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03/04/2025

Personalizing Lung Cancer Management With ctDNA: Where We Are and Where We Are Headed

Dr. Vamsi Velcheti and Dr. Charu Aggarwal discuss the evolution of ctDNA as a critical tool in precision oncology and its implications for lung cancer management, including its potential role in the early-stage setting. TRANSCRIPT Dr. Vamsi Velcheti: Hello. I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I am a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. The management of small cell lung cancer has rapidly evolved over the past few decades, and today, molecular testing and biomarker testing for lung cancer are absolutely critical in terms of designing treatment options for our patients with metastatic non-small cell lung cancer. Today, I'm delighted to be joined by Dr. Charu Aggarwal for a discussion on ctDNA (circulating tumor DNA) and the role of ctDNA in lung cancer management. Dr. Aggarwal is the Leslye Heisler Professor of Lung Cancer Excellence and section chief of thoracic and head and neck oncology at University of Pennsylvania Abramson Cancer Center. You'll find our full disclosures in the transcript of that episode. Dr. Agrawal, it's great to have you on the podcast today. Thank you for being here. Dr. Charu Aggarwal: Thank you for having me. Dr. Vamsi Velcheti: Let's start off with setting the stage for ctDNA technology. These technologies have rapidly evolved from experimental conceptual stage to essential clinical tools for day-to-day clinical practice. Could you briefly discuss how recent advancements in ctDNA technologies are shaping our approach to precision medicine, especially in lung cancer? Dr. Charu Aggarwal: Absolutely. And you know, I think we need to just level set a little bit. What exactly is circulating tumor DNA? This is a way to assess exactly that. Every tumor sheds little pieces of tumor-derived DNA into the bloodstream, and this occurs in a variety of solid tumors. But now we have the technology to be able to derive this DNA that's actually being shed from the tumor into the bloodstream, these minute fragments of DNA, take them out, amplify them and sequence them with a variety of different mechanisms. They can be DNA sequencing alone, they can be DNA and RNA sequencing, they can be whole transcriptome sequencing. The technology, as you rightly pointed out, Dr. Velcheti, has significantly improved from just being able to look at circulating tumor DNA to now being able to amplify it, sequence it, and use it to offer personalized therapy. I think lung cancer is definitely the poster child for such an approach as we have a lot of data that has shown clinical utility and validity of being able to use circulating tumor DNA next-generation gene sequencing to guide therapy. Dr. Vamsi Velcheti: There have been so many technological leaps. It's really impressive how far we've come to advance these sequencing platforms. Recent advances with AI and machine learning are also playing important roles in interpreting ctDNA data. How are these computational advances really enhancing clinical decision-making in day-to-day clinical practice? Dr. Charu Aggarwal: I think while we have firmly established the role of ctDNA in the management of patients with metastatic lung cancer, some of the approaches that you talked about are still experimental. So let me backtrack a little bit and set the stage for how we use ctDNA in clinical practice right now. I think most patients, when they come in with a new diagnosis of stage IV lung cancer, we want to test for biomarkers. And this should actually be the established standard. Now included in the NCCN guidelines and actually also international guidelines, is to consider using blood-based testing or plasma-based testing to look for biomarkers, not just tissue-based testing which had been our historical standard, but to use these plasma guided approaches to identify the seven to nine biomarkers that may be truly implicated in either first- or second-line therapy that are called as your immediately actionable mutations. What you're talking about is AI computational methods. I think there's a lot of excitement about how we can use genomic signatures that are derived from either tissue or ctDNA-based biomarker testing, combine it with radiomic features, combine it with histologic features, look at H & E patterns, use AI algorithmic learning to be able to actually predict recurrence scores, or can we actually come up with predictive signatures that may be extremely helpful? So, I think some of the techniques and technologies that you're talking about are incoming. They are provocative. I think they're very exciting, but very early. Dr. Vamsi Velcheti: I think it's really amazing how many advances we have with these platforms. You know, the challenge really is the significant gap in terms of uptake of molecular testing. Even today, in 2025, there are significant gaps in terms of all metastatic lung cancer patients being tested for all biomarkers. So, why do you think there's such a challenge in testing patients with lung cancer? In most academic practices, we try to achieve 100% testing for all our patients, but we know from recent studies that that's not the case across the country. What do you think the gaps are? Dr. Charu Aggarwal: Biomarker testing is so essential, like you pointed out, for us to be able to guide the right therapy for our patients. And we see this in our practice every day as you and I see patients with lung cancer, that a large proportion of our patients either don't get tested or they start therapy before their test results come back. So, I think this is a real problem. However, to add some optimism to this problem, I do think that we are making a move in the right direction. So, four or five years ago, there was a lot of data being presented at national meetings, including ones from the American Society of Clinical Oncology, where we saw that, nationally, the rates of biomarker testing were probably in the rate of 40 to 50%. However, now with the availability of both tissue and plasma, I do think that the rates of biomarker testing are increasing. And if you were to survey a sample or even perform retrospective data research, I believe that the number is closer to 70% of all patients with metastatic non-small cell lung cancer. And you know, you asked why is it not 100%? I think there are many reasons. I think the number one reason is tissue availability. Many times, the biopsies are small, or the tumor is very necrotic. So, either the tissue quantity itself is small, or the tissue quantity is insufficient to perform gene sequencing. And that's exactly where plasma comes in. When you don't have tissue availability, we have shown, as have others, that you can use plasma effectively to increase the proportion of patients who are not only tested but also receive the right therapy. I think there are also other barriers, including inertia. You know, I think this is both patient and physician inertia, where patients want to get started quickly, they don't want to wait. Physicians are very busy and sometimes want to be able to deliver treatment as soon as possible. We have seen there are some institutional barriers. Not every institution has in-house gene sequencing testing. So how do you really operationalize, send out these tests in a fast, efficient manner so that you get results back? Is it a pathologist who sends out the test? Is it the medical oncologist? Is it the pulmonologist or the interventionalist? I think there is this need to develop reflex testing mechanisms which some institutions do really well and some don't. And then finally, there are financial implications as well. How do we do this in a most cost-efficient fashion? So there are many barriers, but I'm happy to say that we are making a move in the right direction as we are understanding that it's important to do it, it's easy to do it maybe with a value add of plasma, and finally, as you said, you know, as these technologies become more available, they're actually getting more cost-effective. Dr. Vamsi Velcheti: Dr. Aggarwal, you've been at the cutting edge of these advanced platforms and testing. So, what do you do in UPenn? How do you handle all these barriers and what is your workflow for patients in University of Pennsylvania? Dr. Charu Aggarwal: One of the things that I mentioned to you was there may be institutional barriers when it comes to gene sequencing. So, we actually, several years ago now, instituted a very robust reflex testing paradigm where almost all of our patients, regardless of stage, with a non-squamous non-small cell lung cancer diagnosis, would automatically be reflexively sent to our molecular pathology lab where they would get gene sequencing both for the DNA as well as with an RNA fusion-based platform. And the reason we did this was because we wanted to expedite and reduce the turnaround time. We also wanted to ensure that we were not just doing DNA testing, which I think is really important for our listeners here. There are many fusions as well as certain skipping mutations like MET exon 14 that may be missed on DNA testing alone. So, it's really incredibly important to run both DNA and RNA samples. So, we do this routinely, and based on our research and others, what we also do routinely is that we send concurrent tissue and liquid biopsies or plasma MGS testing upon initial diagnosis. For example, if a patient comes in with a diagnosis of stage IV non-small cell lung cancer, their tissue might already be at my molecular pathology lab based on the reflex mechanism that I just described to you. But upon their initial meeting with me, we will send off plasma. And I will tell you this, that Penn is not just one institution, right? We have a large network of sites. And as part of my research, one of the things that we wanted to do was implement wide scale means to improve bio

