in both arms. However, these analyses are performed with a relatively short, medium follow-up time, and a low number of events. So, in conclusion, this report from the PALLAS trial shows that higher BMI was associated with a more favorable safety profile, especially regarding hematological toxicity, and a lower risk of treatment dis

In this "Podcast Takeover," Dr. Lidia Schapira guest hosts to discuss with Dr. Shannon Westin her own JCO paper, which reports on the DUO-E Trial. Dr. Ramez Eskander also joins in this lively discussion. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor of the JCO and Gynecologic Oncologist by trade. And actually, I'm super excited today because we are going to have a podcast takeover because we are discussing my own work, which was simultaneously presented at the European Society of Medical Oncology 2023 Congress and published in the Journal of Clinical Oncology on October 21st, 2023. And this was the DUO-E trial, “Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer.” Because we’re discussing this work and we wanted you to have an unbiased podcast discussion, Dr. Lidia Schapira, who is a Professor of Medical Oncology at Stanford University and an Associate Editor of JCO and the Art of Oncology podcast host, is going to take over this podcast and really just pepper me with questions about this exciting work.  Welcome, Dr. Schapira.  Dr. Lidia Schapira: Thank you so much. It's such a pleasure to be with you. Dr. Shannon Westin: And before I turn over the reins, I also want to introduce one of my colleagues, who’s going to be providing quite a bit of insight on this topic, Dr. Ramez Eskander, who is Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Diego. And you will know he’s the principal investigator of the GY-018 study, which established pembrolizumab and chemotherapy as the new standard of care in endometrial cancer. Welcome, Ramez.  Dr. Ramez Eskander: Thank you. Thank you, Dr. Westin. It's a pleasure to be here. And congratulations again to you and your study team for this exceptional work.  Dr. Shannon Westin: Thank you. And congratulations to you.  Dr. Schapira, thank you for being here and please do take it away. Dr. Lidia Schapira: So let's start by having you tell us a little bit about the standard of care for women with endometrial cancer and advanced endometrial cancer prior to this study. Ramez, I'm going to direct this question to you first. Dr. Ramez Eskander: For many years, actually since about 2012, carboplatin and paclitaxel, which ironically is a chemotherapy backbone really across all of our gynecologic tumors, emerged as the preferred doublet chemotherapy regimen for the management of advanced-stage metastatic or recurrent endometrial cancer. It evolved through a series of different clinical trials, in fact taking us from whole abdominal radiation, systemic chemotherapy, comparing single agents to doublets and then triplet regimen of TAP to carboplatin and paclitaxel, which ultimately, then, following the presentation of GOG Protocol 209 and its publication, as the chemotherapy backbone, being carboplatin and paclitaxel. And it’s been that way for many, many years. Dr. Lidia Schapira: And how effective is the regimen? Dr. Ramez Eskander: The response rates to carboplatin and paclitaxel are actually quite reasonable in the patients who have advanced-stage disease, particularly if they haven't had prior systemic chemotherapy. Response rates in the 50% to 60% range. The issue is that the responses tend to be limited and disease recurrence is an expectation in these patients who have advanced-stage disease. And so that really highlighted the importance of trying to continue to advance therapeutic opportunities in these patients to improve long-term outcomes.  Dr. Lidia Schapira: As we think about improved long-term outcomes, we're thinking about a better treatment and also a kinder treatment, perhaps one that is also less toxic. Can you talk a little bit about the population of women with endometrial cancer? Are these older women? Do they have comorbidities?  Dr. Ramez Eskander: What we’re seeing is, interestingly, there has been an evolution a bit in this space. Historically, we used to think about endometrial cancer as—the phrases we used to use are type I and type II. These type I tumors, we would say, are estrogen-driven malignancies; they tend to be seen in overweight or obese patients. And we would identify them in a theoretically younger patient population. And then we had these type II, or what we termed estrogen-independent malignancies, that we would see in an older patient population. Of course, with obesity came metabolic syndrome and other cardiovascular comorbidities, etc. But really, that narrative has evolved dramatically, and that’s really something that will be highlighted in, I think, our discussion of these studies today, where the nomenclature that we used to historically use has evolved because of our understanding of the molecular characterization of this disease. So we’ve really gone away from that, and now we understand that we’re seeing all of these different heterogeneous endometrial cancer types amongst patients of different ages, different comorbidities, different races and ethnicities. And so it’s created a more complex picture for us. But certainly, there are comorbidities that