Developing Story: What Biomarkers Tell Us with Dr. Neil Vasan
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Live from Stage 4 | Episode #043 | 08/25/2026 | Developing Story
GUEST
Dr. Neil Vasan, MD, PhD, is a distinguished breast oncologist, physician-scientist, and the Director of Translational Research in Breast Cancer at NYU Langone Health. Armed with an Ivy League background—including degrees from Harvard and Yale—he has dedicated his career to bridging the gap between laboratory discovery and patient care. Dr. Vasan’s groundbreaking research famously identified double PIK3CA mutations as an oncogenic biomarker, a discovery that has successfully transitioned from bench to bedside to guide target treatments. In addition to running the Vasan Lab and treating patients, he serves as an Acting Chair and Standing Member of the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC), positioning him at the absolute forefront of evaluation for next-generation cancer therapies.
Quick Summary
Biomarkers are reshaping breast cancer care, but understanding what they measure is key. This episode breaks down three essential types: DNA biomarkers that identify genetic mutations, RNA biomarkers that reveal which genes are active in your tumor, and protein biomarkers like HER2 and PD-L1 that show what's actually happening at the cellular level. Learn why this distinction matters for treatment decisions and how emerging liquid biopsy platforms are making real-time tumor monitoring more accessible
Key Topics Covered
DNA biomarkers reveal genetic mutations and structural changes in the tumor's genome (like BRCA1/BRCA2) — they show what's in the blueprint.
RNA biomarkers measure which genes are actively expressed in your specific tumor — they show what's actually turned on.
Protein biomarkers reflect the functional output of gene activity (HER2, PD-L1) — they show what the tumor is doing.
PD-L1 is a predictive biomarker that helps determine if immunotherapy checkpoint inhibitors are likely to work for your tumor.
PD-L1 expression varies — it can be heterogeneous within the same tumor, and how it's scored depends on the assay and antibody used, making it an imperfect but clinically meaningful measurement.
In triple-negative breast cancer, PD-L1 status directly influences treatment selection decisions.
Liquid biopsy platforms are making it easier to monitor tumors through blood tests and enrolling patients nationwide in real-time research studies.
Understanding which layer of biology your biomarker testing is measuring — DNA, RNA, or protein — helps you ask better questions about what results mean for your treatment plan.
Clinical Trials Cited
SERENA-6 — Studied ESR1 mutations and oral selective estrogen receptor degraders (SERDs) for response prediction in metastatic breast cancer
TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial)
TBCRC 048 (olaparib expanded) expansion cohorts: Phase 2 study of olaparib monotherapy in patients with metastatic breast cancer (MBC) with germline mutations in PALB2 or somatic mutations in BRCA1 or BRCA2 - Dr. Nadine Tung Clinical trial information: NCT02032823.
ReDiscover-2 - Phase 3 Study of RLY-2608 + Fulvestrant vs Capivasertib + Fulvestrant as Treatment for Locally Advanced or Metastatic PIK3CA-mutant HR+/HER2- Breast Cancer NCT06982521
KEYNOTE-522Pembrolizumab for Early Triple-Negative Breast Cancer
lidERA Breast Cancer — A Study Evaluating the Efficacy and Safety of Adjuvant Giredestrant Compared With Physician's Choice of Adjuvant Endocrine Monotherapy in Participants With Estrogen Receptor-Positive, HER2-Negative Early Breast Cancer NCT04961996
the PREDICT-DNA trial— Circulating tumor DNA, pathologic response after neoadjuvant therapy, and survival: TBCRC 040 Clinical trial information: NCT02743910.
Genes & Biomarkers Mentioned
BRCA1, BRCA2 (DNA biomarker, germline, high penetrance)
PALB2 (DNA biomarker, germline, high penetrance gene)
TP53 (DNA biomarker, germline, high penetrance gene) Inherited changes in TP53 point to Li-Fraumeni syndrome, a rare condition that raises the lifetime risk for many types of cancer
ATM, CHEK2 (DNA biomarker, germline, moderate penetrance genes)
PIK3CA (DNA biomarker, truncal, somatic mutation, ~40% of breast cancers)
ESR1 (DNA biomarker, drug resistance mutation, subclonal (acquired) somatic mutation, -20% of metastatic breast cancer)
PD-L1 (protein biomarker, important in triple-negative breast cancer)
ER, PR, HER2 (protein biomarker, receptor status)
Drugs Mentioned
PARP inhibitors (olaparib, rucaparib, talazoparib)
CDK4/6 inhibitors
Alpelisib, capivasertib (PIK3CA inhibitors)
Elacestrant, imlunestrant, vepdegestrant (oral SERDs)
Gedatolisib (sold under the brand name Revtorpyk(approved July 14, 2026) (dual PI3K/mTOR inhibitor)
T-DXd (HER2-targeted therapy, now in adjuvant setting)
Pembrolizumab
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Victoria Goldberg: 00:10
Could a cure for cancer be closer than you think? Welcome Live from Stage 4, where MBC takes center stage as we talk to experts, share inspiring stories, break down signs, and shine the spotlight on what matters most. Because when it comes down to it, this pod for us and by us is all about us. If you are living with metastatic breast cancer, your medical record is full of tests blood work, imaging, biopsies, and buried in those reports are strings of letters and numbers. They can look like a code you were never given the key to. But that code is your biomarkers, and cracking it could change your treatment and your prognosis. I'm Victoria Goldberg, and this is Live from Stage 4. In this episode, I'm joined by Abigail Johnston and Dr. Ellen Landsberger. We're diving deeper into what biomarkers are, which ones matter most for metastatic breast cancer, and how they're shaping the future of precision medicine. Our guest today is an old friend of the show, Dr. Neil Vasan, a physician scientist at NYU Langone, who treats breast cancer patients in the clinic and runs a lab studying how these cancers evolve and resist therapy. Few people can translate the cutting edge into plain language the way he can. And before we started, I talked about how much we enjoyed our last interview. And this is just as important and even more important for our listeners. So let's not waste any time. Let's get into it. Who wants to start? Abigail?
Abigail Johnston: 02:49
Absolutely. So let's just dive in. And if you could, Dr. Vasan, give us a definition of what a biomarker is. I know there's a lot of different kinds of biomarkers. And so if we can just start with the basics and then move into the more complicated.
Dr. Neil Vasan: 03:07
Yeah, first of all, it's great to be here. It's great to hear with old friends and new friends. Thank you for having me. So biomarkers are substances, whether they're genes or proteins or other factors that show important details about a person's cancer or cancer risk. That would be cancer biomarkers. Obviously, we look at biomarkers in all sorts of medical conditions and diseases. But of course, today we'll be talking about cancer biomarkers. And this is a very fast-moving field. It's a field where we get better and better tools, better and better magnifying glasses to help us really hone in on all the different aspects of a patient's cancer and not just their cancer, but also the way that their body is responding to the cancer. That's a different and related thing. And I think that it's one of the most important questions that we talk about in cancer. We have prognostic biomarkers, which are biomarkers that give us a sense of is this cancer more aggressive, less aggressive? Does it tell us something about its behavior? But that's more of a correlation versus a predictive biomarker where someone has actually gone in and asked a question, like if we have this test and patients who have this result from the test, if we randomize them to getting X therapy versus Y therapy, what are the outcomes? And those are called predictive biomarkers where we make really firm clinical decisions based on that. It's a great time to be talking about biomarkers, I think, because there are a lot of things in flux. I talked about the different types of magnifying glasses we have, the tools get better and better, but we're also thinking about what we're testing. Are we testing a tissue? Are we testing blood? Are we testing something else? And really what questions we're trying to ask?