03/04/2025

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19 min
04/01/2024

Germline Testing in Patients with Breast Cancer: ASCO-SSO Guideline

Dr. Isabelle Bedrosian and Dr. Mark Robson discuss the new guideline from ASCO and SSO on germline testing in patients with breast cancer. They discuss the framework for which patients should be offered BRCA1/2 testing, and what additional moderate- and high-penetrance genes may be considered for inclusion in germline testing. They highlight key aspects of personal and family history, recommendations surrounding counseling for genetic testing, and the impact for patients and their families. They close the conversation with a discussion of gaps in the research. Read the full guideline, Germline Testing in Patients with Breast Cancer: ASCO-SSO Guideline TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02225 Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Isabelle Bedrosian from the University of Texas MD Anderson and Dr. Mark Robson from Memorial Sloan Kettering Cancer Center, co-chairs on "Germline Testing in Patients with Breast Cancer: American Society of Clinical Oncology – Society of Surgical Oncology Guideline." Thank you for being here, Dr. Bedrosian and Dr. Robson. Dr. Mark Robson: My pleasure. Dr. Isabelle Bedrosian: Thank you, Brittany. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bedrosian and Dr. Robson, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content of this particular guideline, Dr. Bedrosian, could you give us a general overview of both the scope and the purpose of this guideline? Dr. Isabelle Bedrosian: Yeah, sure. So, in the last decade or so, the whole area of clinical cancer genetics has become incredibly complicated, driven, I think, predominantly by the development of extended gene testing. And in the midst of this complexity, our goal here was to try to give providers a framework through which they can think about the application of germline testing within their patient population. And really, this framework was to help them think through how testing can best be applied to patients that were both newly diagnosed with breast cancer or had a history of breast cancer, and also to help them think through the scope of that testing as well, be it BRCA testing or testing in a more extended fashion that may help inform longer-term decisions such as risk management. Brittany Harvey: Absolutely. We appreciate your efforts to provide recommendations in this framework in this complicated space. So then, I'd like to review the key recommendations of this guideline developed by the expert panel. So first, Dr. Robson, who should be offered BRCA1/2 testing? Dr. Mark Robson: Thank you. I think this is perhaps one of the most important things that comes out of the guideline is that we, and the group, are now recommending that anyone who is either newly diagnosed with breast cancer at or before the age of 65, or if they're over 65 and have suggestive personal or family history criteria, or alternatively, if they are eligible for PARP inhibitor therapy, that they all be offered BRCA1 or BRCA2 testing. And the same would hold for women who had a personal history of breast cancer but were not currently under active treatment if their diagnosis had been made at or before 65 or older than that, with certain criteria then they should be offered testing. This is a much simpler way to look at things than the rather complicated existing criteria, which are perhaps a bit both difficult to remember and unfortunately inadequately sensitive in a setting where there is such critical, both therapeutic and risk management implications to the identification of a BRCA mutation. Dr. Isabelle Bedrosian: Yeah, I would just also add there's one other, albeit a much smaller group of women for whom BRCA testing could be considered, and those are women who develop a second primary breast cancer. That's another group that I think we can think about offering BRCA1/2 testing to. Brittany Harvey: Understood. I appreciate you both reviewing those recommendations for BRCA1/2 testing. So, Dr. Bedrosian, which additional genes does the panel recommend including in germline testing? Dr. Isabelle Bedrosian: Yeah. So, in this area, outside of BRCA genes, Brittany, I think the panel didn't make any definitive recommendations or any specific genes that should be tested for. I think the panel felt that the decision to test for additional high penetrance genes and also for some moderate penetrance genes should be guided by the specifics of the individual case, whether the identification of germline mutations makes sense in the context of the patient's personal history and family history. So, in other words, is there a worrisome pattern in the family that might warrant more in-depth testing beyond BRCA, and also considerations around the implications of those test results. Would it change the management for the patient themselves? Either in the treatment of the index malignancy, which, in the case of most of these non-BRCA genes, there really is not changes to the management of the breast cancer that would be offered based on the finding of non-BRCA germline mutations. But potentially, the finding of a non-BRCA germline mutation in a breast cancer patient might help better understand risks of second malignancies that would then be addressed. And certainly for families as well of the patients, identifying those that are carriers could offer opportunities for risk assessment, risk mitigation. Dr. Mark Robson: I totally agree with Dr. Bedrosian. One thing I think it's important to understand is that most commercial testing done in the United States now does involve panels of genes. And the group certainly did not intend to suggest that that practice not continue. So, I think if somebody has a history of breast cancer, I think the panel felt that it would at least be reasonable to test for breast cancer susceptibility genes. However, this issue of do you test for all of the high penetrance genes when the family history doesn't suggest it, was certainly something we left open and we did not want to imply that it was obligatory to test for a large number or large panel of genes that weren't related to the patient's personal and family history. So, in other words, didn't want to imply that it was obligatory to do an extremely large panel just as a target of opportunity, if you will. Dr. Isabelle Bedrosian: I think really a key part of these guidelines was that we wanted to afford the oncologist flexibility. It's very difficult beyond BRCA to be prescriptive. There are so many considerations about testing, and those considerations will be applied differently in every patient context. So, we really wanted to let providers know that while they have to think about these other genes, and oftentimes there'll be good reason to do these other genes as part of the overall germline testing, again, that it's not obligatory to do so. It's not a fixed set that needs to be tested for. And really, the understanding of the patient's personal history, family history, therapeutic goals, and risk assessment goals should be used to determine kind of the ultimate scope of the testing. Brittany Harvey: It sounds like these decisions will be individualized, based on patient characteristics and with working between both patients and their clinicians. So that leads into my next question. But, Dr. Robson, how should patients with breast cancer considering genetic testing be counseled? Dr. Mark Robson: With this recognition and emphasis on the therapeutic implications for patients with breast cancer, both surgical and potentially systemic using PARP inhibitors, the approach has gradually moved away from the concept of testing for personal utility, in other words, just wanting to know, and more towards the idea of this being a clinically useful test that's to some extent necessary for the appropriate management of a fair number of patients. And so the counseling is usually- the pre-test counseling is perhaps more educational than we have used in the past, rather than this extensive discussion of whether or not somebody wants to know. Obviously, it's always the patient's ultimate decision whether or not to be tested, and we have to give them the same elements of education that we would have given back in the day. But it can be delivered in a more didactic type of context rather than necessarily the back and forth that takes place with formal genetic counseling. Now, for patients who have complicated or extensive family histories or who have histories that may suggest predispositions other than those for breast cancer, the type of thing that Dr. Bedrosian was talking about earlier, they could certainly benefit, again, from a more formal evaluation by a provider experienced in cancer genetics to help select what the scope of the testing should be, for instance, and also to help interpret those results. And certainly anybody who had a pathogenic variant or a likely pathogenic variant identified should be considered for meeting with somebody who's experienced in clinical cancer gene

04/01/2024

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16 min
03/08/2021

Adjuvant PARP Inhibitors in Patients with High-risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update