these patients face, and that’s important as we look to identify treatments strategies that are both effective and tolerable. Dr. Lidia Schapira: My final question before we jump into this very exciting study is about the Cancer Genome Atlas work. Can you tell us how that’s changed the thinking and the design of the studies? Dr. Ramez Eskander: It was a seminal publication, really, back in 2012/2013 looking at an assessment of endometrial cancers to try and determine whether or not all of these "endometrial cancers" that we used to enroll on a single study are similar or divergent. And it’s important because the study I referenced that really established the standard of care, GOG Protocol 209, as carboplatin and paclitaxel, there was no real consideration of molecular characterization at all. We enrolled all patients onto this study without thinking about these variables, of course, because it was designed, conducted, and completed before the TCGA data emerged. But what we learned from the TCGA is there appeared to be four distinct molecular subgroups. There were the POLE-mutated patient population. There was the mismatch repair deficient or MSI-high endometrial cancer population. There was the copy number-high or what we say are the p53-mutated. And then the last cohort was called the NSMP (no specific molecular profile). But now, that’s even evolved; some people term it TP53 wild type. That’s a bit of even a heterogeneous cohort amongst itself. So we’re going to take these subsets, independent of POLE and an MSI-high, and we’re going to look at TP53 or copy number-high, and that will probably be divvied out further, and the NSMP, and that will probably be subdivided. But really, it gave us these four components, which has then evolved. Many of you may have heard of the ProMisE algorithm or ProMisE Plus, which looked to take the data from TCGA so that we can start to really look at it in clinical practice. So it’s really revolutionized how we think about these patients, how we think about the disease, and how we design trials.    Dr. Shannon Westin: And I just want to add to that because I think that it's so important, what Ramez said about the way we were developing trials, the way we were designing trials. We knew that these classifiers—we were learning these classifiers are prognostic. Now what we’re really trying to hone in on is how predictive they are. And certainly, one of the major classifiers that we’re going to talking about today is mismatch repair status, and that is most definitely predictive of response to therapies. But we’re still learning about the other classifiers and how we might adjust the way we treat people, even deescalating care for certain patients. That is still being proven in clinical trials, although we suspect that it’s going to be borne out as other clinical trials report. Dr. Lidia Schapira: It's a perfect segue to this current trial. Tell us a little bit about the objectives and the design of DUO-E. Dr. Shannon Westin: As Ramez said, the standard of care was chemotherapy. And so we wanted to see if there was a way to improve outcomes for these women with advanced and recurrent endometrial cancer in a really clinically relevant, meaningful fashion for patients. And so we knew that this TCGA classifier, the mismatch repair, was so important, and we thought that the addition of immunotherapy to chemotherapy would most certainly work in that population but could even work in the entire population because, generally, endometrial cancer seems to be a little bit more responsive to immunotherapy and to activation of the immune system than, say, some of our other gynecologic malignancies. And so we set out to see what the addition of durvalumab, which is a PDL-1 inhibitor, would add to chemotherapy. And this was two chemo as well as followed by durvalumab maintenance.  But even further, we had some really kind of exciting science data from our lab that said that if we combined a PARP inhibitor with immunotherapy that we could accentuate on the response to therapy and we could get more benefit. And there's kind of a lot behind that, but essentially, what we thought was that the damage that's caused by the PARP inhibitors would create an activation of different immuno-pathways, like STING pathway and activating cytokine release, and that we would get this synergistic activity. So one of the other objectives was to see if the addition of the olaparib, the PARP inhibitor, to durvalumab in that maintenance setting could even further impro

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 between risk and benefit, especially in patients that are very pretreated, searching for these kind of sweet spots between the toxicity and the efficacy. So I just wanted to put in context a little bit the data that you reported in the manuscript. Dr. Jacob Sands: Yeah, that's right. So, like phase I’s go, we started with a low dose at 0.27 milligrams per kilogram, and dose escalations occurred up to 10 milligrams per kilogram. The 10 milligram per kilogram dose did have toxicities that really made it not considered to be tolerable, and that mostly being mucositis and skin. And so it was then back down to 8 milligrams per kilogram. And then there was a dose expansion at 4, 6, and 8 milligrams per kilogram. The 4 and 6 milligram per kilogram doses had 50 patients