Abigail Johnston: 04:47
And so if we think about metastatic breast cancer and some of the biomarkers that are looked at in breast cancer generally, we think about being an ER positive or the cancer being fueled by estrogen. We think about progesterone and then her2 the big ones in breast cancer. So for metastatic breast cancer, how important are those particular biomarkers?
Dr. Neil Vasan: 05:09
Yeah, this is a holy trinity of biomarkers, the receptor status, just as you said, Abigail.
Victoria Goldberg: 05:20
Okay, this is our first pause, and I promise you it's not going to be the last. The topic of the biomarkers is that important. So we just talked about predictive and prognostic biomarkers. And I heard Abigail mention receptor status. And I started to ask myself, is receptor status a prognostic biomarker or a predictive one? It's both. But they mean very different things. So let's break it down quickly. A prognostic biomarker tells you how a cancer is likely to behave independent of a treatment. So when we say ER or PR-positive tumors tend to do better overall, that's prognostic. But here is where it gets really useful clinically. Receptor status is also predictive, meaning it tells you who is going to respond to what treatment. ER or PR positive, you're looking at endocrine therapy, tamoxifen, aromatase inhibitors, HER2 positive. That's your signal for anti-HER2 agents,trastuzumab, pertuzumab. So receptor status isn't just telling you how bad the cancer is, it's telling you how to deal with it. That's why it's considered one of the most powerful biomarkers in all of oncology.
Dr. Neil Vasan: 06:41
It's important because these are all different diseases. Whether a woman has ER-positive breast cancer or HER2-positive breast cancer or triple negative breast cancer or even triple positive breast cancer. They're all different diseases with different behaviors, different prognoses, different responses to therapy. Very important to point out just from the get-go that essentially everything I'm talking about is at the population level. We know that individual patients can do better than what the average patient does. Unfortunately, we know the reverse is true as well, where these therapies don't work for certain patients. And that's the big challenge here. But yes, ER, PR, and HER2, very important. And to drill even further, when a woman gets diagnosed with metastatic breast cancer, we always get a tissue diagnosis of that first lesion. Because in the historical data, something like 10 to 20% of women can actually have what's called receptor switching, such that if they had breast cancer many years ago, and let's say it was ER positive, we do have groups of women when they develop metastatic disease, the disease changes and they have triple negative breast cancer. So getting that first diagnosis, that sort of first foothold on the mountain is very important. And to do that with tissue. And that's the standard of care in this country.
Victoria Goldberg: 07:47
Dr. Vasan, I wanted to ask you a follow-up on this. So, as you said, 10 to 20% may flip from the early stage to their metastatic diagnosis. But taking it a step further, can it flip while you are metastatic?
Dr. Neil Vasan: 08:04
One of the things I love about this chat is that you immediately go to the cutting edge. And that is very cutting edge. That is a controversial question in our field. We don't really know the answer to that. And this is where, again, we talk about populations and then we talk about an individual patient. This is where we get down to an individual patient. How is the cancer responding to therapy? Sometimes we see that all the lesions will get smaller. And then we think, okay, all of the cancer sort of behaving more homogeneously, more similarly. But then other times there might be heterogeneous responses where some lesions respond and maybe some stay the same or some, God forbid, get bigger. And so that type of heterogeneity are certain times when we might go in and actually ask, okay, what's going on with this one lesion? Maybe we'll biopsy it and see if there's something different that might change what therapies we give. We certainly see scenarios as well where if patients develop, let's say, brain metastases, sometimes the brain metastasis is different in its receptor subtype than what's going on in the rest of the body. So we can get additional clues. There's a new test that's been developed that's FDA approved, which I would call it sort of an imaging biomarker, which is basically a radioactive version of estrogen. It's called FES PET. So traditional PET scans are looking at a radioactive version of glucose, and that goes everywhere in the body, and it hones in on metabolically active tissues like cancer. And so there's a lot of work right now. This is very cutting edge, is trying to use that imaging biomarker to try to understand, just as you're saying, Victoria, the heterogeneity that patients can have.
Victoria Goldberg: 09:32
Okay. Dr. Vasan just mentioned FES PET, and I want to pause on this for a second because it's such a clever idea. A regular PET scan uses a radioactive form of glucose, sugar. Cancer cells are metabolically hungry, so they gobble it up, and the scan lights up wherever the cancer is active. That tells you where the cancer is, but not what's driving it. FES PET flips that instead of tagging sugar, it tags estrogen. F-18 fluorestrodiol. So the trace only lights up where there are estrogen receptor actively binding it. In other words, you're not just seeing the cancer, you're seeing which lesions are still ER-positive and estrogen driven in real time across the whole body without biopsy. FES PET is essentially a whole body receptor map. That's why it's called an imaging biomarker.
Dr. Neil Vasan: 10:43
And I think that the holy grail would be if we can take all of that data and somehow put it together for a really individualized treatment decision. And those are the real avant-garde questions that we deal with in the clinic all the time. I want to say that breast cancer is a common disease, and some patients have what I would call textbook responses, responses that sort of make sense based on everything we know. But plenty of women have different responses. And it's really important to look at every individual patient, what's going on in their scans, what's going on in their labs, what's going on with treatments and side effects and all of these things to really understand the best way to treat a woman.
Dr. Ellen Landsberger: 11:18
So basically, you're saying that at initial diagnosis, we need to define what subtype the cancer is to know how to treat it best, whether it's ER/PR- hormone receptor sensitive, HER2 positive or triple negative, and that things can change. These markers can change over time. So when there is a progression, if there is a change, do you test for those new biomarkers? And if so, how is that testing done?
Dr. Neil Vasan: 11:51
Yeah, so in general, second line, third line biopsies are actually not really the standard of care. And when I say standard of care is a textbook answer that oncologists will do. If there are scenarios like I had pointed out where there's heterogeneity and response, sometimes that prompts us to get a second tissue biopsy. But generally, for treatment decisions, we're really looking at liquid biopsies. And I think there's a lot of reasons for this. Number one, it's easier for the patient. There's no question about that. And this might be an artificial question, but if you said to a patient, like, we can get, for all intents and purposes, all the information from a liquid biopsy versus a tissue biopsy, which one do you want? Everyone's going to choose a liquid biopsy, obviously. So we have that. And I will say that the liquid biopsy, a lot has changed in the last 10 years. First of all, they're quick. It used to be many years ago that these could take a month to come back. And now they come back within almost a week. So that is the right amount of time to really make quick clinical decisions that patients need. The second is the depth and the breadth of the testing. A very long time ago, we used to test just individual sites in individual genes. And that's obviously just a really tiny glimpse of what's going on in the whole cancer. And now we get what's called panel testing, which is measuring hundreds of genes, genes that we care about in cancer, and looking for those changes. And so we're able to get a depth that we really haven't been able to get to before. And when I was talking before about the magnifying glass getting better and better, that is very cutting edge. And we're able to get more resolution out of smaller amounts of tissue, smaller amounts of blood, et cetera.