An interview with Dr. Nadine Tung and Dr. Dana Zakalik, co-chairs on "Adjuvant PARP Inhibitors in Patients with High-risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update." They discuss the results and impact of the OlympiA trial, the updated recommendation, and outstanding questions on the use of PARP inhibitors in the adjuvant setting. For more information, visit www.asco.org/breast-cancer-guidelines. TRANSCRIPT [MUSIC PLAYING] ANNOUNCER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines Podcast Series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.ASCO.org. My name is Brittany Harvey, and today I'm interviewing Dr. Nadine Tung from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and Dr. Dana Zakalik from Beaumont Health in Royal Oak, Michigan, co-chairs of the Management of Hereditary Breast Cancer Guideline Expert Panel and this rapid recommendation update, Adjuvant PARP Inhibitors in Patients With High-Risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Guideline Recommendation Update. Thank you for being here, Dr. Tung and Dr. Zakalik. DR. ZAKALIK: Thank you for having us. DR. TUNG: Thank you so much. Pleasure to be here. BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online. Dr. Tung, do you have any relevant disclosures that are directly related to this guideline topic? DR. TUNG: I do receive research funding from AstraZeneca, as I run a trial using a PARP inhibitor in breast cancer. BRITTANY HARVEY: Thank you. And Dr. Zakalik, do you have any relevant disclosures? DR. ZAKALIK: I do not. BRITTANY HARVEY: Thank you. Then let's get into the meat of this rapid recommendation update. So, Dr. Tung, what prompted this rapid update to a recommendation from the Management of Hereditary Breast Cancer Guideline? DR. TUNG: The OlympiA Trial, which was presented at ASCO this past June and published the same day in the "New England Journal of Medicine." OlympiA was a large Phase III trial, which demonstrated that a year of adjuvant olaparib, a PARP inhibitor, significantly improved both invasive disease-free survival by nearly 9%, and distant disease-free survival by a similar improvement, in germline BRCA mutation carriers with HER2-negative breast cancer and a high risk of recurrence. Overall survival was numerically better with olaparib, but it didn't yet reach significant improvement as a stringent p-value was required for this early reporting. And I say early reporting because the trial was reported early after the first event-driven interim analysis showed a benefit with olaparib. 1,800 patients had been enrolled with a median follow up of 2 and 1/2 years at the reporting. But the follow up was 3 and 1/2 years for the first 900 patients enrolled, known as the maturity cohort. And it was comforting that the significant improvement in invasive disease-free survival and distant disease-free survival was also seen when just looking at that maturity cohort. So for those who might think that it's too early and that these benefits might not hold up with longer follow up, it's very comforting that in that maturity cohort with longer follow up, the results were really the same. And last year, ASCO published guidelines on managing patients with hereditary breast cancer, including women with inherited BRCA mutations, meaning a pathogenic or likely pathogenic variant. At that time, PARP inhibitors were recommended only for BRCA carriers with metastatic disease, based on the OlympiAD and EMBRACE trials. So when OlympiA was published, we felt the need to update the guidelines to recommend olaparib in the early-stage setting for some germline BRCA carriers. BRITTANY HARVEY: So then, based off this new data from the OlympiA trial, Dr. Zakalik, what is the updated recommendation from the guideline expert panel? DR. ZAKALIK: The updated recommendation states that for patients with early-stage, HER2-negative breast cancer with a high risk of recurrence, and who carry a germline BRCA1 or 2 mutation, one year of adjuvant olaparib should be offered after completion of adjuvant or neoadjuvant chemotherapy and local treatment, including radiation therapy. And this data was specific to a high risk of recurrence subgroup of these patients, defined as, for those with triple-negative breast cancer having a tumor over two centimeters, or with any involved lymph nodes, or for those who received neoadjuvant chemo, any residual disease in the triple-negative setting was sufficient to qualify. For patients with hormone receptor positive disease, these were high-risk patients for recurrence, again, and that was defined as having at least four positive lymph nodes, or any residual disease following neoadjuvant therapy. But in addition, having a clinical stage and pathologic stage estrogen receptor status and tumor grade, otherwise called the CPS+EG score, of greater than or equal to three, which is really defined as looking at estrogen receptor status grade and clinical and pathologic stage. So again, a high-risk group for risk of recurrence was included in this study. And again, in order to apply these findings, we have to be mindful of patients who meet these inclusion criteria as being high-risk for recurrence. Again, both in the triple-negative hormone receptor-positive setting, if they met these criteria, there was a significant benefit in terms of outcome in lowering the risk of recurrence. BRITTANY HARVEY: I appreciate you going through that recommendation. So then, given that updated recommendation. Dr. Tung, what should clinicians know as they implement the use of adjuvant olaparib into clinical practice? DR. TUNG: For those who have not used olaparib, it's worth saying that it's an oral medication. Typically patients take two pills twice a day. And it's important to be familiar with the side effects. I would say that generally, olaparib is well-tolerated. But it can have side effects. And the two most common are nausea, and then anemia. So for the nausea, we use the typical antiemetics we would use for any chemotherapy. And it's worth saying to patients who do have nausea that quite often, that lessens with time. It decreases. So I would say nausea's one of the side effects. Some patients can have fatigue, although I don't think that's all that common. And anemia is the other one. And we do check bloodwork monthly for patients on olaparib. The anemia can come suddenly, even after months of really not having any. And grade 3 anemia was probably the most common, grade 3 or higher, toxicity that was seen in OlympiA, although it's only 9% of patients that had grade 3 or higher anemia. But I would say those are the two side effects to look for most. And then I think one other thing that's worth saying is that for the BRCA carriers with triple-negative breast cancer, currently our standard therapy for patients who have residual disease after neoadjuvant chemotherapy is capecitabine. But olaparib should not be given with capecitabine. There is no safety data for that. So oncologists are going to need to choose between what I think is our standard therapy right now, capecitabine, and olaparib. And there's no data directly comparing these two medications in the early-stage setting. But in the metastatic setting in BRCA carriers, in both OlympiAD and EMBRACE, olaparib was compared to chemotherapy. And olaparib with superior. And in both of those studies, about half the women in the chemotherapy arms received capecitabine. And olaparib, again was superior. So olaparib may be the better choice in the early-stage setting. But I can't say that there's any direct data. But the message would be not to give them together. And I think it would be better probably not to give capecitabine first and then olaparib, because there's some data that the earlier you give a PARP inhibitor the better. BRITTANY HARVEY: Those are important notes for clinicians and particularly for safety. So then building on that, Dr. Zakalik, how will this update impact patients with breast cancer? DR. ZAKALIK: This data will significantly impact the therapeutic options that we have for patients with high-risk disease in the setting of a BRCA germline mutation. And that will happen in the sense that patients who have these certain specific features that render them high-risk will now be able to be offered a very impactful therapy that has been shown in this landmark study to significantly decrease their risk of recurrence. And these are patients who otherwise would face a significant risk of potentially facing a recurrence in the future. So the outcomes we anticipate to be dramatically improved for patients who have triple-negative or high-risk hormone receptor-positive breast cancer in the setting of a BRCA germline mutation. But furthermore, whereas genetic testing in the past was predominantly focused on identifying individuals who are at high risk for developing breast cancer so that we can offer early detection or prevention options, this is the first time that we're able to broadly apply the benef

03/08/2021

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16 min
07/06/2023

HER2 Testing in Breast Cancer: ASCO-CAP Guideline Update

Dr. Antonio Wolff and Dr. Kim Allison discuss the latest ASCO-CAP guideline update on HER2 testing in breast cancer. This guideline update affirms previous recommendations, and provides commentary based on data from the DESTINY-Breast04 trial. Dr. Wolff and Dr. Allison review the questions from the oncology and pathology community raised by these results, and provide commentary on patients with HER2 IHC 1+ and 2+ and ISH-negative metastatic breast cancer. Read the guideline update, "Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-CAP Guideline Update" at www.asco.org/breast-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.22.02864 Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Antonio Wolff from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Dr. Kim Allison from Stanford University School of Medicine, co-chairs on 'Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-CAP Guideline Update'. Thank you for being here, Dr. Wolff and Dr. Allison. Dr. Antonio Wolff: Thank you. Dr. Kim Allison: Thanks for having us. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in developing its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the full guideline panel, including our guests on this episode today, are available online with the publication of the guideline and the Journal of Clinical Oncology, linked in the show notes. So now jumping into the content, to start us off, Dr. Wolff, what prompted the update expert panel to revisit the 2018 ASCO-CAP recommendations on HER2 testing and breast cancer, and what is the scope of this update? Dr. Antonio Wolff: Thank you, Brittany. We appreciate the opportunity of being with you today, and it's great to be here with my colleague, Dr. Kim Allison, as well. What triggered this informatory update was the release from data in trial DESTINY-Breast04, which tested the antibody-drug conjugate trastuzumab deruxtecan in patients who in the past would have been considered to have HER2-negative disease. This ADC, trastuzumab deruxtecan, has a topoisomerase inhibitor payload that is linked to the antibody trastuzumab. And in the past, from all the previous data we had, trastuzumab alone, or in combination with chemotherapy, or as part of another antibody-drug conjugate T-DM1 was essentially active in patients with HER2-positive disease, which is traditionally defined as having overexpression of the HER2 protein, which almost by default is a result of gene amplification of the HER2 gene. And what data from initial studies appear to suggest is that patients who would not be traditionally considered HER2-overexpressed or HER2-amplified were potentially benefiting or having evidence of clinical activity against this disease in the study of metastatic disease. And this was a randomized clinical trial for patients with metastatic breast cancer whose tumors were centrally determined to have IHC 1+ or IHC 2+ expression and would not have been called HER2-positive, would not have been called HER2-overexpressed. And for the tumors that were HER2 2+, they also had to have absence of gene amplification by an in-situ hybridization assay. And what was very interesting is that there was a meaningful, clinically significant improvement in survival for that patient population. And that has some clinicians to begin asking whether there is a different subset of patients who would have in the past been called as having HER2-negative disease that now could potentially be a candidate for this drug. And is there a difference between these patients and patients who, in the past, would have been called as HER2-negative on the basis of IHC 0? And so what complicated things for us a little bit is that patients with IHC 0 were not eligible for this trial. And what is left unanswered by this clinical trial is whether all patients who don't have HER2 protein overexpression or HER2 gene amplification would potentially have benefited from this drug. Kim? Dr. Kim Allison: Yeah, agree. I think the main impetus for the update was the exciting results from the DESTINY-Breast04 trial and the questions then that the pathology community and the oncology community had about whether this should change HER2 testing guidelines. Brittany Harvey: I appreciate that background on what prompted the panel to revisit this guideline. So then, Dr. Allison, how did the panel come to the conclusion that the previous recommendations are current and valid? Dr. Kim Allison: Right. So, as Antonio mentioned, the whole reason HER2 testing was first initiated was HER2-targeted therapies that showed response in the overexpressed or amplified tested population. And so guidelines have really been fine-tuned and crafted around distinguishing the HER2-positive for over-expression and amplification from negative. And this trial really questioned that in that maybe we can target lower levels of the HER2 protein, but this assay really wasn't designed for that. So we looked at the data from the trial and some of the limited other data that's out there and really came to the conclusion that, look, everyone in DESTINY-Breast04 benefited. The whole population benefited, whether you were 1+ or 2+. And because 0s were excluded from the trial, we don't know if they benefited. So we thought it was premature to create a new category, a new result category, and change our current reporting to a HER2-low category, mainly because we don't know that there's a new predictive threshold for response to treatment. So essentially, what we've got is a trial that showed great benefit but didn't create a new biomarker that is predictive or prognostic. Instead, it repurposed this older test as a trial entry criteria. And so now we're kind of stuck with 1+ or 2+ ISH negative as their trial entry criteria that gives you eligibility for trastuzumab deruxtecan. So essentially, we reaffirmed our prior recommendations with acknowledgment that what these categories: positive, equivocal, and negative, refer to is for protein overexpression or gene amplification and that we should continue to use the same scoring criteria, 1+, 2+, 0, and interpretation as were used in DESTINY-Breast04 for their clinical trial criteria. But awareness is important. Dr. Antonio Wolff: Yeah, the other thing that I would add, Brittany, I think we need to go back to what was the purpose of HER2 testing back in 1998 when we identified the survival benefit from trastuzumab in metastatic disease. And then, in 2005, when we had evidence of adjuvant benefit in improving disease-free and then overall survival for patients with early-stage disease. And the immunochemistry assays at that time were developed to differentiate between patients who had HER2 overexpressing disease or HER2 gene amplified disease versus not. At that moment, it was clearly identified that patients were considered as having HER2-positive disease that defined a biological entity, a tumor subtype, a group of patients who had worse prognoses in the absence of therapy. But then when they were treated with, for instance, chemotherapy with anthracyclines at that time, but then with HER2 targeted therapies with antibodies, these patients that otherwise would have a poor prognosis now were having an improved outcome. HER2 was a marker of poor prognosis but also a marker of a good chance of deriving clinical benefit, so there was a predictive benefit. And everything else, IHC 0, 1 or 2+, ISH-negative, there has been no evidence that targeting the HER2 pathway was clinically important. Or even more meaningful, there was no evidence that these patients have– within the subset of patients that don't have HER2 positive or overexpressing disease - there has been no evidence that those patients have a different outcome based on low levels of expression of HER2. A couple of years ago, in terms of trastuzumab, the NSABP reported findings in the data from NSABP B-47 where the antibody trastuzumab was added to chemotherapy to patients who were considered to have low levels of IHC expression, and in that case, was IHC 1+ or IHC 2+ gene non-amplified. And that settled the issue for sure, that there was absolutely no benefit in the adjuvant setting from the addition of trastuzumab. So we know that there's something different going on here. We know that if you now combine trastuzumab with a specific payload, in this case, the drug deruxtecan, which is a topoisomerase inhibitor, we are potentially targeting the HER2 protein. But these are tumors that are not considered HER2 addicted. These are not tumors whose biology is dependent on the HER2 pathway, so this is simply a better drug delivery. And in this sense, data and evidence from Michael Press, a pathologist at USC that has done some seminal work with HER2 and HER2 testing, he once proposed that the vast majority of breast cancers have some level of HER2 present. And a lot of what is considered IHC 0 is an artifact related to suppression of the detection of the HER2 protein. So there's a chance that the tumors that are truly HER2 negative or HER2 0 are going to be a very small proportion. And IHC assays were never optimized to measure very low levels of HER2. They just don't have the dynamic range for t