enrolled within those cohorts and 80 patients within the 8 milligram per kilogram cohort to then get much more data, of course, for efficacy and tolerability within those levels. Ultimately, each of them really demonstrated some efficacy as well as general tolerability. The 6 milligram per kilogram dose was really the one selected overall for further testing and future trials based upon the data out of this one that we're going to discuss further. Davide Soldato: What were the main side effects that you observed in the trial? And particularly, do you think that there is some kind of special toxicity that should be looked at when using this novel type of ADC? Dr. Jacob Sands: Certainly there are some novel toxicities to really pay attention to. And maybe I'll just point out before diving into the toxicities, that this is in many ways chemotherapy. The antibody drug conjugates, as listeners probably know, are an antibody that has a linker bound to chemotherapy, what's called the payload. And in this case, it's a topoisomerase I inhibitor with the antibody, the TROP2. So the cells on the surface, when there's TROP2 expression, the drug binds to that, gets pulled into the cell and releases that chemotherapy intracellular, but it is still chemotherapy. And so some of the toxicities are things that we commonly see with chemotherapy drugs. Although, broadly speaking, I would say we're able to deliver higher doses of that chemo to the cells in this kind of targeted dosing of chemotherapy to give the chemo intracellular.   Now, that being said, some of the toxicities that we see from this drug in particular that are a bit different is the stomatitis, mucositis. That is something that has occurred. Now, I've found that if it's really severe, then with a dose reduction that has really substantially improved any toxicities with future dosing. And at a 6 milligram per kilogram dose, a dose reduction to 4 milligram per kilogram is still within a dose range where we saw plenty of efficacy within the trial that we're discussing. That being said, if one can help patients tolerate it better, if it's more mild symptoms, if it's not severe, then that's better in maintaining that dose. And interesting things like ice chips at the time of infusion, so cold within the mouth, kind of like the cold caps to try to reduce alopecia at the time of infusion of the chemo may help some steroid rinses also can be helpful. But really these are things to help prevent stomatitis from being severe. It's harder when that occurs, then the treatment for improving it is a bit different.   We do know, though, that that does improve with time. So even when it was severe with that infusion, it does improve as patients get further out from those doses. Of course, another one is dry eyes or irritation within the eyes. And if that is severe, then or even mild actually, I'd say when there's any known toxicity like this is to involve ophthalmology. Now, within this trial, ophthalmology was involved and patients had to get a baseline eye exam and they would get checked at different time points throughout the course of the trial. And so they were being monitored. I did not have anyone who needed to stop the drug because of this. The patient I had with the longest standing response to therapy did have some dry eye. It was not bothering him so much. And he had this real aversion to using eyedrops. It was very hard for him to make himself use these. But when I told him, “Look, if this gets worse, you might have to come off the trial, that it might not be our decision just by the way the trial describes it, if this gets worse.” And so for him, the fear of having to come off the drug was really the thing that helped him to then start using his eyedrops, which really helped to control that a bit more. And so that is something to monitor for.  But the biggest thing really is interstitial lung disease. This is something that is a complex topic, I think because it's something that we need to be very aware of and monitor for. At the same time, a diagnosis of interstitial lung disease can be challenging. There really were not cases where we had pathologic confirmation of this diagnosis. These are clin

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 transportation and seeking care, accommodations for people who need to receive radiation therapy multiple days in a row at a different healthcare facility than where they live, childcare costs. These things really start to add up in addition to the medical costs associated with cancer treatment. Dr. Shannon Westin: I really was intrigued by the intervention here that you all are studying around this Cancer Patient Assistance Fund. Can you tell me a little bit more about exactly what that was or is? Dr. Caitlin Biddell: Yeah, absolutely. So this is a program at the North Carolina Basnight Cancer Hospital, located within the Lineberger Comprehensive Cancer Center, and it started back in 2013, actually, and has really grown in size. But the main goal of this program is to ensure that patients do not face the nonmedical financial barriers to care that Dr. Wheeler was just talking about. So thinking about giving patients gas cards so that they are able to drive to and from treatment. Lineberger has a catchment area of the entire state, so many people are coming a long distance to come for cancer treatment. They also provide things like lodging and accommodations, as Stephanie mentioned, and then even paying patients’ utility bills, things to keep them housed with electricity, the lights on, while they're undergoing cancer treatment. So just last year, in 2022, they distributed almost $350,000 to over 700 patients, and most of this is funded by philanthropic grants to ensure that patients can access the care they need. And it is a program that's really targeted to patients with low incomes. So they target patients with household incomes less than 250% of the federal poverty level. Dr. Shannon Westin: And how does a patient get connected to the fund? How do they find it and get hooked up?  