Victoria Goldberg: 13:22
Let's put this in perspective. Because the leap from old-fashioned tissue biopsy to panel testing is huge. The classic workup went like this a surgeon or radiologist takes a physical piece of the tumor with a needle or in the OR. A pathologist looks at it under a microscope and runs a handful of stains, ER/PR/HER2, one procedure, one side, a few markers. And if the cancer changed over time, a little bit different in another part of the body, what happens then? You would need another biopsy to know. Panel testing is a different animal. From that same small sample, or even just a tube of blood, we can sequence hundreds of cancer-related genes at once. Instead of asking three or four yes or no questions, we're reading the pages of the tumor playbook. Which mutations are driving it, which resistance mechanisms are emerging, which targeted drugs might work. So think of it this way: the biopsy under a microscope tells you what the cancer looks like. Panel testing tells you what the cancer is planning. And as Dr. Vasan just said, we can now get all of that from smaller and smaller amounts of tissue or blood. The magnifying glass just keeps getting better.
Dr. Neil Vasan: 14:56
Getting these tests, I think, is very important. And a lot of us are really depending on that more in the later line settings than a tissue biopsy. But again, it's very individualized for each patient. And we talked about receptors. Obviously, we're also interested in germline mutations as well. That's mutations in cells everywhere else in the body that might be contributing to why someone developed breast cancer, but they're in genes that can be passed on to your kids that your siblings have, et cetera. So in that mutation realm, there's a lot of questions we have there and granularity.
Dr. Ellen Landsberger: 15:29
Can you identify some of those? The germline mutations that we'd be interested in, and also then the other mutations that occur over time with treatment. Maybe separate them out.
Dr. Neil Vasan: 15:43
Yeah. I'll talk first about germline. There's more of a history around that, obviously, with BRCA 1, BRCA 2. There are other genes as well, PALB2, which has gotten a lot of notoriety. There was a New York Times article PALB2 in the last year and how this is a gene that does predict for response to PARP inhibitors. It hasn't ever been tested in a phase three trial, but we have excellent earlier phase data. Nadine Tung and Melinda Telli and others have really led this field. Those are what we call the high penetrance genes, meaning that if a patient has that mutation in all the cells in her body, the chance that she would develop breast cancer is a high chance. Then we have moderate penetrance genes like ATM,CHEK2. These are other genes that are, again, moderate penetrance. These are tricky genes because they do predispose to breast cancer and other cancer types. There's a lot of controversy into what to do with patients who have these germline mutations. Do they get additional scans? Do they get ultrasounds of the pelvis? All these other types of cancer that the genes can predispose to. We're actually not sure. And I will say that this is a tough area because even the different professional societies disagree on what they recommend, which is not great for patients at the end of the day. That's something we have to figure out as a medical community how to harmonize that. And then there are a lot of these low penetrance alterations we see on reports, and we don't necessarily change anything or do anything different because of that. I will say that there's a big difference between what we call a pathogenic mutation, which is a mutation where we know that this leads to a loss of function of that gene or loss of function of the protein, versus what we call a VUS or a variant of uncertain significance. Are theoretically, we don't know what they do, but what's happened in the last 10 years is due to a lot of work actually in the laboratory, we as a field have been able to reclassify some of those alterations so that what was once called a VUS is now called something pathogenic or normal.
Victoria Goldberg: 17:37
Let me slow down on this one. Because a pathogenic mutation versus variant of uncertain significance trips up almost everyone, and the difference really matters. Think of a gene like BRCA-1 as a recipe for a protein. In this case, a protein that repairs a damaged DNA. A pathogenic mutation is a typo in that recipe that we know will ruin the dish. The evidence is in that this change breaks the gene, but the protein doesn't work, and DNA repair prevails. That's a finding you act on enhanced screening, preventive options, and it can even uh open the door for specific drugs like PARP inhibitors. A VUS, a variant of uncertain significance, is different. It's also a typo, but one we haven't seen enough times to judge. Maybe it changes nothing. Maybe it matters. We just don't have the data yet. And here is the key clinical point. A VUS is not a diagnosis. Guidelines say you should not make major medical decisions like preventive surgery based on a VUS alone. And VUSs aren't rare. On a big multi-gene panel, finding one is actually common, which is exactly why genetic counselors are so important for interpreting these reports. The good news? These labels aren't permanent. As labs test more variants and more families, VUSs get reclassified, upgraded to pathogenic or downgraded to benign. Which is exactly what you're about to hear in the Chris Everett story. A variant that got reclassified, a phone call from her doctor and care that changed in real time.
Dr. Neil Vasan: 19:30
And I bring this up because actually in the lay press, Chris Everett, the tennis star, I'm sure you've heard the story. Her sister died of BRCA-associated ovarian cancer. She herself has ovarian cancer that has been documented in the public. And one thing that was really, I think, fascinating about her story is that her alteration was initially not really classified as pathogenic, and then it was classified as pathogenic, and her doctor gave her a call. So we're seeing changes of this in real time. That's a great example of where laboratory innovation directly changes patient care. And I think that's a good example. I will say that sometimes women are worried that maybe they've gotten tested and people have forgotten about them. No one has forgotten about you. All the companies are keeping these data, and when these variants get reclassified, we track down patients.
Abigail Johnston: 20:13
If a person presents to their doctor and they have one of these germline mutations, and their doctor is not aware of what to do with that information, as many community oncologists are just not able to stay up on the research on all of the different germline mutations. What would you recommend to a person at that point in their cancer experience when they carry perhaps, and of course, you know, I carry an ATM germline mutation. For some of us that have these germline mutations, not BRCA, not PALB2, something where we have targeted therapy, we know what to do with that. What do you recommend for those of us with these moderate risk or moderate penetrance germline mutations?
Dr. Neil Vasan: 20:57
Yeah, I think when you see different doctors, you might even get second opinions on what to do just because the different professional societies have different recommendations about screening, imaging, and things like this. I would make sure that it's in the note. Doctors' medical notes, in some ways, they're legal notes, and in some ways they're just sort of communication notes, making sure that when I'm thinking about a patient, I remember that she has an ATM germline mutation because it may change things in the future. It may change how we think about things. So just making sure that's part of the record. And then it's always reasonable to just ask: does this change anything? Because the interpretation of these genes is in flux a lot. And I believe that in 10 years, we may have therapies against these types of genes. We find that these types of genes, when they're mutated, cause dependence on something else, and we can target that. I fully believe. And that's a whole field of science called synthetic lethality where people try to find those exquisite dependencies.
