Developing Story: Your Cancer's DNA and the Trial Using It to Cure You with Dr. Pedram Razavi

What if metastatic breast cancer didn't have to mean a lifetime of treatment? For a subset of HER2-positive patients, that question is no longer hypothetical.

In this episode of Live from Stage 4, hosts Victoria Goldberg and Dr. Ellen Landsberger sit down with Dr. Pedram Razavi, breast oncologist, translational researcher, and principal investigator at Memorial Sloan Kettering Cancer Center, to discuss his groundbreaking Phase 2 clinical trial, the HERizon Breast Trial.

Dr. Razavi breaks down how liquid biopsy and circulating tumor DNA (ctDNA) are changing what's possible in metastatic breast cancer, from detecting microscopic disease invisible to scans, to setting a new gold standard for treatment response: molecular complete response, sensitive enough to find one cancer cell among a million.

This is one of our most science-heavy episodes, so we've built in plain-language explainers throughout, covering liquid biopsy, ctDNA, tumor-informed assays, epigenomics, the blood-brain barrier, CNS metastasis, and antibody drug conjugates. No medical degree required.

The HERizon Breast Trial is currently enrolling. If you or someone you know has HER2-positive metastatic breast cancer, this episode could be directly relevant to your care.

🔬 Topics covered:

• What is liquid biopsy and ctDNA?
• The difference between panel testing and tumor-informed (bespoke) assays
• What "molecular complete response" means and why it's a higher bar than a clean scan
• The HERizon Breast Trial: design, goals, and who qualifies
• Could treatment de-escalation become a reality for metastatic breast cancer?

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Until next time, take care and keep pushing for progress.

Transcript

SPEAKER_00 0:09

Could cure for cancer be closer than you think? Welcome to Life 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 part for us and by us is all about us. What if metastatic breast cancer didn't have to mean a lifetime of treatment? What if, for some patients, the goal wasn't just to manage the disease, but to eradicate it? That's not a hypothetical. That's the question at the center of a phase two clinical trial being run right now at Memorial Sloan Catherine Cancer Center. And today, you're going to hear directly from the doctor who designed it. This is Life from Stage 4. I'm Victoria Goldberg, joined by my co-host and friend, Dr. Alan Landsberger. And our guest today is Dr. Pedron Razavi, breast oncologist, translational researcher, and the principal investigator behind the Horizon Breast Trial. Fair warning. We're going deep. Liquid biopsy, CT DNA, clonal hematopoiesis, the blood brain barrier, CNS metastasis, antibody drug conjugates, all of it. But don't let that intimidate you. We have built this episode to make sure you don't have to have a medical degree to follow along. Throughout the conversation, we'll be pausing to break down the terminology, explain the signs in plain language, and give you the context you need to actually understand what's being said and why it matters. Because it does matter. This trial is open, it's enrolling now. And if you have HER2-positive medicine breast cancer, what you're about to hear could be relevant to your care. So settle in, take notes if you want to, and share this one. Because somewhere out there, someone needs to hear it. Let's get into it. And today I'm joined by my friend and co-host, Dr. Ellen Lenzberger. Hi Ellen, how are you?

SPEAKER_01 2:50

Hi, Victoria. Thank you for inviting me to join you on this great discussion. We have Dr. Pedrin Rosavi here, and we're really excited to speak with him about several topics. Dr. Rosavi is a scientist clinician at Memorial Slunk Kettering. And Dr. Rosavi, could you please introduce yourself to our listeners?

SPEAKER_02 3:13

Hi both. Thank you so much for having me and inviting me to your podcast. Really an honor to be here. I'm a big fan.

SPEAKER_00 3:22

It's mutual. We're big fans as well.

SPEAKER_02 3:26

Thank you, thank you. I'm a breast oncologist at Memorial Sloan Kettering Cancer Center. Along with seeing my patients, I also run a group focused on translational oncology and translational research. In breast cancer, we do a lot of research on genomic and clinical genomic aspects of breast cancer. They have a big focus on liquid biopsy and ct DNA. And I think more importantly, a big focus of the group is just to bring all the discoveries and everything that we find in the lab and through our analyses back to our patients. That's a big focus as well. Really glad to be here.

SPEAKER_00 4:06

We're so glad you're here. And the topic of our conversation is your new phase two trial, Horizon Breast. We love the name. But before we talk about the trial itself, I was wondering if it would be a good idea for our listeners to actually hear from you what liquid biopsy is. What is CTDNA? Because even for me, it still sounds more like science fiction than reality.

SPEAKER_02 4:36

And honestly, it was science fiction 10, 20 years ago as well. But the concept is not new. It concept goes back to the 1940s when Mantel and Mate started looking at the body fluids with electron microscopy and started finding fragments of the DNA in body fluids. They look at almost every single body fluid and they found evidence of the fragments of DNA. But the field was pretty silent for many years until the person who is considered to be the father of the field, Dennis Lowe, did prenatal testing and discovered that the fetus' DNA is being shed into the blood. And we can identify abnormalities in the fetal DNA through analysis of the mother's blood. But he also came up with this idea at the time, and he very nicely put it in one of his publications that tumor also is not dissimilar to a fetus. Half of the DNA of the fetus is different from the mother's, but tumor also makes a lot of changes in its DNA. So we should be able to identify tumor DNA in the blood. And that was the start of the field. But the field was moving forward relatively slowly because the technology was not there. There is a very little amount of tumor DNA in the blood. So every cell when they die, they shed some of their DNA into the bloodstream. This is normal cells, tumor cells, everyone. But the tumor cells, because they grow fast and they are not often as fit as the normal cells, they shed more DNA. So they grow fast and they also die fast. There is a lot of turnover. There is a lot of the shedding of the DNA from these cancer cells, disproportional to the number of tumor cells if you consider the number of cancer cells. And then some of this DNA ends up being in the bloodstream. And liquid biopsy or circulating tumor DNA testing, CT DNA testing, is simply analysis of the cell-free DNA that we have in the blood and identify the DNA fragments that come from the tumor. And then there are many, many ways for us to characterize them. We can quantify the amount of DNA. We can say simply just, is there evidence of cancer? Yes or no? That's the MRD testing that we do, or minimal residual disease testing. Or we can actually characterize the cancer. What are the mutations? What are the genomic alterations? We can focus on DNA, we can focus on RNA, we can focus on the methylation and epigenomic factors of the tumor based on what's going on in the cephylalian tumor DNA or Cithrian tumor nucleic acids. And the field has been moving forward so fast in the past few years. And I'm so glad because finally the technology is where it's supposed to be for breast cancer. The earlier versions of technology, at least for detection of minimal residual disease, didn't have enough sensitivity. So they were finding cancer at levels of 100 parts per million or so. And that was not enough for breast cancer. In early stage breast cancer, obviously that threshold was too high. And I should say, even for metastatic disease, we have many patients who don't have detectable CT DNA with those versions of the assay. But when you go and analyze those samples with the more modern next generation assays, we can actually find the tumor DNA. But that provides an opportunity for us to monitor the disease at extremely low levels now with these modern assays.