07/06/2023

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25 min
13/03/2025

Botensilimab Plus Balstilimab in Advanced Sarcomas

Dr. Shannon Westin and her guest, Dr. Breelyn Wilky, discuss the JCO article, ""Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas." TRANSCRIPT Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on research that has been published in the Journal of Clinical Oncology. I am your host, Gynecologic Oncologist and Social Media Consultant Editor of the JCO, Shannon Westin. I serve here from the University of Texas MD Anderson Cancer Center. And I am so excited to welcome Dr. Breelyn Wilky. She's an Associate Professor and the Director of Sarcoma Medical Oncology in the Department of Medicine Division of Medical Oncology, and the Cheryl Bennett & McNeilly family endowed chair in Sarcoma Research, the Deputy Associate Director of Clinical research at the University of Colorado Cancer Center. Welcome. Dr. Breelyn Wilky: Thank you so much. I'm delighted to be here. Shannon Westin: And with all those titles, I'm super impressed that she was able to complete the manuscript that we're going to discuss today, which is "Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas." And this was published in the JCO on January 27, 2025. And please note, our participants do not have any conflicts of interest. So this is exciting. Let's first level set. Can you review with us just the current state of sarcoma incidents, survival outcomes, that kind of thing so we all know where we're starting? Dr. Breelyn Wilky: Yes. So, you know, sarcomas are really, I like to call them the black box cancer type. And the big thing is that there's really more than a hundred different kinds of sarcomas, which collectively altogether make up only 1% of adult cancers. And so we talk about these as being bone and soft tissue tumors, but really, the heterogeneity is just incredible. You're talking maybe 10,000 to 12,000 new cases of soft tissue sarcoma per year, which is pretty rare in the grand scheme of things. And the trouble with these is that while you can cure sarcomas if you find them early and they're localized, when they metastasize and spread and are not resectable, we're looking at median overall survivals of really only 12 to 18 months, even, you know, with our best therapies that we have. So, really there's just a dire need for new treatments for this really tough group of diseases. Shannon Westin: Yeah, I agree. I'm a gynecologic oncologist, and we have our little subset of sarcomas that I know there's a little bit out of every one. So I'm really excited to pull this manuscript as one of our podcasts offerings because I think we're all seeing these patients in the clinic and certainly our listeners that have sarcoma or have family members with sarcoma, this is so good to have a real focus on a rare group of tumors that have been a little bit lumped together. Now, with that being said, I know this is such a heterogeneous population, but can you briefly overview a little bit around the standard of care for treatment of recurrent sarcomas? Dr. Breelyn Wilky: We have actually been using the same drugs really since about the 1970s, and up until very recently, nothing had really challenged doxorubicin, the old 'red devil', like we used to call it. And this has been the mainstay of treatment for metastatic sarcomas and really used across the board. In the GYN literature, for uterine leiomyosarcoma, we did see some promising activity with the combination of doxorubicin and trabectedin coming out of the French group. But, except for that study, no combination therapy or new drug has been proven better in terms of overall survival compared to doxorubicin monotherapy, really over 40, 50 years. So it's definitely a tough situation. Now, we do have other drugs that we use, so most patients will wind up getting doxorubicin-based therapy. There's a couple of other regimens that we'll reach to, like gemcitabine docetaxel. And once you get into the specific subtypes, we have some approvals in liposarcomas and leiomyosarcomas for some other drugs. But really the median progression for survival for most of these regimens is somewhere four to six months. And response rates typically are somewhere like 10%, 15% for most of these. So it's really just a very tough field and a tough group of patients to try to make an impact for. Shannon Westin: So let's talk a little bit more kind of getting focused on what you've studied here. What's been the role of immunotherapy thus far in the treatment of sarcomas maybe prior to this particular study? Dr. Breelyn Wilky: Clearly, we all know that immune therapy has just changed cancer care forever over the last few years for so many different types of cancers and diseases like melanoma and renal cell and lung cancer have just been transformed by checkpoint inhibitors specifically directed against PD-1 or CTLA-4 or both. And so, of course, you know, sarcoma docs we're super excited to try to see if these might potentially have activity in our tumors as well. I never had seen myself in my career getting into immunotherapy until I was able to run an investigator-initiated study during my role in Miami, where we combined pembrolizumab, so PD-1 inhibitor, with axitinib which was a pan-VEGF inhibitor. And lo and behold, like I had patients that I was seeing responses when other treatments, all those chemotherapies I was just talking about had failed. And one of my first patients I treated was about a 60-year-old lady with something called cutaneous angiosarcoma. So this is a blood vessel sarcoma all over her face. And we had treated her with 10 different therapies, all the chemotherapy regimens, targeted therapies, clinical trials, and nothing was working. But I put her on a phase 1 trial with a baby dose of CTLA-4 and this woman had a complete response. And so for me, once I saw it work in even just those couple of patients, like that was nothing that we'd ever seen with our chemotherapy regimens. And so that sort of shifted my career towards really focusing on this, and this is about the time where some of the studies started to come out for sarcomas. And the take home with sarcoma is about 20% of sarcomas have this sort of immune hot physiology. So what that basically means is if you look at gene expression of immune related gene signatures, or you look for infiltrating T-cells, sort of the SWAT team of our immune system, like you can find those in the tumors. And it's sort of evidence that the immune system had some clue for that 20% of patients that this was a foreign tumor and that it should be attacking it and maybe just needed a little help. But globally, about 80% of sarcomas are these immune cold tumors, which means the immune system has no clue that these things are even a threat. And there's almost no immune activation, very, very few antigens. In other cancer types, high neoantigens or tumor antigens help the immune system work better. And so that basically goes with what we've seen with trials of PD-1 or CTLA-4 blockade. About 20% of sarcomas, with some exceptions, can respond. But really 80% across the board, you're stuck, you just can't get them to be recognized. And so that's where I think this data is so interesting is there's some signals of activity in these immune cold tumors which, at least historically with the trials we've done so far, we really haven't seen that with sort of the traditional checkpoints. Shannon Westin: So I think now this is a great time to maybe talk about the study design in general, the eligibility and just give us kind of a run through of that. Dr. Breelyn Wilky: So this trial was a phase 1 trial of a drug called botensilimab, which is a next generation CTLA-4 directed immune modulator. So what makes botensilimab different is that the CTLA-4 end is very similar to other CTLA-4 inhibitors that are out there, but it's been engineered on the back end of the molecule that binds to Fc gamma receptors to basically bind tighter with higher affinity. And what this translates to in laboratory models and increasingly now in patients is it does a better job of priming, of educating our T cells, our, again, these highly intelligent antigen specific cells, but also natural killer cells. It does a better job of sort of educating those. It helps to activate macrophages and other supporting actors in the immune response. And so the idea here is that there's evidence that botensilimab may do a better job at creating new responses in immune cold tumors. The study combined either botensilimab as monotherapy or in combination with a PD-1 inhibitor called balstilimab. And this was all comers, really a variety of tumor types. And to date I think we're close to about 500 patients with a variety of solid tumors that have been accrued to this study, this C-800-01 phase 1 trial. This paper reports on the sarcoma patients that were enrolled as part of this study. And so, again, given what I've told you about sarcomas being really immune cold, we were just so excited to have the opportunity to enroll on a next generation immune therapy for these tumors that really we were running into roadblocks trying to use immunotherapy previously. Shannon Westin: It's a very compelling idea and I'm so excited for you to tell people what you found. I think first things first, it was an early phase trial. So why don't we talk a little bit about the safety of the regimen. Was there anything that you didn't expect? Dr. Breelyn Wilky: Right. So similar to other checkpoint inhibitors, you know, the idea is that these drugs can cause immune mediated toxicities, right? So essentially you're revving up the immune system and it can sometimes get a bit confused and start attacking our