Victoria Goldberg: 21:50
A few weeks ago, in our episode on triple negative breast cancer, I walked through an example of synthetic lethality. Using the BRCA and PALB2 genes and PARP inhibitors. It's worth repeating it here.BRCA1/2 are genes whose job is to repair damaged DNA in your cells. When one of them is mutated and not working properly, damaged DNA goes unrepaired, and that can allow cancer to grow. PALB2 is a lesser known gene that partners with BRCA2. BRCA2 is the repair crew, PALB2 is the dispatcher who tells the crew where to go. So when PALB2 is mutated, BRCA 2 can't do its job either, with similar consequences. This is where PARP inhibitors come in. PARP is another DNA repair protein. Think of it as the backup generator that cancer cells lean on when the BRCA and PALB2 system is down. PARP inhibitors shut off that backup, so a cancer cell that's already struggling to repair its DNA because of a BRCA or a PALB2 mutation and then loses its last resort to a PARP inhibitor simply cannot survive. That's synthetic lethality, exploiting two weaknesses at once to kill the cancer. While healthy cells, which still have a working repair system, are left largely unharmed. The key thing to know is that this strategy only works if you actually carry one of these mutations.
Dr. Neil Vasan: 23:43
We know that these drugs work in the metastatic setting. They work even better in the adjuvant setting and actually improve overall survival. So just to be very clear that there's a group of women who, when they get PARP inhibitors, if they have curable breast cancer, will be cured thanks to the PARP inhibitor. And I think that's really important to point out. It's also very important to know about these alterations in terms of risk reducing surgeries, risk reducing mastectomies, risk reducing oophorectomies, removal of the ovaries. There's a lot of innovation there in terms of fallopian tubes versus ovaries. That's a different conversation. And then the issue about family. If you know that you have a mutation that you could have gotten from your parents, your siblings may have it. You may be passing that down to your kids, where it's very important that if you test positive for this, you need to talk to your oncologist, but you definitely need to talk to a genetic counselor, make your family tree, come armed with all that information, and then people will have to get sequentially tested. And that's a process, and that is scary, and that is a lot of new information, but it's something that we need to understand. And I think that's very important for patients to know. It's called cascade testing. And you could imagine that it's very hard to do this in the real world, to make sure that everyone who needs testing in that scenario gets it. And there's also questions around what are you going to do with children, ethical questions around that. I tell patients, I hope we never have to open that box because it's a big box and it's a complicated box, but we have tools to deal with it.
Victoria Goldberg: 25:05
So let's just take a step back. We've been talking about the germline mutations, and we've mentioned the most common ones, the ones that we all know about, the BRCA 1 and 2, PALB2. What other mutations matter to MBC patients?
Dr. Neil Vasan: 25:24
There are other mutations that cause other cancers in the germline, Lynch syndrome, things like Li-Fraumeni, TP53. TP53 is a higher penetrance gene as well. They can also be associated with breast cancer, but those are the most common ones where we have therapies that are associated with those alterations.
Victoria Goldberg: 25:41
Last question on CHEK2. That's of personal interest. And though we don't really usually ask personal questions, but what is the significance of this mutation? And it's a relatively new one, right? When I was diagnosed with early stage breast cancer in 2004, I had a genetic test and it didn't show that I had BRCA 1, BRC2, and it didn't show anything. But 20 years later, when I moved on to MSK, Dr. Razavi, who's my oncologist, ordered another test and it showed that I had CHEK2 mutation. What is the significance of it? And should people who had early stage cancer many years ago ask to be retested?
Dr. Neil Vasan: 26:25
The first part about what CHEK2 is, it is a DNA damage gene. It can increase the risk of breast cancer, prostate cancer in men. There are some other cancer types that are lower risk, but that are associated with CHEK 2. Right now, my understanding is that we recommend breast cancer surveillance and prostate cancer surveillance in men. But this is an example where your medical oncologist may not know all the details about something like this. And it's really important to make sure that you speak in some capacity with a genetic counselor or someone who is thinking about these genes all the time and what the recommendations are. Medical oncologists, we do think about these genes all the time, more in the context of therapies and in the somatic mutation space. But it's very important to make sure that you're talking to the person who is an expert in that. That's a very interesting story, Victoria. It also just points to how things change over time, that some of these things were, we didn't have a name for it, and now we do, and we may not know what to do with it, but we know what it is. So that's a very powerful story. And in terms of the question about retesting, this is tricky because some of the tests are very good. First of all, the tests are all different. If a woman is Ashkenazi Jewish, we're really only going to be looking for the founder mutations in BRCA because those are the ones that are in that ethnicity.
Victoria Goldberg: 27:40
You may be wondering what a founder mutation is. A founder mutation is a specific genetic change that can be tracked back to a single ancestor, a founder in a population's history. When a community stays relatively small or isolated for many generations, whether for geographic, cultural, or religious reasons, a mutation carried by one of its early members can be passed down and become much more common in that group than in the general population. The classic example is in people of Ashkenazi Jewish descent, with three specific founder mutations, two in BRCA 1 and one in BRCA 2 are found in roughly one in 40 people. That's about ten times more common than BRCA mutations in the general population. Why does this matter for testing? Because if you belong to a group with known founder mutations, a lab can start by looking for just these few specific changes rather than reading through the entire gene. It's the difference between checking a few known addresses versus searching the whole city. That makes testing faster and cheaper. Though Dr. Neil Vasan notes, your family history may still call for a broader panel.
Dr. Neil Vasan: 29:03
If a woman has a high family history, then sometimes those panels are a little larger. We see anywhere from these small three-gene panels, nine-gene panels, all the way up to 48, up to much higher in certain patients. So that decision making, I think, really needs to be done with a genetic counselor about figuring out the right test for you for germline testing. There's a lot of variance. And I will say that compared to the somatic testing world, where things are more similar than different, I think in the germline testing world, the tests are actually quite different. And so it's really important to talk to your doctor. Sometimes when patients have really compelling family histories, because we're always trying to understand why this young woman got breast cancer in the first place. Just saying that it's bad luck is not a good answer for anyone. So we want to know there might be reasons that your doctor really wants to press for that higher level panel or that higher level panel testing.
Victoria Goldberg: 29:52
Thank you. All right. We'll move on to more interesting things. First, let's define what a somatic mutation is.