SPEAKER_00 8:28

Hold on, let's break that down. When cancer cells die, they shed tiny fragments of their genetic material called nucleic acids into the bloodstream. Nucleic acids are the building blocks of genetic information. DNA is the master blueprint stored in every cell, while RNA is the working copy the cell makes to actually carry out instructions. Scientists can now analyze these shed fragments in multiple ways. They can read the DNA sequence to spot mutations. They can study the RNA to see which genes are actively switched on or off in the tumor, and they can look at epigenomic factors, chemical tags that sit on top of the DNA and act like dimmer switches, controlling how loudly or quietly each gene is expressed without changing the underlying code itself. Together, these give a remarkably detailed portrait of the tumor from a simple blood drop. But for years, the detection technology wasn't sensitive enough to act on that information. Imagine trying to find a handful of red marbles mixed into a jar of a million white ones. Early tests could only spot cancer when roughly one in 10,000 cells was cancerous. For early stage breast cancer, that bar was way too high. The newest tools are far more sensitive, and that changes everything. And now, back to the conversation with Dr. Razabi.

SPEAKER_02 10:03

So, what is important for our listeners to know is that the amount of CTDNA in the blood is very correlated with the level of disease. So the more disease the patient has, the higher the levels of CT DNA. And we've shown that in multiple of our studies, we presented some of the work last year in ASCO, but we even did a matched analysis, a paired analysis of CT DNA and PET scan, and we showed that the volumetric assessment of the disease based on PET scan was highly, highly correlated DNA levels in the blood, but there were some discordancies. And I should simplify our study. I would say CT DNA was superior in those discordant cases, finding the disease progression earlier or response earlier than imaging. And also there were some diseases, especially in lobular breast cancer, bone-only disease, some of the liver disease that was obscure to imaging. And CT DNA was able to identify that better. And we have started using CT DNA in an exploratory manner, just we were exploring the utility in clinic, and it is extremely helpful. It is a very unique biomarker. It's very different than the tumor markers that we have in clinic. Those are protein biomarkers. And those protein markers have a very long half-life. They are not very specific, as you guys all know. Some sites, a little bit of inflammation of the bowels, a little bit of an infection, all of them result in tumor markers to go up, and we're not relying much on those tumor markers. This is part of the work that we do, but we rely heavily on imaging to understand if the disease is responding or what is the status of the disease. But with the tumor DNA is highly, highly specific. We cannot be more specific than this, finding tumor DNA in the blood. And it's also a very, very dynamic biomarker. It goes up and down. The clearance of ct DNA is in minutes and hours. So it's constantly shed and constantly clears from the blood screen. And that provides an opportunity for us to serially monitor the disease in a way that it was completely unprecedented. We could never do this before. And I would like to clarify: this is not instead of imaging, it is de-escalation of imaging.

SPEAKER_00 12:36

In conjunction.

SPEAKER_02 12:37

In conjunction. So in some patients who are having a fantastic response and CT DNA is at extremely low levels, do those patients need imaging every three months or four months? Or they can just have a phlebotomist go to their home, get the blood sample, get the results a week after. And then if the disease is low, we avoid the whole contact with the healthcare system coming for imaging, get the PET scan, the stress of getting the imaging. This would be highly convenient for the patients. At the same time, I think it's a better reflection of the disease. Because as part of the work that I just presented at EsmoPress and also the work that we presented at ASCO last year, we are showing that CT DNA have a good lead time compared to imaging and can predict the progression very accurately, actually. So if that's the case, we can rely on CTDNA, but we have to show it in a prospective manner. We have developed a model to predict progression and also to evaluate CTDNA levels in a serial manner. So we will optimize that assay and that tool with the first few hundred patients, and then after that, we will randomize the patients.

SPEAKER_00 13:52

So you will be using your own assay, not one of the MD.

SPEAKER_02 13:55

No, no, no, we use one of the commercial MRD assays. I think it's important to use bespoke MRD assays here. These assays are very, very specific and are also sensitive. And they have a lower margin of error around measurements of the tumor DNA. So the levels are also very accurate. So I think we would like to use one of those. The panel testing, in my opinion, is too expensive and not practical. So you cannot do panel testing every three weeks or four weeks. These are expensive assays. But those types of assays, as soon as the panel is designed for the patient, the subsequent ones are much cheaper. There is a very small part of the genome unique to the patient and also her tumor that will be analyzed on the subsequent CT DNA analyses. And that is far cheaper and easier way and more accurate way of assessing CTDNA levels in the blood compared to the panel testing. Panel testings are extremely important when we are looking at the genes of interest, when the patient has progression, what are the genes that are resulting in resistance? What are the drivers of progression? What are the drivers that I can target and are actionable? So for that reason, panel testings, and many of our patients have panel testing routinely in metastatic setting. Those are extremely helpful. But I think for the monitoring, we need something that can be reliable and also doesn't have a lot of variation. So these bespoke assays don't have much variation.