Dr. Caitlin Biddell: Yeah, there's a couple different ways. So one path is through the outpatient social work team. So they often perform distress screening for new cancer patients. So they use the Distress Thermometer, which was developed by the National Comprehensive Cancer Network. And it measures a variety of different factors that may be contributing to distress, but that does include financial stress, job stress, and the expense of daily living stress. And so, when a patient scores a certain amount on that thermometer, a social worker will meet with them for a full assessment. And then part of the referral pathway from that assessment includes the Cancer Patient Assistance Fund. Patients who are in inpatient will often be screened with the Social Determinants of Health Module, which is housed in the electronic health record. And so that can also generate referrals for assistance. And then beyond the kind of standard pathways, there's also many other ways that a patient may express concerns to a nurse, a care coordinator, an oncologist, and then that provider can reach out directly to the Cancer Patient Assistance Fund. Dr. Shannon Westin: Your objective was to basically try to formally assess the impact of this fund on missed radiation or chemotherapy appointments. And so what was kind of your rationale for choosing this endpoint? And kind of take us through the design. Dr. Caitlin Biddell: Yeah, absolutely. So the idea for this study actually came about from the program coordinator of the Cancer Patient Assistance Fund several years back. We were just having a conversation about the program. I was commenting how important I thought it was, how interesting it was. And she was saying, “You know, I know anecdotally that this program makes a difference, but we've never really known how to quantify that.” And that's becoming increasingly important as they apply for philanthropic grants and really need to show that their program is having an impact. So that's what originally started our plan for evaluating the program.  And then, in thinking about endpoints, of course we imagined this program could have an impact on a range of different endpoints. So missed appointments is quite practicable. We also imagine it could influence patient health-related quality of life, patient symptoms associated with their cancer treatment, even potentially other long-term outcomes like mortality. But for the purposes of this evaluation, we needed to identify an endpoint that we believed could be measured, the association could be measured, in the data we had. And so we had electronic health record data. Missed appointments is something that is routinely captured in the electronic health record data because it's an endpoint that matters financially to health systems. So they are regularly tracking missed or no-show appointments. And it's also an outcome that matters financially to the health system, so they want to reduce this.  So we thought if we measure the impact of this program on missed appointments, there's potentially an opportunity to kind of align financial incentives so that if we show that the program has an i

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.  So then the treatments were divided into chemotherapy alone, chemotherapy with immunotherapy, and then immunotherapy with and without targeted therapy. So there were three types of treatment, which is sort of an important update because Al and I had published something in 2015 on chemotherapy and the outcome of what was called palliative chemotherapy at that time. And this was sort of a very refreshing–well, not—I shouldn’t say refreshing, but important update to our study, which had said that there are questionable outcomes of palliating someone with palliative chemotherapy so far along in the disease. And then the question became, well, is it different? Is it different with immunotherapies? Is it different with targeted therapies? And that's why I was delighted to see this paper, because it answered…  Dr. Alfred Neugut: I'd have to say there are probably differing views on this, but Holly and I are probably relatively nihilistic in terms of thinking that chemotherapy in late stages or near terminal patients is probably not all that helpful. Third-line, fourth-line therapy probably not going to get you very far. And maybe it's best to be thinking more about hospice care and supportive care. And now we have terrific palliative care programs at most or all cancer centers, and we really should be taking advantage of this. I think a real benchmark study was the Temel study from 2010 or 2011, which really—for those of your listeners who haven't read it or seen it, they should really take a look at it. It really changes the playing field and makes you realize that treatment is not really always the best thing for patients, and there are other options. And we go to hospice care or palliative care really, I think, too late in the game a lot of the time, and we really should be thinking otherwise.  