Dr. Neil Vasan: 29:59
Yeah. So a somatic mutation is a mutation that is in the cancer that is not in any other cell in your body. So this is very important. This is not a mutation that you would pass on to your kids. This is not a mutation that you got from your parent. Now, it is true that, of course, we just talked about how certain germline mutations predispose for other cancers. And so women who have BRCA mutations in their germline, their cancers also have BRCA mutations because it's part of their body. But this is different. The idea of what somatic mutations matter, you're going to get different answers from different people. I always think about what matters in terms of what we know about therapies that use these mutations as predictive biomarkers. And then also certain mutations where we have an idea of prognostically if they define a group of women who do better or worse. And those designations are very different for each cancer type. I want to be really clear about that. So what a pancreatic cancer doctor will be thinking about for somatic mutations is completely different from what a breast cancer doctor will be thinking about. There's some similarities, but there's a lot of differences. So right now, there are many genes in the cancer that when mutated, in some way, predict for response to a drug. They either predict it because when you change this gene, something else turns on, or when you change this gene, the actual protein that gene codes for is different and the cancer is more dependent on it, and you can target that. And so the two most common genes that when mutated predict for response to drugs are PIK3CA, which is found in about 40% of women with breast cancer. It's found in all receptor subtypes, both ER-positive, HER2 positive, and triple negative. Right now, the drugs that are approved are Pelicib and Capiva Certib for women whose breast cancers have PIK3CA mutations. Capivasertib (Trucap) is also approved for mutations in P10 and AKT, which are rarer, but we do see them. And there are some new drugs as well that are going through clinical trials. Some of those trials have already reported. One drug is called Gedatoliscib. This is a dual PI3 kinase mTOR inhibitor, and it has efficacy in both women whose tumors do not have PIK3CA mutations, as well as for women whose tumors do have PIK3CA mutations. And so we're gonna find out in a couple weeks if the drug gets approved in women whose breast cancers do not have PIK3CA mutations.
Victoria Goldberg: 32:18
We recorded this episode on July 8th, and this is a perfect example of just how fast this field moves because our information is already stale. On July 14th, 2026, just six days after we sat down for this conversation, the FDA approved the dual PI3K/mTor inhibitor getatolisib. It's approved for HR-positive, HER2-negative, locally advanced, or metastatic breast cancer without a detected PIK3CA mutation. So the answer to the question Dr. Vasan was waiting on, it's a yes.
Dr. Neil Vasan: 32:57
So very fast-moving space. And then there are these mutant selective inhibitors, which I really view as a triumph in the balance between efficacy and toxicity, which we hope is going to solve a lot of the toxicity issues we've seen from these drugs. And those drugs are going through early phase clinical trials, and these specifically target the mutant protein that is made from PIK3CA mutations.
Victoria Goldberg: 33:18
Let's unpack what makes these mutant selective inhibitors so exciting. Here is the challenge with the current generations of PI3K drugs. The PIK3CA gene makes a protein that every cell in your body uses for normal, everyday functions. Things like processing insulin and managing energy. In cancer cells with a PIK3CA mutation, a slightly altered, overactive version of that protein is driving the tumor's growth. The older drugs can't really tell the difference between the two. They block the mutant protein in the cancer, but they also block the normal protein in your healthy cells. And that's where side effects like high blood sugar, rash, and diarrhea come from. So for patients, those side effects are tough enough that they can't stay on the drug. Mutant selective inhibitors are designed to recognize and lock onto only the mutant version of the protein, the one found in the cancer cell, while leaving the normal version in your healthy cell alone. Think of it like a key cut for one specific lock. The hope is that you get the same or better cancer fighting effect with a fewer side effects, which could also allow higher doses and better tumor control. That's why Dr. Vasan calls this a trial in the balance between efficacy and toxicity. One example to watch is RLY2608, a mutant selection PI3K alpha inhibitor being tested in the Rediscover trial in combination with fulvestrant for HR-positive, HER2-negative, metastatic breast cancer with a PIK3CA mutation. Early results have shown encouraging tumor shrinkage with notably less of the high blood sugar problem that has plagued the older drugs. And it has moved into a pivotal phase 3 trial. Other mutant-selective drugs like STX478 are close behind it in earlier phase trials.
Dr. Neil Vasan: 35:34
So ESR1 codes for the estrogen receptor itself. And we know that mutations in the part of the estrogen receptor that bind to a lot of compounds like estrogen itself, like tamoxifen, that binding can be altered when it's mutated. I said that with PIK3CA, it's about 40% of women with breast cancer. ESR1, the true number, I think is still a little controversial. It's anywhere from 10% to maybe 20%, in my estimation. I say this because some of the trials, when they've done retesting in the blood, they've come up with larger numbers, depending on what the denominator is. This is getting into the weeds of the epidemiology or what the denominator is. Numbers anywhere from 10% to as high as in the 40% range. There's one company that uses in their advertising materials, like someone holding up the finger one to say one out of two, i.e. 50%. It's not 50% in the real world. That's not what we see, but it's anywhere from, let's say, 10 to 20%. So it's almost always found in women where the aromatase inhibitor has stopped working. Maybe they were on it for five years. And the problem is we don't know if it stopped working because that's in the curative setting. But the remnant of that is that patients can develop these ESR1 mutations in their tumors. And so it's a drug resistance mutation, meaning that a small amount of that mutation can prevent an otherwise really good drug like fulvestrant from working or an aromatase inhibitor from working. That's very different from something like PIK3CA, which is what we call a truncal mutation. The vast majority of women who have PIK3CA mutations in their metastatic breast cancer also had it in their primary breast cancer. That's why we call it truncal, like trunks versus branches of a tree. So it's in every clone. They mean different things, but we sometimes use the word clonal as well to mean that they're in every single cancer cell that a woman has. So we view that very differently than these drug resistance mutations like ESR1, which can only be present in 1% of a patient's cancer cells and still wreak a lot of havoc. And this was, of course, the whole rationale for the SERENA-6 trial, which we spoke about last time, that even these tiny amounts of the mutation, which could be detected by blood before tissue, could maybe theoretically predict for response to oral SERDs. And that's the drug class that has really dominated the space. Right now, we have three FDA-approved oral estrogen receptor degraders, elasestrant, imlunestrant, and veptigestrant, which is a proTAC, which just got approved a couple months ago. So we now have three drugs. We also have positive phase three data from liDera. This is the adjuvant giradestrant study, so in the adjuvant in the curative setting. And this trial met its primary endpoint, I think we're going to find out at the end of November if that gets approved by the FDA, right before San Antonio. And so again, a very fast-moving space as well, but that is really a mutation that we want to know about. PIK3CA, ESR1. I think most oncologists are attuned to this. And I am attuned to it enough where I put it in a patient's what we call the one-liner, the short description of what's going on with the patient at this particular time. I will write in PIK3CA alteration, ESR1 alteration, this sort of thing, because I always want to know what other therapies are available for a particular patient. There are some other alterations that very rarely come up in breast cancer. NTRK is one. These are mutations that are found in a subtype of breast cancer called secretory carcinoma. And so if you have that, that's something worth talking to your oncologist about. If there's a role for sequencing, there are some other alterations as well that we have some clinical trial data for EFGFR1 and other genes. I'll say a couple other things. I think that most of these alterations we're talking about are in ER-positive breast cancer because that's where the drugs are approved. There is still a role for testing in women with HER2-positive metastatic breast cancer and triple negative metastatic breast cancer. The odds of finding something are always a lot lower, but we really need to be testing patients when they get to a certain point. I think the utility of testing in the first or second line setting with those breast cancer subtypes is a lot lower. But I'm of the mindset, and this is just a philosophy, that every woman at some point should have somatic tumor testing with metastatic breast cancer, because we do sometimes find alterations that matter for patients because at the end of the day, we want the most number of options for our patients.
Dr. Ellen Landsberger: 39:46
Let's ask about one other alteration, the PDL1 and triple negative. Can you talk about that a little bit?