SPEAKER_01 15:28

When you say the panel testing, is that also what you would call tumor-informed testing?

SPEAKER_02 15:34

No, the bespoke assays are the tumor-informed assays. At MSK, we have MSK Access or Garden 360 Foundation. There are many of these assays. Tempest has one, everyone has a panel. This is a fixed panel of genes or parts of the genome relevant to cancer that are being tested and the mutations and alterations, copy number changes, mutations, structural variants, all of them are being reported as part of this. So this is not individualized, this is not tumor informed, it's just a blood draw.

SPEAKER_00 16:12

Let's unpack that. MRD stands for minimal residual disease, as you already know. The tiny traces of cancer that can remain in the body after treatment are too small to show up on a scan, but still detectable in the blood. An assay is simply a test designed to detect and measure something specific. There are two fundamentally different approaches to MRD testing, and the distinction matters enormously. Panel testing casts a wide net. Instead of targeting your tumor specifically, it scans a large, fixed menu of hundreds of known cancer-related genes, looking for mutations, copy number changes, and structural variance across a broad slice of the genome. Tests like MSK Access, Garden 360, Foundation 1, and TEMPAS all work this way. Think of it like a security system that monitors every door and window in a skyscraper simultaneously. The broad sweep sounds thorough, but it has two major drawbacks. First, because it's scanning so much of the genome, it requires far more sequencing, driving the cost into thousands of dollars per test. For a patient who needs monitoring every three or four weeks throughout treatment, that's simply not sustainable. Second, and more importantly, it's not personalized. It's the same test for every patient, regardless of what the specific tumor looks like. Tumor-informed testing, also called bespoke testing, takes the opposite approach. First, your tumor is sequenced to identify its unique mutations. Then a custom test that is built that hunts specifically for those signals in your blood. Think of it like switching from monitoring every door in the skyscraper to installing a camera that only watches the two entrances your specific suspect is known to use. It does less, but it does it with far greater precision, and at a fraction of the cost per test, making regular monitoring actually feasible. So when the doctor says bespoke and tumor informed, those two words mean the same thing. A test built around your cancer, not a generic panel designed for everyone. The nuance is that bespoke means custom built for the individual patient, while tumor informed means the test is designed using information from the tumor tissue first, then used to track those tumor-specific mutations in blood. So in practice, the terms are often used interchangeably for the same class of MRDCT DNA tests. But tumor informed is the more precise technical description. All right, back to Dr. Razavi.

SPEAKER_02 18:57

But the point is those assays have to look at a relatively large part of the genome. Also, we don't know what we're looking for, so it's also subject to noise from many sources of noise in the blood. Tumor is not the only part of the body that sheds DNA into the blood. For example, bone marrow, there is a lot of cell-free DNA coming from the bone marrow, and the bone marrow stem cells can develop mutations. And those mutations we call them clonal hematopoiesis.

SPEAKER_00 19:32

Let's pause for a second because clonal hematopoiesis or CH, that's a mouthful, isn't it? Is a term you're going to hear a lot in plain English? It's a byproduct of aging. As we get older, the stem cells in our bone marrow pick up random mutations. When those mutated cells multiply, they create a clone of blood cells that all carry the same genetic glitch. Here is the catch for cancer testing. These mutations allowed. They show up in the blood in high volumes, and the liquid biopsy can't always tell the difference between a harmless age-related mutation and an actual tumor. It is a mutation and flags it as cancer, even when it isn't. The false signal is a huge hurdle for clinical accuracy. Okay, back to the conversation.

SPEAKER_02 20:24

They actually are not trivial number of mutations. There are a good amount of clonal maturesis and mutations coming from CH in the blood. And those panel testings often report CH as somatic variants. So CH mutations that happen in the bone marrow stem cells are some of the most active cells in the body. They give rise to all the blood cells, white cells, red cells, platelets, all of them. And these bone marrow stem cells sometimes develop mutations. So all the offsprings that come after these stem cells also have those mutations. Many of these mutations are just passenger mutations. They are not important mutations. Some of them are important mutations in a sense that result in that particular clone of the clonal matoasis, that clone of the stem cells, to start growing and expanding, give them some growth advantage. And many of them are now recognized. I don't want to bother our listeners with the name of those genes, but some of them are genes that are associated with risk of leukemia. Many of those are benign, but they give rise and they give fitness advantage to that clone. But some of them are also breast cancer genes that we are very familiar with. P53 mutation is one of the main ones. So the patient can have a TP53 mutation coming from CH or have a TP53 mutation coming from breast cancer. And it's very difficult to distinguish between these. And that's not the only one. We go down the list of the CH variants, these are not the most common ones. These are very high on the list. Then you have NF1, then you have SF3B1. They have all these genes that are important in breast cancer, but can also come from CH. So those panel testings are extremely helpful and we use them very often. But in my opinion, for monitoring the disease, they are a little bit too noisy and too expensive.

SPEAKER_00 22:26

This is a very nice moment and a segue. What do you think, Alan, to get into the Horizon breast trial?