13/03/2025

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21 min
11/02/2025

TORS in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma Guideline

Dr. Chris Holsinger shares the new guideline from ASCO on transoral robotic surgery (TORS) for patients with oropharyngeal squamous cell carcinoma. He reviews the evidence-based recommendations on baseline assessment, the role of TORS in HPV-positive and HPV-negative disease and in the salvage/recurrent setting, which patients are eligible or ineligible for TORS, and the role of adjuvant therapy. He discusses the importance of multidisciplinary collaboration and shared decision-making between patients and their clinicians. Read the full guideline, "Transoral Robotic Surgery in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma: ASCO Guideline." TRANSCRIPT This guideline, clinical tools, and resources are available at asco.org. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Chris Holsinger from Stanford University, lead author on "Transoral Robotic Surgery in the Multidisciplinary Care of Patients with Oropharyngeal Squamous Cell Carcinoma: ASCO Guideline." Thank you for being here today, Dr. Holsinger. Dr. Chris Holsinger: Thanks, Brittany. We've been working together for years on these guidelines and what a pleasure to get to meet you at least virtually today. Brittany Harvey: Yes, it's great to have you on. And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Holsinger, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So let's jump into this important guideline. Dr. Holsinger, to start us off, can you provide an overview of both the scope and purpose of this guideline? Dr. Chris Holsinger: Absolutely. And again, thanks for the opportunity to be here, Brittany. I appreciate the invitation to participate in the ASCO Guidelines and to work with the great people on this paper that's now out there. I think it's a really important guideline to be published because it really talks about surgery, specifically transoral robotic surgery, a minimally invasive technique, as a new way to treat head and neck cancer. Why that's so important is that what is now known as head and neck cancer is completely different than what we saw even 25 years ago. Around the turn of the century, some really thoughtful epidemiologists working at Hopkins and UW in Seattle started to see this connection between the human papillomavirus and head and neck cancer. And since then we've seen this precipitous rise in the number of throat cancers specifically due to HPV. The results from the American Cancer Society showed last year that head neck cancer, in particular these cancers of the oropharynx, actually were one of the few cancers that still had an increasing incidence, I think it was around 2.5% per year. And other studies have shown that almost 50% of the cases we're seeing across the United States now are actually HPV-mediated throat cancers. That's bad news because we're seeing this rise in cases, but it's good news in the sense that this is a cancer that is highly curable and I think opens up a lot of different treatment avenues that we didn't have a couple of decades ago. And when patients are facing a mortality risk that's two or three times lower than the formerly HPV-negative smoking-driven cancers, it really behooves us as clinicians, as oncologists to think about treatment selection in a completely different way. And for years, the only function-sparing option, surgery certainly was not, was radiation therapy with concurrent cisplatin chemotherapy. In 2009, the FDA approved the use of surgical robotics using a transoral approach, a minimally invasive approach to resect the primary tumors and to perform neck dissection. And so now when patients walk in the door, they not only have this gold standard option in the path of radiation therapy with chemo, but also frontline surgery. And with some recent publications, especially the ECOG 3311 study, there's some really good evidence that for HPV-mediated throat cancers, we can actually de-escalate the intensity of adjuvant therapy when we start with surgery first. So who we choose that option for, which patients want that option - these are all really important new questions that we try to grapple with in these guidelines. Brittany Harvey: That background is really key for setting the stage for what we're about to talk about today. And so next I'd like to review the key recommendations across the clinical questions that the panel addressed. So you just talked about the importance of treatment selection. So to start that off, first, what is recommended for baseline assessment for patients with oropharyngeal squamous cell carcinoma who are being considered for transoral robotic surgery? Dr. Chris Holsinger: So I think here we tried in the guidelines to really standardize the workup and approach of this disease, in general, but with a strong focus on who might be a good surgical candidate. As I mentioned in the introduction, I mean, this is a disease that is very new. Our workup is in flux. And so what we tried to do, especially in items 1.2 and 1.3, is to really standardize and confirm that the tumor that we're dealing with, which oftentimes presents in a metastatic lymph node, is in fact associated with the human papillomavirus. So how biopsy is done, how high risk HPV testing is performed, whether you're doing that with an in situ hybridization, a DNA based study, or a p16 immunohistochemical study. And we try to tackle these issues first to really make sure that the patient population we're considering is actually indeed eligible for this kind of treatment de-escalation with surgery. Brittany Harvey: Understood. So it's important to consider which patients could be eligible for TORS upfront. So what is the role of TORS in patients with HPV-positive oropharyngeal squamous cell carcinoma? Dr. Chris Holsinger: Yeah, exactly. So I think first of all, surgery is ideally suited, and the robot is FDA approved for early-stage cancers - T1 and T2 cancers that are amenable to a minimally invasive approach. And we really try to emphasize, especially in our patient selection section of the guideline, who is really an ideal candidate for this. It's not just the T1 and T2 tumor. It's a tumor that is lateralized so that we can maybe consider managing the neck concurrently just on the side of the tumor, rather than doing bilateral neck dissection for most patients. Which patients might get the best functional outcome is a really critical component of this. And in fact, that actually goes back to a guideline that we didn't have time to chat about earlier, which is that we think every head neck cancer patient, whether or not they're being considered for transoral robotic surgery or frontline radiation therapy with cisplatin, every patient should have a pre-treatment assessment by a speech and swallowing expert. They're called different names across the country: speech language pathologists, speech pathologists, etc. But having a really good functional assessment of the patient's ability to swallow before treatment selection is really critical. And why that's important with frontline surgery is that there's a period of about one or two weeks after which that patient really needs intensive rehabilitation. And so for every patient being considered by TORS, we want to work really hand in hand with that speech pathologist to do pre-habilitation and then immediate post-operative rehab and then long longitudinal rehabilitation so that if radiation is needed down the road in a month, that patient just hopefully sails through this de-escalated treatment that we're offering. Brittany Harvey: Great. I appreciate you describing which patients can be considered for transoral robotic surgery. So beyond that, which patients with HPV-positive oropharyngeal squamous cell carcinoma aren't really good candidates for TORS? Dr. Chris Holsinger: We talked about that sort of ideal patient, but you know, we're not always living in an ideal world. And so I think it's important, and I'm really happy about the multidisciplinary discussions that led to these final guidelines because I think it helped engage radiation oncologists, medical oncologists, and surgeons around who's maybe not a good candidate for this because radiation therapy, with or without cisplatin chemotherapy, remains a good option for many of these patients. But I think the consensus, especially among the surgeons in this group, were that patients with tumors were more endophytic - that's the old fashioned oncology and surgical oncology term that refers to tumors that seem to not be as evident on the surface and have more of an infiltrative deep growth pattern - these are not ideal tumors. Whereas an exophytic tumor that's growing upwards, that's more readily seen on flexible endoscopy during a routine clinic assessment, or frankly, better seen on imaging, those exophytic tumors are better suited to a surgical approach because the surgeon has a better chance when he or she sees the tumor to get a good margin. When we can appreciate not just the surface mucosal margins that need to be taken, but also have a better chance to appreciate their depth. And with those infiltrative tumors, it's much harder to really

11/02/2025

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22 min
19/07/2021

Management of the Axilla in Early-Stage Breast Cancer: OH (CCO) and ASCO Guideline