Dr. Neil Vasan: 39:54
So all the biomarkers that we've been talking about are gene mutations, DNA mutations. There are other biomarkers as well that are obviously worth talking about, things like RNA, which is actually what Oncotype tests, oncotype tests gene expression. And of course, there are many protein biomarkers, as you're pointing out, Ellen. And ER/PR and HER2 are measured usually with immunohistochemistry. So these are antibodies that are binding to the protein. So it's a measure of the protein. And PDL1 is very important in breast cancer, especially in triple negative breast cancer. We know that in the metastatic setting, if women's breast cancers have PDL1 expression, and that PDL1 is a marker that basically marks cancer cells for the immune system. And the idea, of course, is that if you give a therapy that inhibits that, you awaken the cancer to the body's own natural immune system. And so PDL1 positivity, this is getting into the weeds a little because you'll also hear a term called CPS in addition to PDL1. So PDL1 testing commonly refers to, not always, but commonly refers to just the cancer cells, what's on the cancer. But CPS also refers to that PDL1 expression in the tumor microenvironment, in the cells surrounding the cancer, their immune cells or cells very close to the cancer. And I say that because every trial that has tested immune therapy has used a different antibody, a different type of PDL1 testing. And it can actually be very confusing for oncologists and for patients. The bottom line is that with any of these scores, 10% or greater is considered positive. If your tumor has that, then we want to know. In the curative setting, where we use immunotherapy as well, it doesn't seem that the PDL1 status matters, which is very interesting. And we don't really know why that is, but we give now Pembrolizumab in the curative setting for women with triple negative breast cancer in the keynote regimen KEYNOTE-522. We give that very commonly now. And there's even a regimen for women with ER-positive breast cancer in the neoadjupant setting. We know that some of these women have breast cancers that are in between ER-positive and triple negative. And it seems like in phase three clinical trials, there is a group of women with ER-positive breast cancer who also benefit from immune therapy, regardless of their PDL1 status. And so again, a very fast-moving area, but these are all biomarkers that any patient should ask about, regardless of what cancer type they have. There are even clinical trials. We think about this in triple negative, but there are clinical trials right now looking at this in HER2 positive and in ER-positive as well, where immune therapy doesn't have a great track record. But these are still questions that are really important for patients to ask.
Victoria Goldberg: 42:22
Okay, I have a question, actually, two questions, about mutations that are known as germline mutations, but they could be somatic as well. So BRCA 1 and BRCA 2 could be a somatic mutation. And I've known people who had it. Could you talk a little bit about it and how, if people have that mutation, is it actionable and what they can do with it?
Dr. Neil Vasan: 42:50
Very cutting edge. We have a little bit of clinical trial data that was run by TBCRC looking at this very question. And this was a trial that was run by Nadine Tung at Beth Israel as part of TBCRC, looking at women whose breast cancers had mutations in BRCA 1 or BRCA 2, but they did not have germline alterations, germline mutations. And those cancers had a really great response rate to PARP inhibitors, is the bottom line. This is a really exciting area and one that I hope will get into a phase three trial, because while we as a field can obtain PARP inhibitors for those women, there are times when insurance companies are hemming and hawing about it and we have to go to bat for our patients, which we do, of course. But I hope that idea will go to a phase three trial so that it can eventually have a positive trial and get approved by the FDA. When ovarian cancer, where BRCA mutations are also predisposed to ovarian cancer, women can have germ lab mutations, even if they have somatic mutations, they also respond to PARP inhibitors. So the idea is there from a different cancer type. But again, this is where having the most data possible, I think, is valuable. It's valuable for a patient. For their oncologist. I'm a big proponent of this. This is what's different, I think, from 10 years ago to now. We are in an era of big data right now that we were not in 10 years ago. So I actually think all of the stakeholders, patients, oncologists, diagnostic companies, everyone wants these data. We have to make a decision about what to do with the data. There are times when patients have certain alterations and we're like, we're not really thinking about that right now for X, Y, and Z reasons. But having the information, I think, is very important. And God forbid we're in a position where, and sometimes we do see this, where patients got care from someone who maybe wasn't testing for all these things. And then we find out in their sixth line of therapy, oh, they never actually got genomic testing. We're seeing them for the first time. We sometimes see that unfortunately. And that's just not a great situation to be, as you could understand. Maybe I'll talk a little bit about when we do the testing.
Victoria Goldberg: 44:47
Yeah, let's do that.
Dr. Neil Vasan: 44:48
This is something that's changed a lot. I remember one of the first conversations I had with Abigail many years ago, we were talking about this. And at that time, most oncologists were testing in the second line setting because CDK4/6 inhibitors are used in the first line in ER-positive metastatic breast cancer. And we give that regardless of what someone's genetic alterations are. But now, since the testing is quick, it's easy with liquid as well. We are very commonly doing genomic testing right from a woman's metastatic diagnosis. And I'm a big proponent for this. I think it's very important, not just for standard of care therapies, it's very important for clinical trials because now we have first-line clinical trials. So I think a lot has changed in the last five or six years to where there's a lot of utility into knowing the full extent of what a cancer is at a particular time point. Years ago, we had these academic conversations about is there really utility because we're not using that information? But I think now everything is quick enough. There's more harmonization around what we do with these alterations. I do think that knowing what a lot of the options are right from the get-go is really helpful for patients. I don't like this idea of after a drug stops working, then we reopen the box and see what else is there. I think having just a fluid, these are all the options that we think of right now. That's a better approach. It's a philosophy at the end of the day. A lot of these therapies are very different. Some of them are oral, some of them are IV. Gedayplisib a drug that we're giving three weeks out of four. That looks very different in someone's life than oral therapy that they're taking and checking in every month with their oncologists. These therapies look different, they feel different, they have different side effects. Just having an idea of what that looks like, I think, is very important. It's not like all of these drugs are like chemotherapy that we give every three weeks. There's so much diversity. It's very hard for patients and for oncologists to not know what the plan is. And I think having more options is just better for everyone.
Dr. Ellen Landsberger: 46:38
I would agree. We're so fearful when we get the initial diagnosis and to know that there are more treatments available. And if this first line doesn't work, there's something else down the pike. I think that the more information patients have up front, the better off we are. And uh most of us want that. And for those of us who may not want that information and put everything in the doctor's hands, you can find that out easily enough and can respect their wishes. And also we're seeing there was just a paper in Nature about looking at mutations and genetic composition early on in the patient that can predict whether the CDK4-6 inhibitor is gonna work. And right now everybody's getting that. And I think the more you know up front, when these new tests come along and these new findings are discovered, then we can incorporate that. So I think it's really helpful and it's very forward-thinking, and that's where we like to be.
Dr. Neil Vasan: 47:44
That's where we like to be. And I think that when we think about other sectors of society, business and law and finance, we're always thinking about what's cutting edge and we want to be there. It's aspirational. Not everyone can get those resources. There's a lot of issues there, but we as a whole community should be outfitting patients and giving all the resources that we can. And I do think we're seeing that. I think we're seeing that in a lot of ways. Again, I think patient advocacy groups have been a huge part of this information dissemination, just spreading the gospel around all of these issues.