SPEAKER_02 22:36

So let me tell you a little bit about Horizon because I'm very excited. All of us at MSK are very, very excited about this. A group of us have worked on the design of this study for one and a half years, and we tried to be thoughtful. And we engaged our patient advocates also very early on and got input from them to see what our patients want. What do they ask us to do and where do they want us to go? So we put together all of our thoughts and we worked on this design. But the idea was yes, we tried before to cure metastatic breast cancer and we were not successful. But that was in the another era. We didn't have all these new treatments, we didn't have all these new technologies, we didn't have a way to monitor breast cancer in molecular level, we didn't have all these fantastic anti-HER2 therapy drugs and new ADCs and new class of treatments that have completely revolutionized the way that we treat our patients. So should we revisit that? But one way to do it is obviously the way that historically was done: give everything back to back together and see if we can improve the patient's outcomes. And that's one way of doing it. And that's the way that we historically have done this type of studies. But what we try to do was to take a different approach. And we actually studied what our colleagues in hematologic malignancies do. They cure a large proportion of their patients and they use liquid biopsies, they call it MRD, and they use those types of biomarkers very often in their analyses and their treatments. So if a patient with leukemia has only a few molecules coming from the glucemic cells in the blood after they receive definitive therapy, the patients receive allogenic transplants or CAR T cells based on evidence of disease. These are very heavy treatments, but they have a goal. They know they can cure patients, and they go all in very aggressively to cure their patients. So we thought we can learn from our hematology colleagues who have been curing a lot of patients and then design the study based on some principles. So one principle was to guide treatment, escalation and de-escalation based on MRD, based on ct DNA levels. So that's one. Then to find a group of patients who will potentially have a better chance of being cured. And obviously, those were HER2-positive breast cancers. That's a group of patients for whom we've had major success in the past few years. And we have many patients in our clinics that have been treated with HER2-positive disease for years and years and years, and they have no evidence of disease. So we do have a long tail and a relatively large number of patients. That's around 10-14% of the patients who were treated years ago, and they have had no evidence of metastatic breast cancer. So we thought that's a good group of patients to focus on. And we went for the patients who are diagnosed with metastatic breast cancer and hair to positive disease. And that's a large proportion of our patients, around 60% of our patients now in the modern era, what we call de novo metastatic. So they are diagnosed with stage four breast cancer, and they have HER2-positive breast cancer at the time of diagnosis. So we are focusing on those. We did some analysis in our data and look at some of the data from clinical trials. We think that's the group of patients that have that better likelihood of giving us a chance to eradicate cancer.

SPEAKER_00 26:20

Because their treatment naive?

SPEAKER_02 26:22

Their treatment naive. So the tumor has not seen any of the anti-HER2 therapies. The tumor has not had a chance to develop any resistance, and those resistant clones haven't expanded. That being said, I think there is a large group of recurrent HER2-positive breast cancers can also be cured, potentially. But this is the first-of-a-kind study. So we wanted to be sure we wanted to give it the chance as much as possible to be a positive study because we are trying to change paradigms here. You know, the paradigm is that metastatic breast cancer is not curable. So we should go for a subset of patients where we have a chance and prove that we can actually cure a subset of patients or potentially cure a subset of patients. And then this paradigm will expand and hopefully we go another pocket of patients here, another pocket of patients. And then we start expanding that. And then after a while, we're going to have a substantial number of patients, but each patient, the patient groups, need different approach, different treatments. I think the era has changed. We are not going to treat everyone uniformly the same way as we did in the curative intent era, like years ago. All of them received high-dose chemotherapy in the beginning. Those days are gone. We have far better treatments.

SPEAKER_00 27:40

Let me ask you the group that you have chosen, de novo HER2 positive patients, were you looking at the oligometastatic disease? No.

SPEAKER_02 27:51

They don't need to be oligos. The only thing that at this point we exclude, and I think it is important for us to exclude, is the patients who are diagnosed with brain metastases. Because those patients need a different approach at the beginning. They need either surgery, radiation, and extensive monitoring. And sometimes change of therapy because the CT DNA is not very good in capturing the tumor DNA coming from the brain and the CNS system very well. I think those patients are potentially not good candidates to begin with. So we exclude only the patients who are diagnosed with brain metastases at the time of de novo metastatic diagnosis. Otherwise, any extent of disease is allowed. And then the idea was to give them sequential therapy, focus a lot on CNS. We just talked about CNS. And you know, and our listeners who are listening to your podcast know because you just had Nancy very recently here, and you talked about this as well. It is a sanctuary side, especially for her to positive breast cancer. Many of our patients, unfortunately, at the end, succumb to their disease because of the CNS disease, and they don't have anything systemically. And so we focus significantly on CNS disease to the point that all the patients who are enrolled will have a lumbar puncture at baseline. I think it is important because we would like to get the CSF sample and analyze the CSF samples for circulating tumor cells, for circulating tumor DNA, along with all the standard care that we do to make sure there is no evidence of cancer in the CSF. And if there is evidence of cancer in CSF, can we clear it with the treatments that we give our patients?

SPEAKER_00 29:53

Let's pause here because Dr. Rizavi just introduced a few terms that are worth unpacking. CNS stands for the central nervous system. That's your brain and spinal cord. When cancer spreads there, it's called CNS metastasis, and it's one of the most serious and difficult to treat complications in advanced breast cancer. CSF, on the other hand, stands for cerebrospinal fluid, the clear fluid that surrounds and cursions the brain and spine. When cancer begins creeping into the CNS, they often leave molecular fingerprints in the CSF before anything shows up on a scan. That's why testing the CSF through a spinal tap or lumbar puncture can catch CNS involvement earlier than imaging alone. Now here is where the blood-brain barrier comes in. Think of it as a highly selective security wall between your bloodstream and your brain. It is designed to keep toxins and pathogens out, but it also blocks most cancer drugs from getting through. That's a major problem when you're trying to treat a tumor that's taken up residence in the brain. Many standard treatments simply can't cross it. What Dr. Rizavi is saying is this his trial is not just excluding patients who already have active CNS metastasis. It is actively monitoring everyone on the trial with regular brain and spinal MRIs and CSF testing. What is the goal? To catch CNS involvement earlier while the blood brain barrier may still be intact. And to see whether the treatments being used can actually clear the cancer from the CSF before it progresses further. It's a level of neurological surveillance that's not standard of care. And it's one of the most ambitious parts of the study. Okay, back to the conversation.

SPEAKER_02 31:48

And many of those treatments have CNS penetration capabilities. So that's a huge emphasis of the study. The patients will get more of the brain and the spine also very regularly, which is not standard care.

SPEAKER_00 32:01

You're saying that one of the exclusionary criteria are active CNS metastasis. But if at the outset people on the trial do not have CNS metastasis, but they develop them later on, they will not be removed from the trial.

