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Welcome to the Quick Consult podcast, brought to you by Metall. Before starting this podcast, please review the faculty information, disclosure statements, and learning objectives using the link in the episode description. To claim your CME credit, complete the evaluation using the link in the episode description. This podcast episode is a continuing education activity managed and accredited by Global Education Group in collaboration with MTA. This activity is supported by an independent medical education grant from Pfizer and Arvina. Hello and welcome to the Metal CME podcast, an expert-led podcast series from Medal Education. I'm your host, Doctor Phil McIlmay, and this series is part of a broader educational initiative designed to advance the understanding and treatment of endocrine receptor positive, HER2 negative metastatic breast cancer. And in this episode, So we're going to be looking at how to put biomarkers to work and tackle a dynamic gap in oncology today. It gives me great pleasure to introduce our expert guest today, who is Doctor Seth Wander, and Doctor Wander is a medical oncologist at the Mass General Hospital with a clinical and translational research interest in metastatic breast cancer and cancer genomics. Doctor Wonder, thank you so much for joining us. My pleasure. Thanks for the invitation. I wanted to dive straight into, to putting biomarkers to work, and biomarkers like ESR1, PICC3CA, HER2 low are increasingly important in guiding treatment. How do you approach incorporating these results into your real world treatment decisions? Yeah, thanks for the question. Uh, we've entered a really exciting. time, uh, as you were alluding to a moment ago in the treatment of hormone receptor-positive HER2 negative metastatic breast cancer, I would say we are well into the era of precision medicine and personalized oncology for, for this very large, uh, patient population. Now, if you were to ask that question to 5 or 10 different breast cancer oncologists, you might hear slightly different answers as to how we approach testing for the various biomarkers you mentioned. In My own practice, at the time of metastatic diagnosis, will typically have a tissue sample that we use to identify metastatic disease. I will send that sample for targeted sequencing. And we have an in-house uh panel of, you know, 300 to 400 genes, but there are many commercially available uh assays that you can use for that as well. I will also send a liquid assay, a circulating tumor DNA assay at the same time. So, at the time of medicine, Static diagnosis in my own practice, I'll have a solid biopsy, and I'll have a liquid assay. The concordance rates between those are about 80+%, but occasionally, you might see an alteration that's picked up on one, but not on another. Then the patient will go on first-line therapy, and at the time of progression, I will typically repeat the liquid biopsy. I won't redo a solid biopsy, unless there's a, a clinical reason to do that, like One lesion behaving differently or something like that. What we've seen is that some alterations are present, sort of regardless of when you test or how you test. We call those truncal. They're there early in the course of metastatic disease, and, you know, it's, it's easy to pick them up regardless of which platform or assay you use. On the other hand, something like ESR1, which is an acquired mutation, it tends to occur under select. collective pressure on specific drugs, they might be missed if you're only looking at the baseline or the earlier sequencing. And they might also be missed if you're doing a solid biopsy, but it's being released from some other tumor focus across the body. So, this is the reason why as a field, I think we're moving more toward liquid assays, circulating tumor DNA, and we're moving more toward a place where we're repeating those assays over time. Now, as of today, We typically are doing that at progression, but um we were just talking about the Serena 6 data, where you actually have now prospective clinical trial data to test liquid assay before clinical or radiographic progression, to identify ESR1 as a driver of anti-estrogen resistance. That data, I think is quite provocative. I think it really could change the face of how we treat this disease, but for the moment, we don't yet have an FDA approval or a Guideline-based way to deploy that. I think it's a sign of where we're going as a field more than it is sort of what we're doing right now. To answer your question again directly, I'm usually doing solid and liquid at the time of diagnosis, and then I repeat liquid at clinical radiographic progression. I think in a moment, we'll talk a little bit about how we use those results to change therapy. I think we're moving toward a place where we start to integrate more frequent testing, even before clinical progression. So that we aren't in a situation where patients miss their window of opportunity to get some of these drugs because of more aggressive symptoms and, and clinical features. That's super clear. Some clinicians have reported inconsistent application of biomarker testing. What are the biggest barriers you see to its