Dr. Ellen Landsberger: 48:17
There's a lot of discoveries happening about the genomics, and then it seems good and seems reasonable, and maybe this mutation is druggable, but then we have to wait for the clinical trials. And that can take years. So, is there something that we can do to bring those two parameters together a little bit closer?
Dr. Neil Vasan: 48:42
So, this is a really great question. And I do think breast cancer is different than other cancer types in terms of how we practice. So, in cancer types like leukemia and some of these cancers that in large populations are very aggressive and where there are very few therapies. And many oncologists in those fields are able to, and this is a lot of caveats here. Insurance companies have to approve all of these things, but are able to get certain drugs for patients based on smaller amounts of data, smaller tranches of data, not a phase three trial. Someone published a study, we tested this drug in 30 patients, 50 patients, and there was this response rate and things like this. And it's a different mindset. And I think that there's certain mechanisms in terms of access and financial toxicities that get covered. But I also think that part of it might even be cultural as well, that we're lucky in breast cancer in the sense, as oncologists and patients, that we have such gold standard of data for all of these decisions. We have large phase three trials that are the gold standard for a lot of these decisions, but there's a lot of gray area. And I think that this is something that we are going to see more of, a willingness on everyone's part to think about medications that maybe don't have as strong of a track record, but have some interesting glimpse of response. And if patients are okay with that and if their doctors are okay with it, then we try this drug. I will say that I remember when TDxD was DS80201A many years ago. I was a fellow at the time and seeing these Lazarus-like responses in patients. And remember that there were a couple patients that we were getting, it's not compassionate use, but obtaining the drug through a novel mechanism. We're already seeing that in cancer with these incredible successes with Daraxonrasib the RAS inhibitor in pancreas cancer. The drug is not approved yet, but they have this expanded access program because the trial was so spectacular. I think that those broader conversations, they take many tones. There's a financial element, there's a political element, there's an infrastructure element, there's a lot of pieces to the puzzle. But I do think that is entering the field of breast cancer now. And we're going to see some sentinel examples of that in the next couple of years where there's some blockbuster drug that once we show the data, we need to get patients this drug now. And I do think that we're going to start to see examples of that. Ellen, it's such a great question. I think that it's something where we need as much advocacy around this to really move the needle, if that's what patients want.
Abigail Johnston: 51:10
Could we shift a little bit and talk about ctDNA and ctDNA testing?
Dr. Neil Vasan: 51:17
Yes. So ctDNA, I think it's been such a boon for us because we ask patients to do enormous things for oncologists and for themselves, and they get a lot of blood tests. And so we can just add this test on when they're already getting blood and it's very little extra for anyone. And these tests come back very quickly, which is important. I said before how I do think that most tests are more similar than different. There are a lot of details around the different vendors and how many genes they're testing and blah, blah, blah. I wouldn't want a patient to think that if they had a gene panel that was 400 genes instead of 700 genes and somehow they lost something. That's not the case. And I think that's safe to say across the board in breast cancer. But these are really fantastic tests and they give us a lot of clues into what's happening in the cancer. So these are DNA tests. And to I think Victoria's question earlier about ER/PR HER2, while that's testing protein levels, we can sometimes get glimpses of that in the blood. So for instance, women with HER2-positive metastatic breast cancer sometimes will see really high levels of HER2 in their blood as well at the DNA level. That doesn't mean that all women with HER2 positive metastatic breast cancer were going to see that, but we do see these little glimpses. I think of that as almost like a control, in a way, like we would say in the laboratory. There's a lot of information in the packets of information that come out from these companies. Some companies do this a lot better than others. We'll just keep it at that. Some companies, the packet is 30 pages, and 29 of those pages are just irrelevant for patients and really for oncologists who know what they're doing. And so, you know, it's really that first page, I think that's really important that has the spanner information. Some of the things we're thinking about, of course, are the genes that are involved. We're thinking about the quality of the data, the what's called the tumor fraction, how much of the tumor was sampled in that. Sometimes this is more true for tissue. You can have a really low tumor fraction if you had a bone biopsy or something that's a harder-to-biopsy site or a lower yield site. So sometimes patients can have these sequencing reports that look pretty bland. There's not much going on, but maybe the tumor fraction was like 1%, something really low. That's something we think about. We think about this variant allele frequency or VAF. And that is, for all intents and purposes, just the amount of that mutation. Those numbers mean different things for tissue versus blood, but we generally see higher numbers like 20, 30% for PIK3CA, these truncal mutations. ESR1 could be very low and still be biologically meaningful. One question that actually came up in SERENA-6 ODAC is does 1% ESR1 mean something different from 0.1% ESR1? And I think most people would say probably it does, but we don't really know. SERENA- 6 didn't answer that question. So the numbers are important as well. And sometimes we make decisions based on that. As an example, one question I get a lot is do really what we call subclonal low variant allele frequency percentages of PIK3CA, does that really predict for response to drug? We don't have a perfect answer for that in patients, but I would say most of the data suggests that no, there's not a great response to drug. So those are some avant-garde type questions that we can glean from the ctDNA reports. And then we're also interested in what happens over time because some of our patients were going to be getting multiple ctDNA tests. And so we want to understand why this drug stops working. This is something I'm very passionate about. And Abigail and Ellen have been really helpful in this study that we're doing right now, which is this decentralized liquid biopsy platform where we're enrolling women from all over the country who are on capiva certified to try to understand why it stops working. And that's an important question because we really don't know the answer to that question, period. And so ctDNA, I think, has been totally a game changer in not just treating patients, but also in asking questions and trying to find answers. So I think that ctDNA, what I'm excited about for the where is the puck headed, there's a lot more information we can get from liquid biopsies, not necessarily DNA, but other things in the blood. There's information we can get on how ER is binding to DNA and how that changes. That's very important in what we call epigenetics. And there are ways that we can look at that. This is all very cutting-edge stuff. Nothing is ready to go in the clinic yet. There are ways that we can look at RNA in the blood. There are ways, of course, that we can look at what's going on in the normal blood cells in the blood. And sometimes those harbor germline alterations and we can detect that. There's even work that's being done looking at the blood and trying to get a glimpse of what's going on with the tumor microenvironment. There was a nature paper that was just published about a month ago on this topic. So I think that the possibilities for what blood can do is enormous. And I think we are just scratching the surface. And it's my hope that years in the future we're going to be getting a tube of blood and analyzing a lot of things from that. And it's going to give us enormous amounts of granular information. One thing I'll also add is just on tumor markers, because that comes up a lot now. People say that ctDNA, in some ways, is a fancy tumor marker. I don't think that's the right comparison because a tumor marker is measuring something that's related to the cancer, but ct DNA is measuring the actual DNA alteration. So those are different things. We know that there's some correlation, but there can be a lot of discordances. Women whose cancer might be growing and their tumor markers might be flat or even going down, or vice versa. They're very imperfect, but I think of ctDNA as sort of the 21st century version in some ways of what a tumor marker does. It's very different from what a tumor marker is, but we're trying to design trials that really integrate ctDNA. I'll give one more shout-out to a really provocative study that was just, I think, really incredible, done by Ben Park's group at Vanderbilt, where they were looking at women who were getting neoadjuvant hemotherapy for triple negative breast cancer. And we know that a large percentage of those women will have a pathologic complete response, which is that when the cancer is removed and they look under the microscope, there's no cancer cells in the breast. And that's of course a surrogate that hopefully there's no cancer cells in the rest of the body. So if a woman has a pathologic complete response, the chance that she will be cured is a lot higher. And so they looked at these sort of discordances, like this group of women that has a pathologic complete response and their ctDNA and correlations between those two. And what was really fascinating is that there was a group of women who did not have a pathologic complete response who ctDNA negative. And those women retrospectively did just as well as the women who did have a pathologic complete response, and all those women ctDNA negative. And so that's very interesting. That pathologic complete response is a surrogate of what's happening in the rest of the body, but it's not a perfect surrogate. And this is important because in breast cancer, right now, if a woman doesn't achieve a pathologic complete response, we escalate their therapy in every subtype. So might there be a group of women that are actuallyctDNA negative where we don't need to escalate in a her two-positive breast cancer. We're now giving TDxD in the adjuvant setting that's FDA approved. Might there be scenarios, and these are clinical trials that are being designed right now to get at this, thanks to ctDNA being this really incredible new magnifying glass, if you will.