An interview with Dr. Muriel Brackstone from London Health Sciences Centre and Dr. Tari King from Dana Farber and Brigham and Women's Cancer Center, authors on "Management of the Axilla in Early-Stage Breast Cancer: OH (CCO) and ASCO Guideline." This guideline addresses management & timing of surgical and radiotherapeutic treatment of the axilla in early breast cancer. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey. TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcast.asco.org. My name is Brittany Harvey, and today I am interviewing Dr. Muriel Brackstone from London Health Sciences Center in London, Ontario and Dr. Tari King from Dana-Farber and Brigham and Women's Cancer Center in Boston, Massachusetts, authors on "Management of the Axilla in Early-Stage Breast Cancer" Ontario Health (Cancer Care Ontario) and American Society of Clinical Oncology Guideline." Thank you for being here Dr. Brackstone and Dr. King. DR. MURIEL BRACKSTONE: Thank you. DR. TARI KING: Thank you for having us. BRITTANY HARVEY: First, I'd like to note that we take great care in the development of our guidelines in both the ASCO and Ontario Health Cancer Care Ontario program and evidence-based care. Conflict of interest policies were followed for this guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Brackstone, do you have any relevant disclosures that are directly related to this guideline topic? DR. MURIEL BRACKSTONE: No, I don't have any conflicts to disclose. BRITTANY HARVEY: Thank you. And Dr. King, do you have any relevant disclosures that are directly related to this guideline topic? DR. TARI KING: No, I do not have any relevant disclosures. BRITTANY HARVEY: Great, thank you. Then let's get into some of the content of this guideline. So first, Dr. Brackstone, can you give us a general overview of what this guideline covers? DR. MURIEL BRACKSTONE: Sure. This guideline reviews how best to diagnose and treat any lymph node spread in breast cancer patients with early-stage disease. It also reviews the role of radiation and surgery in treating the axilla to reduce the risk of regional cancer recurrence in these patients. BRITTANY HARVEY: Great, thank you. Then I'd like to review some of the key recommendations that this guideline covers. So this guideline addresses five specific objectives. So I'd like it if we could go through each of those. So for each of these objectives, could you give an overview of those high level recommendations? First, Dr. King, the first objective is about which patients with early-stage breast cancer require auxiliary staging. DR. TARI KING: Yes, thank you. So I think the two main takeaway points from this objective-- the first is that sentinel lymph node biopsy really is the standard of care for axillary staging for all breast cancer patients when it is felt that information about the lymph node status is necessary. So this really is in the majority of patients that we see and care for with early-stage breast cancer. We want to know the status of the axillary lymph nodes. That's important in our subsequent treatment recommendations. And there's really no role for axillary lymph node dissection as a staging procedure any longer. Sentinel lymph node biopsy is the staging procedure of choice. Now, there are some patient populations, however, where we may decide that we don't need the information from the axillary lymph nodes to make subsequent treatment recommendations. And one particular group which is called out in this guideline is for those women who are over the age of 70 with early-stage, again, clinically node-negative hormone receptor-positive, HER2-negative breast cancer, where the information from the sentinel lymph node biopsy is not going to alter subsequent systemic therapy recommendations. And this is really based on several lines of work demonstrating that omitting sentinel node in these older women, again, with hormone receptor-positive, HER2-negative breast cancer, does not negatively impact their long term outcomes. And so this is an opportunity for us to tailor our approach to a particular patient population without having a negative impact. BRITTANY HARVEY: Great, thank you, and thank you for reviewing for which patients this is specifically targeted to. So then for the second objective, Dr. Brackstone, is further auxiliary treatment indicated for women with early-stage breast cancer who did not receive neoadjuvant chemotherapy and are sentinel lymph node-negative at diagnosis? DR. MURIEL BRACKSTONE: No. We use this guideline to confirm that in patients who have early-stage disease and go to surgery first, so they're not having neoadjuvant chemotherapy. And in those patients, if their sentinel lymph node excision for staging is negative, that no further axillary surgery is required. Now, with regards to axillary radiation, it may be considered in the subset of patients whose breast cancer risk is high for recurrence-- so the triple negative subtype, patients who are under 50 years of age, or those with medial tumors. BRITTANY HARVEY: OK. And then Dr. King, for the third objective, which axillary strategy is indicated for women with early-stage breast cancer who did not receive neoadjuvant chemotherapy and are pathologically sentinel lymph node-positive at diagnosis after a clinically known negative presentation? DR. TARI KING: Thank you. Yes, so this recommendation really addresses a very large population of our breast cancer patients. Those that present with clinical T1 and T2 but node-negative early-stage breast cancer, we take them to the operating room. We perform a sentinel biopsy, and about 20% to 30% of them will actually end up having positive lymph nodes. And traditionally, we thought that we needed to do axillary lymph node dissection in the setting of positive nodes. But we now have multiple clinical trials that have addressed this question. And we now know that it is safe to avoid lymph node dissection in women found to have one or two positive sentinel nodes. We've had trials that have compared lymph node dissection to axillary radiotherapy or lymph node dissection to observation alone. And with either of those strategies, we've seen excellent local control in the women who have not undergone lymph node dissection. And so it really provides us, again, an opportunity to dial back or tailor our therapies to the patient's individual disease burden. Now, certainly, patients that have more than one or two positive nodes, and the guideline specifically states how to manage patients with three or more positive nodes. And those patients do need additional axillary treatment, either in the form of lymph node dissection or lymph node dissection plus axillary radiotherapy and in some scenarios. Also, the guideline is very clear to define that there are some differences in the level of recommendation for women undergoing breast-conserving surgery and found to have one or two positive nodes as opposed to women undergoing mastectomy and found to have positive nodes. So certainly, we have the larger body of data in the breast-conserving therapy group, but the guideline is very clear to also highlight the data that is available for the mastectomy group. And again, the overall recommendation is that not everybody with positive nodes needs additional lymph node dissection. And that we have alternatives which we know minimize the morbidity of our treatments. BRITTANY HARVEY: Great. Thank you for addressing the evidence base behind both of those recommendations as well. So following that, Dr. Brackstone, for the fourth objective, what axillary treatment is indicated? And what is the best timing of axillary treatment for women with early-stage breast cancer? And when is neoadjuvant chemotherapy used? DR. MURIEL BRACKSTONE: Right. So this guideline was really used to formalize a recommendation against repeating the sentinel lymph node biopsy procedure twice in patients, before and after chemotherapy. We really found that the risk of false negativity in a repeat procedure was too high. So for patients who are having neoadjuvant chemotherapy-- so patients with higher risk cancers-- the axillary ultrasound is useful to guide a biopsy of any suspicious lymph nodes to document if they're positive. If the clinical exam and the ultrasound are both negative, then the sentinel lymph node excision should be done at the time of surgery after chemotherapy. If they do have a positive lymph node that's confirmed by biopsy before their chemotherapy, and those lymph nodes respond really well to chemotherapy and are no longer palpable, then their staging can occur by sentinel lymph node procedure at the time of surgery. And that avoids what we have standardly done up to now, which is the axillary dissection and the risk of lymphedema that comes with that. If the sentinel lymph nodes are negative when you're doing your surgery after neoadjuvant chemotherapy, then we are recommending that no axillary lymph node dissection is required. If any of the lymp

19/07/2021

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13 min
04/08/2022

Chemotherapy and Targeted Therapy for HER2-Negative Metastatic Breast Cancer that is Either Endocrine-Pretreated or Hormone Receptor–Negative: ASCO Guideline Rapid Recommendation Update