SPEAKER_02 32:23

If the patients have molecular evidence of disease in the CSF, I think those patients should stay. The patients do not have anything on imaging. I think it is important for those patients to have a chance to stay on the study, see if we can clear the CSF with the treatments that we offer our patients. And also, more importantly, we will offer them serial testing of the CSF as well to establish that is it cleared or is it not cleared? So I think it is one of those aspects of the study that I'm very excited, and all of our team, Shanu Modi, Sarach and Lapadi, there's a whole team, and we have neurooncologists, radiation oncologists, breast surgeons, everyone is involved. So this is the part that we thought is going to be uncomfortable for our patients. I know that there's always some stigma of its spinal tap. But we now do it in the modern era in a much better way as we used to do it. Now our radiologists who are neuroradiologists and experts in doing this are doing this procedure. It is a very safe procedure. But at the same time, I think this is a big ask from our patients. But I think it's important for them and for us to know if there was evidence of molecular disease in the CNS. Because we know at the end that's the site the disease starts to progress.

SPEAKER_00 33:52

Before we get into the trial design, let's do a quick decodering. Because Dr. Rizavi is about to use some acronyms that get thrown around a lot in the HER2-positive breast cancer world, and it helps to know what they mean. You already know, but it doesn't hurt to repeat again. HER2 positive metastatic breast cancer or HER2 positive MBC refers to a breast cancer that has spread beyond the breast and tests positive for a protein called HER2, which drives aggressive tumor growth. The good news, HER2 positive cancers have some of the most targeted effects of treatments in oncology. Here are the key regimens he's referring to. THP, also called Cleopatra regimen, stands for taxane, her septin, trestousoma, and proteusima, also known as progenum. This triplet combination became the standard first-line treatment for HER2-positive metastatic breast cancer after the landmark Cleopatra trial showed significantly extended survival. It's been the backbone of first-line care for over a decade. TDXD or Trastosimopdruxan, brand name in HER2, is a newer class of drug called an antibody drug conjugate or ADC. Think of it as a guided missile. The antibody finds the HER2 positive cancer cell, and the chemotherapy payload is delivered directly inside it. The destiny breast trials, particularly Destiny Breast 06, demonstrated TDXD's remarkable efficacy, including in patients who had previously received other HER2-directed therapies. And it has now been approved for earlier lines of treatment. HER2CLIME is the trial that established Tucotinib, brand name Tuchisa, as a powerful option for HER2-positive metastatic breast cancer, particularly notable because tucotinib can cross the blood-brain barrier, making it especially relevant for patients with CNS metastasis. So when Dr. Razavi talks about alternating between THB and TDX in his trial design, he's drawing on the fact that these two regimens work through completely different mechanisms, meaning they don't share resistance pathways. A cancer that becomes resistant to one may still respond to the other. Now here's how the trial actually works.

SPEAKER_02 36:21

So let me just tell you exactly how the study is designed because we talked about the principles of study, but we didn't say how the study is done.

SPEAKER_00 36:29

All right, let's do that.

SPEAKER_02 36:30

The study has three sections. One is the induction phase, that we will aggressively treat our patients with standard of care treatment. So there's no treatment that the patient doesn't receive with metastatic care to positive breast cancer. These are either TDXD plus pertusomap, that is what recently approved for patients with breast cancer, or our very old taxane plus her septine pertusumap, THB, that we have been giving our patients for many, many years, that's a Cleopatra regimen, and has been very successful. So this is the only two regimens the patients receive. The difference here is that we monitor the patients not only just by imaging, but also by CTDNA. So if the CTDNA doesn't get eradicated, we the induction one, so it's either THP or TDXD plus P. If it doesn't get eradicated after X number of cycles, and that those number of cycles are limited, then the patient goes to what we call salvage induction. So if the patient received TDXD plus P, now she receives THB. If she received THB as first, she will receive TDXD plus P. And the whole idea here is some of the cancer cells survived. So there's still some cancer cells left. Now that the number of those cancer cells are small, can we go and eradicate them in other very good treatment? So now the patients are going to receive one of the other two regimens. And we know that these two regimens do not have cross-resistance. We know from destiny trials that after patients receive THP, they receive TDXD. Many of them have fantastic responses. And also we have multiple Sendline data and patient-drive models. We know that the resistant mechanisms to these two drugs are different. So they are complementary. So in an ideal scenario, one patient receives the induction, she has a complete response by imaging, she has a molecular complete response based on CTDNA, their CSF was also clean, nothing there, nothing on imaging. Then that patient will graduate to have a surgery. And we do surgery here similar to what we do in early stage breast cancer. So it's the same paradigm the patients can have lumpictomy, axillary sampling, so on and so forth. And we thought at this stage of the game, this is important because from our new adjuvant studies, we know that there is a group of patients that they still have some residual disease in the breast, but they do not have much of a CT DNA in the blood, and also they're systemically obviously negative. But those patients, when you escalate care for them, they actually benefit from escalation. Okay. So if the patient goes here and she has not had the pathologic complete response, she will still receive salvage treatment. And the idea here is that we need to clear whatever residual disease the patient has. So we are combining the concepts that we have developed in early stage breast cancer, concepts from other cancers. Try to be thoughtful. Do not put the patients to harm, then do not receive any treatments that are not FDA approved. And the sequence of therapies are exactly what is FDA approved. And surgery for patients, you know, we often actually offer it in some patients with metastatic breast cancer, not for all, obviously, some patients. So this is the idea of giving the patient every chance to go through this eradication. After we are confirmed that the tumor is eradicated, meaning that the patient has confirmed molecular and radiographic response at least for two consecutive testing, then the patient will graduate to what we call consolidation phase. The idea here is there might be still some molecular disease in the CNS. And one of the best regimens that we have for CNS penetration, obviously TDX, has significant CNS activity, but also the HER2 climb regimen, which is tocatine plus trastusuma plus cape cycabine, capsidabine and tocatinine, both of them have very good CNS penetration. It has been shown in clinical trials that are effective in patients who have CNS disease. And we also hypothesize that even if the blood brain barrier is intact, meaning there is just a very small number of clusters of cancer cells in the blood, this HER2-Kline regimen still should have penetration in the brain because they do not rely on the compromised blood-brain barrier, because these are small molecules, both capesilabine and tocatenine, both of them will penetrate the intact blood brain barrier. So the idea is to give the patients a few months of Hair 2-Kline regimen, mainly to make sure that we are cleaning whatever residual disease in the CNS. And then after that, we go to the phase that we call maintenance or active surveillance. So the patients only receive a few more months of anti-HER2 therapy, plus minus endocrine therapy. If the patients are ER positive, they also get palbocyclibe as per patina clinical trial, but just for six months.