Dr. Holly Prigerson: That is one of the outcomes that we had looked at before. So we had looked at palliative chemo, and not only does it not palliate, and we didn't show that it significantly enhanced survival; we also showed that it resulted in a lower likelihood of earlier enrollment in hospice, a higher likelihood of not dying where your family members thought you would have wanted to die, a higher likelihood of dying in the ICU or getting some kind of aggressive care. So it's not only what the chemo does or doesn't do in terms of treatment or survival or quality of life; it also seems to exacerbate and put someone at risk for very burdensome interventions that having avoided it might have enabled patients to avoid getting very burdensome care that's largely futile. But as Al said, we are probably more the nihilistic type.  Dr. Shannon Westin: Well, I think you bring up a couple of good points because you've got objective data, and these studies that you're mentioning are just some of them that show that early hospice care and early enrollment and even just a palliative care program or a supportive care program or whatever terminology we want to use, people do better, right? They live longer actually from that piece rather than necessarily the more “aggressive measures” of chemotherapy and things. Dr. Holly Prigerson: When there was an extra analysis of the Temel data, I believe they had shown that some of the survival advantage was explained by avoiding toxic chemo. So that's directly relevant. Dr. Alfred Neugut: There is an on the other hand, as always, which is that patients and families often don't want to do that. I mean, they realize that doing that is giving up, so they're reluctant to take hospice care or palliative care as an alternative to another cycle of chemo or another type of chemo. And as you say, you never know; maybe the next one is going to be the winner and there'll be a miracle or there'll be at least some substantial benefit. And then there's always experimental therapy, and now immunotherapy, which is the topic of this article, is the new winner on the block. And it has bright lights around it, and everybody has great hope for it. And it’s the new kid on the block, and everyone hopes that that’s going to be the big savior.  Dr. Shannon Westin: Right, and I think everyone knows of a story of somebody that was “on death’s door” and got immunotherapy or the newest targeted therapy or the newest ADC, so that definitely colors it. And that also colors, I think, the physicians that are offering it, right? Because, yes, I've definitely heard this, and I'm sure you guys have too: nobody should die with such and such cancer without receiving immunotherapy once or without receiving such and such targeted therapy. I hear people say this all the time, and I don't necessarily disagree. It's more that when are we giving it, right? So we should be thoughtful about when we're placing those things. But you're right; there's so many factors that go into these decisions, and it's not cut and dry around what the patients and the family members and the physicians are going to decide. Dr. Holly Prigerson: An

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 unique psychosocial issues that are driven by the extreme disruptions that cancer has on major life milestones. Like Jenny said, they may have young children at home, they may have a new spouse at home, still be trying to advance at work, you name it. So this period of young adulthood is really characterized by constant change. And it's possible that these young adults are being driven to stay present in their lives for really as long as possible to reach some of these goals or even just to support their young families as they reach their own goals. Dr. Shannon Westin: I really appreciate that context, and I'm going to always bring it back to what I know as a provider of gynecologic cancer care, where we see quite a bit of young people at the beginning of their life, at the beginning of their fertility. And I think it is so important to keep that context in mind as we're designing interventions and studies and things like that. So I really appreciate that, having the ability to kind of see from that standpoint. So I think you guys have convinced me this is important. We know the reasons. So why don't we just lay out the objectives of this particular study and give our listeners a brief review of how it was designed? Dr. Jennifer Mack: Great. We wanted to know how often adolescent and young adult patients with incurable cancer have discussions about prognosis and end-of-life care planning before they die. And a secondary goal was to understand whether having earlier discussions would change the type of care that's delivered. So, for example, having those discussions about goals of care earlier in their illness, could that make them less likely to receive intensive measures?  