Victoria Goldberg: 58:11
Are there limitations ctDNA? And what about false positives and false negatives?
Dr. Neil Vasan: 58:18
Yeah, so there are limitations. The positive predictive value is very good, meaning if you test positive, the chance that's like a real finding is very high. But it's the reverse that's not so great. If you're negative, it doesn't mean that nothing is going on. And so that has shifted some of the clinical trials where we're thinking about should we be designing superiority trials based on ctDNA or what are called non-inferiority trials based ctDNA? And you can imagine that if the false positive rate or the false negative rate is high or low, then a non-inferiority trial may not be the best type of trial because you don't want to withhold therapy in someone who might actually benefit from it based on a new diagnostic ctDNA. These are important questions. And they get important as well and more gray area when you start to think about women who don't have cancer. And we're doing now these multi-cancer early detection tests. And this is fraught, I think, with a lot of controversy. We had a large trial from England that was a negative trial. The trial did not meet its primary endpoint, but there were some interesting subgroups that had seemed to benefit, but that was not the primary endpoints. I think there'll be a lot more to come here. But we're starting to think about blood tests in ctDNA for women with metastatic breast cancer, the MRD setting in this earlier stage, where I think there's a lot of exciting glimpses there. And then even in women who don't have any cancer as well, to think about monitoring them. And there, there's very little data, but this is where the field is heading.
Victoria Goldberg: 59:41
So you mentioned that the ctDNA testing is becoming like a biomarker testing, fancy biomarker testing. And for some of us who do get our cancer markers, we do it pretty often, I think once every month or so. Do you envision that this is going to be the same pattern ctDNA testing as well?
Dr. Neil Vasan: 01:00:03
I hope so. And I'll make a plug for NYU, which is my institution, that we're doing true tumor monitoring embedded into the clinical workflow so that whenever a patient with metastatic breast cancer comes in, we're even offering this now to women with early stage breast cancer. Anytime she comes into the clinic, we're drawing blood forctDNA or MRD. And I think that this is where the future is headed. We need to get big data sets and we need to understand the trajectory of a woman's cancer journey and how that affects all of these analytes that we're testing in the same way that you will see in papers when we're looking at tumor evolution with tissue and doing a lot of fancy genetic testing. We want to be able to do this now for patients at scale. And you can imagine we need a lot of patients. We need a lot more data to answer these questions or to even know what the right questions are to ask. We need a lot of data to input. And again, this is not unlike what we're seeing in other sectors of the world right now in terms of big data and AI and having the data sets to really find patterns and make an impact.
Abigail Johnston: 01:01:03
Someone listening to this episode, what would be the one takeaway that you think that a patient should take, someone who's living with metastatic breast cancer, in this context of biomarkers? What would be the question you would send them to their doctor to ask?
Dr. Neil Vasan: 01:01:20
I would say that for anyone right now to go to their doctor and ask them, what do you consider are my biomarkers? I think that will really start the conversation.
Victoria Goldberg: 01:01:33
Excellent. Thank you so very much.
Dr. Neil Vasan: 01:01:36
You're welcome.
Victoria Goldberg: 01:01:37
What is going to be our next topic?
Dr. Neil Vasan: 01:01:40
Oh my goodness. Anytime you need me, I'm here for you.
Victoria Goldberg: 01:01:42
Wonderful. Let's sum it all up. Earlier in this episode, we've learned quite a bit about prognostic and predictive biomarkers as well as the DNA biomarkers. But we have not talked much about RNA and protein biomarkers. So let's break down biomarkers into three categories DNA, RNA, and protein. Because they're measuring different layers of what's happening in a tumor. DNA biomarkers are looking at the genetic mutations themselves. BRC1 and BRCA2 are classic examples. They're telling us about inherited risk and structural changes in the genome. It's the blueprint. RNA biomarkers go a step further. They show us which genes are actually being turned on and off in that specific tumor. So you might have a mutation present in the DNA, but RNA tells you whether it's active or not. Gene expression tests like oncotype -DX fall into this category. Then you have protein biomarkers, the actual functional output. HER2 is one, of course. PDL1 is another. And it's particularly relevant for immunotherapy response. When we measure PDL1 expression, we're asking, is this tumor expressing a protein that's suppressing the immune response? If it is, checkpoint inhibitors might work better. But, and this is important, PDL1 status isn't perfect. Expression can vary within the same tumor. And how we score it depends on which assay and antibody we use. That said, especially in triple negative breast cancer, PDL1 status is clinically meaningful and can shape treatment decisions. Biomarkers are shaping how we treat metastatic breast cancer. Whether it's germline mutations like BRCA and PALB2, somatic changes in genes like PIK3CA or ESR1, or immune markers like PDL1. These tests help oncologists choose the most effective treatments for each patient. And with technologies like liquid biopsy and circulating tumor DNA, testing is becoming faster and more accessible. This is a rapidly evolving field. New drugs, new combinations, and new guidelines are announced regularly. That's why it's so important to work closely with your oncology team. They can help you understand which biomarkers matter for your case and what treatment options might be available. Please keep in mind, this podcast is educational and informational only. It's not medical advice. Always consult with your healthcare provider before making any medical decisions. The information presented reflects the state of research and approvals as of the recording date and may change. A huge thank you to Dr. Neil Vasan for generously sharing his time and expertise with us. Your ability to make the most complex science accessible without dumbing it down is a gift to everyone listening. We're so grateful to have you back on the show. And to Abigail Johnston and Dr. Ellen Landsberger, thank you for the thoughtful, probing questions and for bringing your lived experience to this conversation. You pushed us to go deeper, and that's what makes these episodes matter. This wouldn't have been the same without you both. If you found this episode helpful, please share it with anyone navigating metastatic breast cancer diagnosis.