An interview with Dr. Beverly Moy from Massachusetts General Hospital in Boston, MA, lead author on "Chemotherapy and Targeted Therapy for HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Rapid Recommendation Update." Dr. Moy reviews data from the recently published DESTINY-Breast04 study, and the ASCO Expert Panel's updated recommendation on the use of trastuzumab deruxtecan. For more information, visit www.asco.org/breast-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guideline podcast series brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Beverly Moy from Massachusetts General Hospital in Boston, Massachusetts, lead author on 'Chemotherapy and Targeted Therapy for HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Rapid Recommendation Update'. Thank you for being here, Dr. Moy. Dr. Beverly Moy: It's my pleasure. Thank you for having me. Brittany Harvey: Great. First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Moy, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Beverly Moy: I do not have any relevant disclosures that are directly relevant to this guideline topic. Brittany Harvey: Thank you. Then let's talk about this rapid update. So first, what prompted a rapid update to this guideline on chemotherapy and targeted therapy for patients with HER2-negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor-negative, which was last updated in 2021? Dr. Beverly Moy: First, I would state that ASCO issues rapid guideline recommendation updates when really important advances in the treatment and management of cancer have been presented. This mechanism really allows clinicians to keep up with the rapid advances in cancer management. The fact that a rapid update had to be issued just one year after the full updated guideline that was published in 2021, as you just mentioned, is really a testament to the advances in cancer research and clinical trials that have been made recently. But I will state that the reason why this rapid update was done was because the result of the DESTINY-Breast04 study were so strong and compelling and showed such a large degree of benefit to a large group of metastatic breast cancer patients that we felt as the guideline panel that this rapid update had to be out there. We really wanted to make sure that the oncology community was aware of these results. That's based on the strength of the trial. The DESTINY-Breast04 trial was a very large randomized study that showed that trastuzumab deruxtecan significantly improved progression-free survival and overall survival compared to treatment of physician's choice in patients with metastatic, "HER2-low" breast cancer. Brittany Harvey: So then based off this new data from the DESTINY-Breast04 trial that you just mentioned, what is the updated recommendation from the guideline expert panel? Dr. Beverly Moy: So the updated recommendation is that patients with HER2-low, or to be specific, HER2 IHC1+ or 2+ and ISH negative metastatic breast cancer who have received at least one prior chemotherapy for metastatic disease, if they're hormone receptor-positive, are refractory to endocrine therapy, those patients should be offered treatment with trastuzumab deruxtecan. Brittany Harvey: And then what should clinicians know as they implement this new recommendation for trastuzumab deruxtecan? Dr. Beverly Moy: I think that there are a few things that clinicians really need to be aware of. One is that it significantly improved progression-free survival and overall survival, and that's pretty important. The paper was published in the New England Journal of Medicine, and folks can refer to that study specifically. But to be specific, it improved progression-free survival at a median follow-up of about 18 months from 9.9 months with trastuzumab deruxtecan compared to 5.1 months with treatment of physician choice in the entire study population. Median overall survival was 23.4 months with trastuzumab deruxtecan and 16.8 months with treatment of physician's choice. So that's really a marked improvement in both of those outcomes. It is also important to note that trastuzumab deruxtecan has a very important side effect, and that's the potential of developing drug-related interstitial lung disease or pneumonitis. And that could be very serious. This side effect was confirmed in about 12% of the patients who received trastuzumab deruxtecan, and about 1.3% of patients actually had severe symptoms requiring oxygen, and three patients in the study, so less than 1% actually died of this side effect. So that's something that needs to be monitored for very carefully, and clinicians need to be very cognizant of this potential side effect when using this drug. Brittany Harvey: Thank you for reviewing both the impact on survival and then the adverse event of interstitial lung disease. So how does this guideline update impact patients with breast cancer? Dr. Beverly Moy: So metastatic breast cancer is incredibly common. And this HER2-low, and I say, "HER2-low" because this is a definition that has never been made before. The patients with HER2 IHC1+ or 2+ and ISH negative disease, that's a very large group of patients. That's a lot of patients. So it's really important that this guideline is going to impact a very large group of patients. Again, it's those who've had at least one prior line of chemotherapy in the metastatic setting. And if they had hormone receptor-positive disease, it has to be refractory to endocrine therapy. But that's a lot of patients. And the results of this randomized study do show that trastuzumab deruxtecan is superior to other treatment of physician's choices that were available before this study came out in terms of its efficacy. So this guideline is very significant for clinicians and metastatic breast cancer patients across the world. Brittany Harvey: Definitely. It's great to have a new option and one that has such a great clinical impact for patients. So then finally, Dr. Moy, what are the outstanding questions regarding chemotherapy and targeted therapy for HER2-negative metastatic breast cancer? Dr. Beverly Moy: I think like any good study, this raises a lot of other important questions. Again, this HER2-low definition that I described is an interesting one. It's a very large bucket of patients. One obvious question is, would this drug be as effective in patients who are truly HER2-negative, so HER2 IHC of 0? Kind of, overnight, the results of this study has changed the paradigm for many oncologists because we used to just say HER2-positive or HER2-negative. And now we're looking back at patients' charts to see what their immunohistochemistry results were. Does it really matter if it's IHC 0 or 1+ or 2+? So that would be very interesting. Another outstanding question is: what about the use of trastuzumab deruxtecan earlier in the treatment? I said that it should be offered for patients who've received at least one prior line of chemotherapy? What about first line chemotherapy in the metastatic setting? And there are multiple studies studying this drug in actually early stage breast cancer as well. So lots of unanswered questions about this compound that's pretty remarkable. Brittany Harvey: Great. Well, I want to thank you so much for your time today, Dr. Moy, for discussing the results of the DESTINY-Breast04 trial with me, and for your work to rapidly update this guideline. Thank you so much. Dr. Beverly Moy: Thank you, Brittany. It was a pleasure. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

04/08/2022

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9 min
27/02/2025

Therapy for Stage IV NSCLC Without Driver Alterations: ASCO Living Guideline Update 2024.3 Part 1

Dr. Lyudmila Bazhenova joins us again to share the newest changes to the living guideline on therapy for stage IV NSCLC without driver alterations. She discusses new evidence reviewed by the panel and changes to second-line recommendations for patients with good performance status and HER2 overexpression, and what these updates mean in practice. We discuss ongoing evidence generation as we await further updates to these living guidelines. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3" at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02786 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, co-chair on "Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3." It's great to have you back on the show today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It's my pleasure to be here as always. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the entire guideline panel, including Dr. Bazhenova, who has joined us here today, are available online with the publication of the guide in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into the content here, first, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations has frequent updates to the recommendations. What prompted this latest update? Dr. Lyudmila Bazhenova: Living ASCO guidelines are created to keep up with rapidly changing evidence which affect treatment of our patients with lung cancer. As a committee, we review published literature on a specific topic at the regular intervals and determine if it alters any recommendations. This time, upon our literature review, we felt that there are new data that requires an update in the guidelines and therefore the guidelines were updated. Brittany Harvey: Great. Thank you for that updated information. So then it looks like the panel updated recommendations for second line and subsequent treatment options for patients with good performance status and HER2 overexpression. What is that updated recommendation from the panel? Dr. Lyudmila Bazhenova: Yes, this is correct. We now added an extra recommendation for patients with stage IV non-small cell lung cancer who have overexpression of the protein called HER2. HER2 overexpression with 2+/3+ level via immunohistochemistry is seen in approximately 8% to 20% of patients with lung cancer. And the data behind our recommendation comes from the DESTINY-Lung01 trial where patients with HER2 overexpression were treated with trastuzumab deruxtecan. And we saw that if patients with stage IV non-small cell lung cancer had a HER2 IHC score of 3+, overall response rate was seen at 53% and median duration of response was 6.9 months and, therefore, that in our opinion qualified for updated recommendation. We are still waiting for additional results that will be released later on another clinical trial where we see preliminary data presented at the World Conference of Lung Cancer in 2024. They looked at 36 patients also with HER2 overexpression and saw the overall response rate of almost 45%. It is important to highlight in this smaller study that a majority of the patients in the study were actually having EGFR mutation and the response rate in those patients who had an EGFR mutation was higher than the response rate in patients without EGFR mutations who just had a HER2 overexpression. So for now this is updated in the guidelines, but we will wait for additional data or formal publication of a World Lung Conference presentation and see if those recommendations need to be changed. Brittany Harvey: Understood, and I appreciate you providing the context of some of those ongoing developments as well. So then what should clinicians know as they implement this updated recommendation? Dr. Lyudmila Bazhenova: Number one, we should all start from remembering to test for HER2 via immunohistochemistry. There is a slight difference in what considers HER2 positive in lung versus breast. In lung, we use what's called the gastric scoring and the difference is the circumferential versus non circumferential staining of the membrane. And number two, immunohistochemistry is not always included in next generation sequencing panels. So when you order your next generation sequencing, I think it's important to know if your company that you're using is testing for HER2 via immunohistochemistry. And if it's not, make sure that you find a company that does or work with your local pathology department to make sure that this testing is offered. It is also important to know the difference between HER2 overexpression and HER2 exon 20 insertion mutation even though the treatment for those two abnormalities is the same, which is trastuzumab deruxtecan. But the benefit that you can cite your patients and the rigor of the literature supporting the usage of trastuzumab deruxtecan in mutation versus overexpression is different. Brittany Harvey: Yes. And as you mentioned, it's essential that, in the first place, patients are actually receiving the testing so that we know if they're eligible for these treatment options. So what additionally does this change mean for patients with stage IV non-small cell lung cancer and HER2 overexpression? Dr. Lyudmila Bazhenova: So for patients, it adds another treatment modality which is now FDA approved. So if there are patients listening to me, make sure that your physician has tested your tumor for HER2 overexpression. So I think proactive asking of your physician would be very appropriate in this situation. Brittany Harvey: Absolutely. And then earlier you mentioned an ongoing trial that the panel was looking to for the future. But what other additional trials did the panel review during this guideline update and what is the panel examining for future updates to this living guideline? Dr. Lyudmila Bazhenova: So at this point we reviewed three additional studies. The results of those studies did not make it into a change in guidelines. So we reviewed the HARMONi-2 trial. HARMONi-2 trial so far does not have an official publication and, as per our strategy on how we come up with ASCO guidelines, we need to wait for an official publication. So this is one thing we're going to be expecting in the future. Once this is published, we will review it and decide if we need to make an additional change in recommendations. For those of you who are not aware, HARMONi-2 trial used bispecific monoclonal antibody against VEGF and PD-1 and was a phase III randomized trial comparing their investigational product which is called ivonescimab over pembrolizumab for patients with PD-L1 more than 50. And again, we are waiting for the final publication to make our recommendation. The second trial we reviewed was a LUNAR trial and the LUNAR trial looked at addition of tumor treating fields to chemotherapy or immunotherapy in patients whose cancer progressed with platinum doublet. The key point about this study is that immunotherapy was not required to be administered in a first line setting which is a current standard of care in the United States. And even though the study met their primary endpoint of overall survival, there were more benefits in patients who were immunotherapy naive in the second line. And we felt that given the potential lifestyle implication of wearing a device for 18 hours per day, and the lack of evidence in immunotherapy-pretreated population, and the absence of data in the first-line setting where we currently using immunotherapy in the United States, we felt that there is insufficient data to definitely recommend addition of tumor treating fields to systemic chemotherapy for most patients. And we are waiting for additional trials that are ongoing in this setting to formalize or change our recommendations. And we also reviewed- the final study that we reviewed was TROPION-Lung01. TROPION-Lung01 study was a phase III study in post platinum doublet setting which compared efficacy of Dato-DXd and docetaxel and trials showed improvement in progression free survival but not in overall survival. And progression free survival benefit was more pronounced in non-squamous carcinoma histology subgroup and we felt that the results do appear promising, but the strength of evidence which was based on unplanned subgroup analysis was not sufficient enough to make a change in treatment recommendation at this time. Brittany Harvey: I appreciate your transparency on why some of that data did not prompt a change to recommendations at this time. And additionally, we'll look forward to those future published results and potential incorporation of new data into future versions of this living guideline. So, I want to thank you so much for your work to rapidly and continuously update this guideline and for your time today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It is my pleasure. Thank you so much. Brittany Harvey