So, to do the study, we conducted a retrospective review of health records for nearly 2,000 adolescents and young adults who died between 2005 and 2019 after receiving care in one of three centers—the Dana-Farber Cancer Institute, Kaiser Permanente Southern California, Kaiser Permanente Northern California—and looked for documentation of discussions about care planning. For this study, we focused on patients who either had stage IV disease at diagnosis or who had experienced a recurrence because we wanted to ensure that we had a population of young people who were living with advanced disease and not people who might have died suddenly and unexpectedly during treatment, because they might not have had the same opportunity for end-of-life care planning. So we really wanted to focus on those who had the poorest prognoses. Dr. Shannon Westin: It's a really large group of people and, I think, hopefully fairly representative. I guess my question is, when you're looking at the group that you were able to kind of pull from in this retrospective database, which I think can sometimes be limited, do you feel like it was fairly representative of the population that's out kind of across the States, let's say? Dr. Chun Chao: So I think it's a real strength that we included two different care settings in this study, so a tertiary cancer center and community-based cancer care. Therefore, patients who seek care in each of these settings are representative in our study. I think this design really increased the generalizability of our findings. And on a further note, in this study, we actually observed very similar care patterns across all three study settings. So that was quite reassuring. Dr. Shannon Westin: So reassuring. And I think it brings up a point that I wanted to make, and I also agree was a strength of your study, is having that across the academic center and then a large integrated health plan. And I guess I'm just curious how your collaboration came to be to kind of come across different groups and, of course, the inclusion of Mallory from the patient advocate side. I think this is a testament to your powers of collaboration. I'd just be interested in how that kind of came to be. Dr. Chun Chao: So this goes back to almost 10 years ago. I think, at that time, people started to really recognize that adolescent and young adults with cancer were a very understudied group, but they are also very challenging to study. So, for example, AYA cancers, adolescent and young adult cancers, are fortunately not very common. Although the number is increasing, you do need a large population base to study them. So, at that time, researchers at Integrated Health Systems started to really see that we had an opportunity here to really contribute to this knowledge gap, leveraging the resources that we had at these health systems, especially the ones that have a very large membership and a long-term retention of these members and also a comprehensive electronic medical record system.  At that time, my colleague and I published a study that demonstrated the feasibility of using these resources to do follow-up studies of long-term health outcomes of AYAs with cancer. And I think that we might have attracted people's attention to utilizing the resources at these h

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 blood-based panel was higher than the ones of the two models considered alone. Furthermore, the model had similar predictive performance for both non small cell lung cancer and small cell lung cancer-related deaths.  Subsequently, the authors compared the performance of the combined 4MP and PLCO model with the 2013 and 2021 US Preventive Task Force criteria and observed that the combined model had improved sensitivity, specificity, and positive predictive value for the prediction of lung cancer-specific mortality compared to both types of criteria. Finally, the authors assessed whether the combined 4MP and PLCO model were able to determine the survival probability among individuals who had a smoking history of at least 10 pack-years. Cases and non-cases were classified as either test positive or negative according to model scores at the 1.7 and 1% risk threshold at six years. For both thresholds, the combined 4MP and PLCO model identified a significantly higher number of lung cancer deaths in test positive individuals compared with test negative ones. So, in conclusion, these studies identify patients who are at higher risk of developing lung cancer-specific mortality using a combination of blood-based biomarkers and clinical demographic characteristics. The combined models showed higher sensitivity and specificity and positive predictive value compared to the standard US Preventive Task Force criteria. The results of this study are important because the identification of individuals at higher risk of lung cancer diagnosis and death offers the opportunity for a more favorable tradeoff between potential harms and benefits of the screening process. And so these results could assist in the design of future screening and intervention studies as well as facilitate the uptake of lung cancer screening, especially for those test-positive patients that have a higher risk of lung cancer death. Application of this model could potentially lead to a higher number of patients diagnosed in earlier stages and thus eligible for curative intent treatment.  