SPEAKER_00 41:54

So palbocyclibe will only become available to them at this maintenance phase.

SPEAKER_02 42:03

It's not going to be the first line, but it's going to be at this very end, after we completely eradicate it. And the idea here is that we are going after dormant cells, we are going after different types of population of cancer cells. So let's just keep it for later on. If we can eradicate with the cytotoxic treatments, let's just eradicate as much of a disease as possible. And to get the patient to molecular compete response, then we put the patient on endocrine therapy plus halbo plus HP, but only for a few months. And then the patient stops everything.

SPEAKER_01 42:35

I'm a little unclear. So do they have to test positive for hormone receptor to get the halbocycliber, the CDK4-6 inhibitor?

SPEAKER_02 42:45

Yeah. Think of it as an adjuvant treatment. But I think at the end, the idea is that there is a group of ER-positive, HER2-positive patients that are more likely to have cancer cells that are becoming dormant or not just dormant, maybe slower growing tumors that may not shed much of a ct DNA and may be obscure to us. So giving them a chance to be on CDK4-6 inhibitor for a while, that's just a maintenance adjuvant type of paradigm, bring it to metastatic disease. And then after that, the idea here is that we stop the treatment.

SPEAKER_00 43:24

So we're not doing the same thing they do in an adjuvant setting, five, ten years of endocrine therapy.

SPEAKER_02 43:31

No, we go for five to ten years of hormonal therapy alone. But in early stage setting, the patients stop anti-HER2 therapy after actually a year.

SPEAKER_00 43:40

After a year. And the same thing with the CDK46s, right? It's either two or three years.

SPEAKER_02 43:46

We never officially give CDK46 inhibitors to patients with hair to positive breast cancer. That's not approved. We give it to some patients with heterogeneous disease. They have ER positive and hair to negative and hair to positive disease. But I think. Overall, we are not even offering it in the adjuvant setting to our patients. But I want to go to that concept that, yes, in early stage disease, we stop the treatment for many of our patients. And the rate of recurrence is extremely low in the patients who achieve a pathologic complete response. And here the bar is far, far higher. The bar is not just pathologic complete response. The bar is not just radiographic response. The bar is molecular complete response with an assay that can find cancer in one part per million. And this is an assay that we use in early stage breast cancer. This is a test that we use in early stage breast cancer. The bar that we are setting up is extremely high. And we intentionally are keeping it high because we think that if we can achieve this only in a subset of our patients, we can be confident that these are the patients who potentially can have fantastic outcomes down the line. We know that from the early stage studies that the patients who clear the CT DNA do far better than the patients who do not clear the CT DNA.

SPEAKER_00 45:23

In cancer treatment, doctors use a different yardstick to measure whether therapy is working, and they're not all equal. Radiographic response is the most familiar. A scan, CT, MRI, PAT shows the tumor has shrunk or disappeared. It's visual, it's reassuring. But a scan can only see what is large enough to show up on an image. Microscopic disease is invisible to it. Pathologic complete response that's a higher bar. After surgery, a pathologist examines the removed tissue under a microscope and finds no remaining cancer cells, no visible tumor, even at the cellular level. This is considered a very good sign. And in early stage breast cancer, patients who achieve it tend to do far better long term. Molecular complete response is higher still. It means that even with the test sensitive enough to find one cancer cell among a million healthy ones, remember those red marbles we talked about. There is nothing to find. The cancer's DNA fingerprint has vanished entirely from the bloodstream. The last bar is what this trial is aiming for. And Dr. Razabi is setting it intentionally high because the data already tells us something powerful. In early stage breast cancer, patients who clear their CT DNA consistently do far better than those who don't. Clearing CT DNA doesn't mean removing it from the blood manually. It means treatment has been so effective that the cancer cells producing those DNA fragments have been eliminated. So there is nothing left to shed. The signal goes silent. And an assay sensitive enough to find one cancer cell among a million silent is a very loud result. The hypothesis is that the same principle applies to metastatic disease. If a patient can hit that molecular complete response threshold, it raises a question that medicine has really been able to ask with confidence. Do they actually need to stay on treatment indefinitely? Right now, the standard approach for metastatic breast cancer is treatment that never stops. Because stopping has always felt too risky. But continuous treatment means continuous side effects, accumulative toxicity, and a quality of life that erodes over time. Molecular monitoring may finally give doctors the precision to know when it's safe to ask the question. Back to Dr. Razabi.

SPEAKER_02 48:04

And here is the same concept bringing it to the metastatic disease. And many patients accumulate a lot of toxicity. Our current paradigm is to give the patients treatment forever. And do they need to be on treatment forever? We obviously monitor them very, very closely with imaging for five years. And after that, they will be also monitored of the study. But for officially, as part of the study, they will be monitored for five years with serial ct DNA testing, serial imaging. We also image their brain as well as part of their routine follow-up. So this is going to be brain MRI and total spine MRI, head scans, and also CT DNA. So we're stopping the treatments. They continue with hormonotherapy if they're ER positive, but we're stopping the treatment. But we offer them a very, very aggressive surveillance strategy. So if the disease becomes active, we're going to see small amounts of CT DNA now become positive. This is a patient who was CT DNA negative. Now the CTDNA is positive. That patient will go back on treatment.

SPEAKER_00 49:13

And still part of the trial, right?

SPEAKER_02 49:15

No, at that point the patient goes off the trial that considered the failure and receives stand-of care treatment as part of their care.