27/02/2025

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11 min
13/02/2025

High Omega-3, Low Omega-6 Diet with Fish Oil and Prostate Cancer

Host Dr. Shannon Westin and guests Dr. Bill Aronson discuss the article "High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial" and how Omega-6 are predominant in the American diet while the study significantly lowered the intake of Omega- 6 fats. TRANSCRIPT 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, Dr. Shannon Westin, GYN Oncologist by trade and one of the grateful Social Media Editors of the JCO. And I am very excited to welcome a special guest today, Dr. William Aronson. He is professor of Urology in the UCLA Department of Urology, the Chief of Urology at Olive View UCLA Medical Center, and Chief of Urologic Oncology at the Veterans Administration West Los Angeles. Welcome, Dr. Aronson. Dr. William Aronson: Thank you, Shannon, and delighted to be here. Dr. Shannon Westin: We are so excited to have you discussing your manuscript, "High Omega-3, Low Omega-6 Diet With Fish Oil for Men With Prostate Cancer on Active Surveillance: The CAPFISH-3 Randomized Clinical Trial," which was published in the Journal of Clinical Oncology on December 13, 2024. So let's get right to it. First of all, you know we have a very mixed audience, so can you just level set for us and speak about the population you studied in this important trial - that low risk, favorable, intermediate risk prostate cancer. How common is that? How is it defined? That would really help. Dr. William Aronson: I would say about 50% of the patients that we diagnose with prostate cancer either have low risk disease or what we call favorable intermediate risk disease. So when the pathologists look at the cancer under the microscope, they assign what's called a Gleason grade. Grade 3 is the slower growing type of prostate cancer, grade 5 is the fastest growing type, and grade 4 is somewhere in between. So a low risk group would be only the grade 3, the slower growing type. And the favorable intermediate risk group would actually be the grade 3+4, which means they mostly see the low risk type in there, but they also see the slightly faster growing type, grade 4. So this is what we typically see. We see these patients on a very regular basis when they're newly diagnosed with prostate cancer. Dr. Shannon Westin: Okay, got it. And then can you walk us through just what the management options are typically for this patient population? Dr. William Aronson: So typically for what we call the low risk group, the patients with a low PSA and only that grade 3 type, slower growing type of prostate cancer, the standard recommendations are active surveillance. So typically, we'll periodically monitor these patients with PSA blood testing and periodically do prostate biopsies depending upon the patient's other medical problems. Dr. Shannon Westin: So I think it would also be really helpful just to understand what your typical management options are for this patient population. Dr. William Aronson: So for patients with low risk prostate cancer, they only have the Gleason Grade 3+3 with a low PSA. The standard practice is observation. And so these men will periodically see them and measure their PSA values. And periodically, they'll undergo prostate biopsy to make sure they're not getting progression of their disease. For men with favorable intermediate risk prostate cancer, that's a little different. In some practices, the patient and the urologist will decide to do active surveillance. In other scenarios, these patients will definitely elect treatment, either with radical prostatectomy or radiation therapy or other treatments that are available. Dr. Shannon Westin: So your manuscript notes that there was a high level of interest in dietary supplements and approaches among patients with prostate cancer that do elect for active surveillance. Prior to the results of CAPFISH-3, did we have any data to support those types of recommendations? Dr. William Aronson: We actually don't have any long term prospective randomized trials that support that recommendation. There have been a number of very interesting epidemiologic studies, for example, suggesting maybe a plant-based diet might be helpful. Or a number of other studies suggesting maybe more tomato-based products like tomato sauces or tomato paste may be helpful. But no prospective longer term randomized trials that were positive. Dr. Shannon Westin: Okay, that makes sense. So what led you all to explore the high omega-3, low omega-6 fatty acid diet in this trial? Dr. William Aronson: After our initial omega-6 studies, we subsequently did some studies where we raised the omega-3 from fish oil and lowered the 6, looking at a more favorable ratio of the omega-3 to omega-6. And once again, we found that in our animal models, there was a significant delay in progression of prostate cancer. That then led us to perform a clinical trial. It was a short term trial in men prior to undergoing radical prostatectomy. And in these men, they were randomly assigned to one of two groups, either a western high fat diet or a low fat diet with fish oil. And we found after just four to six weeks, a significant change in the Ki67 level in their radical prostatectomy tissue. And Ki67 is actually a strong indicator of prostate cancer progression, spread, or even death from prostate cancer. Dr. Shannon Westin: Well, and I think that leads us really nicely into the design of the current study. So why don't you walk us through how CAPFISH-3 was designed. And you've already spoken a little bit about your primary endpoint. Dr. William Aronson: Based on the results of what we saw in the lab and what we saw in our short term clinical trial, we decided to perform a one year trial, a longer term trial in men on active surveillance. And these men were randomly assigned to either a diet with slight reduction in dietary fat, specifically reduction in the omega-6 intake as well as increase in foods with omega-3 and fish oil capsules. The other group, we asked the men to just not take fish oil capsules, but they could eat whatever else they wanted during the course of the study. Men in the diet where we lowered the omega-6 and raised the omega-3, they were seen by a dietitian once a month to really ensure that they were compliant with that intervention, which they were. The other intriguing part of our study, which I think is super important, is the precision that was used when these men underwent prostate biopsy. So, at baseline and at one year, when these men underwent prostate biopsy, they had the same site within the prostate biopsied. That's important because it's not so easy to find the same site within the prostate because of heterogeneity throughout the prostate. And so we were able to obtain that high level of precision as they were in an active surveillance program at UCLA with Dr. Leonard Marks. Dr. Shannon Westin: So we spoke a little bit about what's important about the Ki67 index as your primary endpoint. Can you talk a little bit about what the study found with your intervention? Dr. William Aronson: So we found that the Ki67 index increased by 24% in the control group and decreased by 15% in the low omega-6, high omega-3 group with fish oil capsules. So that ended up resulting in a statistically significant change between the groups favoring the low omega-6, high omega-3 group. Dr. Shannon Westin: And then what were the secondary endpoints that CAPFISH-3 explored? Anything of note that you want to review for the listeners? Dr. William Aronson: So a number of positive secondary endpoints from the trial. Firstly, we saw that the triglyceride levels were lower, which is what can typically be seen with omega-3 intake. We also saw reduced levels of a cytokine, a circulating factor in the bloodstream called 'macrophage colony stimulating factor'. And that's particularly interesting because there's a certain type of macrophage which is well known to be involved in prostate cancer progression in men with more advanced prostate cancer, and we've been able to inhibit that in our animal models and in our tissue culture studies. And it was especially interesting to see that we did have an effect on this particular cytokine in this prospective randomized trial. We did not see changes in a number of other measures, including Gleason grade or PSA. These are measures that we use in clinical practice. To see an effect on those would have required a longer term and larger study to be performed. Dr. Shannon Westin: That makes sense. I think it's always great to try to get as much of these types of translational data as we can. But sometimes you just have to do what is reasonable and you get what you get. It looks to me like this regimen was fairly well tolerated. Did you obtain any patient reported outcomes or feedback on the trial? Dr. William Aronson: So, there were four patients in the fish oil group that did have some side effects, and we withdrew them from the study. They did have some effects on their upset stomach, and a number of men also had some diarrhea as well. And so for those four patients, we did withdraw them from the study. Dr. Shannon Westin: And then I guess the last question I have is really, what's next for this intervention? Are we ready to move this to the clinic or what do you see as next steps? Dr. William Aronson: Well, this next step that we're working on right now is to better understand exactly what happened in these patients. So we have blood, we have tissue, we're doing genetic studies on these patients. So that's really the first step, in our mind, to better understand what happened before moving to the next step. I'm particularly intrigued about trying this intervention in men with more advanced prostate cancer, specifically because of what w

13/02/2025

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12 min

ASCO Podcasts by the American Society of Clinical Oncology, cover a range of educational and scientific content, offering enriching insight into the world of cancer care. Hear innovative interviews with the authors, researchers, and clinicians who are defining today’s standard of care and tomorrow’s breakthroughs. You can find all ASCO podcasts and limited series at ascopubs.org/podcasts