That concludes this episode of JCO Article Insights regarding a summary of the article "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.  This is Davide Soldato. Thank you for your attention and stay tuned for the next episode of JCO Article Insights.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. 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 what happens when patients quit smoking after their diagnosis? Any limitations to those data that were available? Dr. David Zaridze: You mean the data which was prior our study? You know, the negative effect of smoking after diagnosis has been shown nearly three decades ago. The information exists already for thirty years, but it was largely ignored not only in clinical practice but also in clinical trials. And I have to stress that in clinical trials this information is still ignored. I came across these studies and decided to review them some time ago. All they were case-control studies and to my knowledge, none of them assessed the effect of quitting smoking. I decided to review these studies and included this review in my book, Smoking: A Major Cause of Cancer, which was published in 2012 and was dedicated to Professor Richard Doll's anniversary. In fact, this was a stimulus for the study we are discussing. And in fact, the component of this study we are discussing today was built in and baked into the existing cohort study to which we added the active follow-up component for assessing the changes in smoking habit and disease status. Dr. Mahdi Sheikh: If you review the evidence, before publishing this study just like a few years ago, we find that there are many studies published talking about the effects of smoking cessation on cancer survival. However, as David mentioned when you go deep into these studies, you’ll find a lot of limitations. First of all, most of these studies are retrospective studies, which means that either case-control or retrospective course that patients developed the outcome, and then some investigators came to see their records to assess or ask family members before they developed the outcomes. There are a lot of biases with these types of studies. And with the epidemiologic study, perspective study that we did, has less limitations compared to retrospective ones. Another one is that when we go into the study you see, they only assess a small number of patients, small sample size. Some studies just assess 10 smokers, some assess like 30. By this study we try to assess a large number of smokers who quit smoking after diagnosis. Another limitation is that– First, let's see what exposure and what setting we are talking about. We're talking about smoking which is a very dynamic behavior. People quit smoking and they relapse smoking and they quit smoking and so on. So if you access this exposure for only a limited time, for example, for one year, then you may miss what happens after that which results in misclassification of some of the participants. So repeated assessment was not done in other studies that we did here in this study. Another one, you are talking about special setting patients who are diagnosed with cancer. These patients have special circumstances, they have treatments, they have family support, they might go under the stress of cancer, and all these different stages at diagnosis. And most studies that are available, they didn’t account for this. They didn't adjust or they didn't try to understand the role of these compounding factors, as we call it in epidemiology, on that, the thing that we're trying to address. And a prospective study, as I said, long follow-up time. Even the very few prospective studies that were available for other cancer sites that have only one year or maximum two years of follow-up with this type of exposure, so it is important to follow them for a long time. Another thing I would say was exposure assessment. Not only did we repeatedly try to assess exposure among participants, but try to call the people– David and his team who did the study in the field, called the participants and tried to ask the family members and sometimes their physicians about their smoking behaviors. When you go to current evidence you see, mostly smoking behavior was assessed using the record that is available like treatment records or patient records, which again has some limitations if you do not assess exposure among qualified participants. Finally, we're talking about a dynamic behavior in the follow-ups. Some people might change smoking. But there is a very important thing, in this study, we also collect at the time of quitting smoking. There's a very important thing in statistics we call Survivorship Bias, meaning that, if you were assessing an exposure doing the follow-up and if you do not pay attention to this, you will assess an exposure that is a proxy of people who lived longer. Meaning that people have enough time, they have a long time, and those who have longer time, will have more time to quit smoking. And then you will be assessing this, actually, not the exposure, but you're only assessing people who quit smoking, and then whatever you assess, you would end up with a beneficial effect. But if you have the time of quitting smoking and follow up and all these statistical things and lower sample size, you are able to account for this very very important