SPEAKER_00 49:23

So what are the endpoints for the trial?

SPEAKER_02 49:26

The primary endpoint is maintenance of the ct DNA clearance. So from all the patients who started this study, we count the patients who make it to the active surveillance phase and also maintain the ct DNA clearance for a period of time. And those are considered to be success. And we put the bar at 30%. We don't want to be naive and think that we can cure everyone, obviously. Historically, that bar has been in 10 to 14%. So we are aiming for 30%. My hope is that this is much higher because no one has done such an approach in metastatic disease so far. So we think that we can potentially achieve higher rates, but it is important to be realistic. More importantly, we are trying to learn from the patients who don't make it. How can we improve the strategy in the next iteration of this study for those patients? Because they develop resistance. Somehow the cancer was not susceptible to eradication by our current treatments. So what was the mechanism of resistance? Huge emphasis on the correlatives here. So we do a very extensive genomic and transcriptomic analysis, looking at DNA, RNA, spatial aspects of the cancer. We look at protein, spatial, multiomics, transcriptomics, all of that to understand which cancers are the ones that are not responding to our treatment and how can we improve that? Also, we are planning to make tumor animal models from some of the tumor samples as well. So we're going to study them also in the lab, which tumors responded, which tumors did not respond. So we try to make PDX, patient-drive xenographs from them as well, so that we learn not only from our success, which is we hope that it's going to be high, but also from the patients who don't make it to the end and the disease is too resistant. And there's going to be a group of those patients that this approach doesn't work. How can we improve the outcome for them so that on the next iteration of the study we can improve our approach and have an approach that works for them as well? So I think this is the part that I'm very excited about. It's one of those studies that we designed and we spent a lot of time, and I didn't go through all the details of this study, but we put a lot of thoughts and we got, as I said, input from our patient advocates as well to make sure that it is not just the aggressive escalation study. There is a significant amount of de-escalation. If one patient is doing really well with all of these treatments, she doesn't need to be on years of treatment. And one more thing that I would like to talk about, Victoria and Ellen, and I think it's important, is how patient-centric is the trial.

SPEAKER_00 52:21

Right. Okay, let's talk about that.

SPEAKER_02 52:24

Yeah, I think that's important because not only are we trying to listen to the patients and also bring what they want to the table here and offer them not just the escalation, but also de-escalation, but also we tried not to be influenced by anyone else in our design. We partner with our pharma colleagues quite often in design of clinical trials. They are the best partner for us in designing clinical trials. But sometimes the paradigms are a little bit too radical for big pharma. We went to our colleagues in pharma and we we introduced the topic, but they were hesitant. Can we truly cure a subset of metastatic patients? Can we do this? Can we do that? Why don't we give a little bit more of this, a little bit more of that? And then we thought we should keep our independence here, keep our design exactly how we think us and our patients want it. And so for that, we fund the study through the foundations and philanthropy only. So we have multiple philanthropists, and we are very lucky at MSK to have philanthropists that provide funding to us and also the foundations. And some of our patients actually donated to our clinics. I want this to be going through your research or the trials that you're doing. The Gateway Foundation had a grant mechanism. We submitted their studies, and I'm very happy that they accepted as one of the trials that they are funding. And also MBC Cure Foundation. We approached them and they did the fundraising for us. And they are also funding their study. So I think we are now fully funded. We are writing some grants to do some of the correlative analyses, so on and so forth.

SPEAKER_00 54:09

Is it open? Is it accruing now?

SPEAKER_02 54:12

It is open. And we actually put our first two patients on this study.

SPEAKER_00 54:16

First two. And how many patients do you expect to have?

SPEAKER_02 54:21

We are planning to accrue 60 patients.

SPEAKER_01 54:24

Okay. And is this open any other site or just at MSK?

SPEAKER_02 54:29

It is open in all MSK sites. So at this point, it's just at MSK. We are hopeful to open it in other sites, but it's an operationally challenging study with a molecular complete response. The surgeons need to be agreed to do a surgery. So we had to talk to our surgery colleagues, get their approvals for these clinical trials. And also there is a good amount of radiation oncology involved because some patients might have a escape lesion. People also utilize local therapy into this. So there is some nuances in the study at this point. We want to keep it at MSK, but as soon as we put the first 10, 20 patients on the study and we know that this is something that can be easily expanded to other sites, we are completely open to opening to other sites as well.

SPEAKER_00 55:15

Right. So there is a good likelihood that there will be people coming to this trial who are not currently patients of MSK, or they'll be coming from different places. So how much of a burden is it on the patients? How often will you scan them?

SPEAKER_02 55:36

For the patients who are coming from outside MSK, what is important is that to see us at the time of metastatic diagnosis, because it's important for us to do the baseline testing, baseline CT DNA testing to make sure CT DNA, what's the level of CT DNA before they start the treatment? I do not want the patients to delay their treatment. They should start treatment as soon as possible, but they can reach out to us and mention the clinical trial and say they want an expedited visit. And we will try to expedite that visit and we'll see them as quickly as we can, usually within a week, to make sure that we discuss it with them. And if this is something that they are interested in, then after that, the visits are very much standard of care visits. So the scans are every three cycles. Official CT DNA testing is also done every three cycles of treatment. We prefer to have the rest of the treatments given at MSK at this point. We might be able to partner with some local providers as well so that they receive some of the cycles over there. But at this point, I think it's important for us to do everything. But we have regional sites.

SPEAKER_00 56:52

Would you be open for the THP part of the trial to have not weekly uh taxel, but something that's given every three weeks?

SPEAKER_02 57:01

Yeah, dossi taxel is also allowed. Dosy taxel. Yeah, dossi taxel is also allowed, and that's every three weeks regimen. So we discuss it. Do they want weekly taxel or do they want every three weeks dossi taxel? And both of them are allowed.