implementation? Can education close, close the gap? I think, I think there are multiple barriers, and it's, it's not easy to, to radically change our Approach to, to cancer therapy. If you look just within the last 5 to 10 years, there are huge, you know, whirlwind changes in terms of how we think about approaching these patients. In the not too distant past, patients were sort of getting the exact same sequence of therapies all the time. And so, there is, I think, an educational gap, right? We have to make sure that, that clinicians are understanding that we now have many more options, but that these options have to be particularly Personalized and deployed based on the molecular genetic changes. It's very hard for, um, and I take my hat off to all of my colleagues who are in community practice setting, you know, they're seeing 20, 30+ patients a day, and they're going from one room with GI cancer, colon, you know, colon cancer, thyroid cancer, breast cancer, lung cancer, and all of these fields are moving at, at, like, warp speed with tons of new data coming in all the time. Now, Now, there also may be examples where we can learn from those other fields, right? Uh, how, how lung cancer is really, I think, a few years ahead of us in terms of using these different molecular alterations to personalize therapy. So, I think partly there's, there's a, an educational gap where we just need to push this information out into all of the different practice settings from academia to the community, from urban to rural, across the country and across the world. We have to be able to digest, you know, these complex Clinical trials and data into a user-friendly, you know, sort of rapid, rapid-fire approach. And then there's also probably an access issue. There's a cost barrier to sometimes getting these tests done. Sometimes there may be issues getting prior authorization or getting insurance companies to pay for them. So, I think, I think we also have to make sure that we're empowering the clinicians who want to do the testing with the data that they need in case there's a problem for the patient. Getting access and getting and getting coverage. I, I, I'm hoping that that's becoming less and less of a problem as this data continues to, to move forward in time, but, but I think it's, it's never not a problem, completely. So that's another, I think, a piece of that puzzle. Could you help us with an example? How does biomarker testing change the treatment pathway? Yeah, I, and, and I think we're actually seeing examples now in multiple lines of therapy for endocrine. Positive disease. But let me just give you a couple of examples. So, to start, imagine that we have a patient who is on adjuvant endocrine therapy. So, this may be a patient with stage 12 or 3 breast cancer. She's doing great. She's on, pick your drug of choice, uh, for example, anastrozole or letrozole, and she's 345 years in, and then she develops a metastatic recurrence. This type of scenario where a patient's on endocrine therapy and develops metastatic disease, most People would agree is more challenging than a patient who's never had endocrine therapy in the past. The disease is inherently more resistant, and up until just a number of months ago, all of those patients were treated in primarily the same way. They would get the biopsy, and if it's ER positive, HER2 negative, they would get fulvestrin, typically with a CDK inhibitor. But now, we have data from a Nova 120, where those patients who meet that, that scenario and also have PICC 3. can get a triplet regimen, Fulvestrin, palbociclib with the PI3K inhibitor, and novelissib, and that provokes better progression-free survival, disease control, and overall survival. So, there is a patient who's technically first-line metastatic, and by using the circulating tumor DNA or the, the solid biopsy, identifying PICC3CA we're actually changing our therapeutic plan and we're changing the course of disease. It gets even more. Complicated. When you look at the traditional scenario, patients are on first-line therapy with an AI and for example, ribocycllib, and they progress. Now, we have multiple alterations, ESR1, PICC-3CA, P10, AKT, all of which could open up opportunities to get multiple new drugs. For the PI3K pathway altered patients, we have alpeliib, Kapivasertib. For the ESR1 altered patients, we have Elisestrin and immunestrin, with many more in late-phase clinical development. Anti-estrogen, next-generation targeted drugs, single-agent anti-estrogen, doublet, and in the future, even triplet regimens. So, we have an ever-expanding toolbox, and in order to understand kind of which tool we need to pull out in any given scenario, we really have to have that circulating tumor DNA sequencing. Information, often at the start of metastatic disease, but certainly after progression in the, in the second line setting. With HER2 low, now recognized as a meaningful category, how do you explain its clinical importance to colleagues who may still see HER2 as binary, positive, negative? This is another really important question. Everything in medicine, I think you'll agree with me, is more complex than it might initially seem when we start to approach, and this is not true.