SPEAKER_01 57:14

Okay. At the beginning of this discussion, you said that you're looking at her two positive disease, because it's obviously the way to start. So my question is when and do you think that there's going to be an opportunity to do something similar in the hormone receptive positive space? Same thing with de-escalating, people who've been on treatment for a long period of time.

SPEAKER_02 57:37

Fantastic question. And obviously, that's 70% of our patients. We do know that there is a large number of patients with ER positive breast cancer that have a fantastic response and they stay in what we call a stage four NED space, no evidence of disease space for years and years.

SPEAKER_00 57:57

Can you quantify that? What would you say percentage of patients?

SPEAKER_02 58:02

If you look at the trials, I don't know if there is any real world data published on long-term outcomes, but if you look at the long tail of the early CDK4-6 clinical trials, that is around 10% to 20% of the patients, depends on which trial we're looking at. But the problem with those trials is that they haven't gone long-term outcomes. Like Cleopatra, they published the eighth-year outcome for the patients. For those clinical trials, the outcomes have not been updated yet. But you know, I expect that to be within that range. But the challenge with ER-positive breast cancer is there are also dormant cells. So we did, as part of the study, we presented it actually at ASCO, and we are working on the manuscript now. We did ultra-sensitive monitoring with CT DNA on patients who were ER-positive on first line CDK4-6 inhibitors. We just wanted to know all these patients are what's the CT DNA dynamics. And it was very, very interesting that on treatment, around 20 to 40% of the patients, depends on where on treatment we get the samples, they have ct DNA levels that are below 100 part per million. If you remember, that's the threshold for the first generation CTDNA MRD assays. So they have all the way down to one part per million. So even in metastatic disease, many of the patients can have very low levels of disease. But more importantly, we had seven patients that participated in the study, the MSK Link study, and they were stage four NED. Out of these, four of them had extremely low levels of CT DNA detected. So they were net on imaging, they were on CDK for six millimeter for years, but they had a very small amount of disease just fluctuating. And then there were three patients for whom CTDNA went to zero, remained zero, even with an ultrasensitive assay. So, in my opinion, there is a group of patients that we were able at least to achieve eradication of CTDNA below those ultrasensitive ranges. Do they still have disease or not? Or the disease is dormant and it's not shedding any ct DNA possibly, but do they need to be on CDK46 inhibitors continuously while the CT DNA is not detectable? I'm not sure about that, but that's something that we're going to tackle in the next stage. I think at this point we need to go for a because the bar is metastatic breast cancer is not curable. So let's just bring the bar to the point that we can talk about cure. And to me, that's HER2-positive disease. And then we find a subset of ER-positive breast cancers that can have outstanding responses to certain therapies. And for that, we are developing models to predict these patients. Who are the patients who have a chance to become outstanding responders on CDK46 inhibitors? And we actually are developing a model, we're calling it CDK Predict. It's a clinical and genomic machine learning model. I presented some of this before, but the manuscript is far more impressive than what we presented before. The model performs really, really well. And we put our hands on two very large external cohorts that the model never seen before and still has a fantastic performance. So I'm very confident on the performance of the assay, takes into account the very baseline clinical and genomic aspects of the disease and comes up with the individualized, personalized prediction for the patient. What are the chances of progression in the next five years and comes up with the risk score? Is it a high risk, low risk, or intermediate risk patient? And there is a good group of patients, and that is in this analysis, around 20 to 30% of the patients will be categorized into the low-risk group. These are the patients that often actually come with a good amount of disease, with high volume of disease, but they have fantastic responses to hormonal therapy and CDK-4-6 inhibitors. And I think that would be a very good group to focus on eradication potentially, because we know the tumor is responding to many of the good treatments that we have. But at this age, we have to start somewhere. And I think here too positive disease is where we want to start.

SPEAKER_01 1:02:48

I hear you. I read in some of the Facebook patient chat rooms and groups that people who have had long-term eradication, long-term NED status, many doctors are taking them off of their drug or giving them drug holidays and that sort of thing. It would be really great to have more data and scientific evidence that's going on and we should be studying that.

SPEAKER_02 1:03:14

I should say I do that also very cautiously in my clinic as well. I offer the patients CTDNA monitoring at that point because we simply don't know. And I have now a good amount of data from our research side to know that they have NED and we have NED. They're completely different. There is an NED with low-volume disease below the threshold of imaging, and there is NED with no ETDNA detectable. And I think it is important to still monitor the patients, but I do agree every four weeks CBCs is just too much for a patient who has been no evidence of disease for four or five years. Why should they come so often? And can we start de-escalation? Also, the long-term effects of these drugs have not been studied. We don't know. And these are the patients that can potentially stay free of cancer, or we cannot say completely free of cancer, but free of progression of metastatic cancer for years. So I think it is important for us to start looking into this. I think you guys are very familiar with Stop HER2 trial that was designed by my good colleague Heather Parsons. And I think that would be a good first step. We had a different version of that study. She did the study first before we opened our study, and we really liked her study. So we just participated in her study.

SPEAKER_00 1:04:41

Just for the HER2 population.

SPEAKER_02 1:04:43

But with ER positive, also, I think we can have similar studies. So I think with ER positive, we can have can we start de-escalating the CDK46 to keep the patients on hormonotherapy, but start de-escalation? Can we include also those models that we developed to define the risk if the patient is considered to be low risk and also ct DNA negative? That's a good patient to start de-escalating and we monitor them and then we see how things go. So I can think about these designs and talk about these. Quickly back to our patients. I think that time frame for me is extremely important. They cannot wait too long. And it is on us to bring our discoveries as quickly as possible. What we do is absolutely impossible without the partnership with our patients. So they come, they participate in our liquid biopsy studies, they participate in our genomic studies, they go on clinical trials, therapeutic clinical trials. And then that allows us to define and devise new treatment strategies, not only for them, but also for the other patients with metastatic breast cancer that come after them. So just wanted to talk about this because I think this is the most important part of this.

SPEAKER_00 1:06:44

Thank you. And I'm so glad you talked about it. We want to give you at least a few minutes before your next meeting. And thank you so much for being here.

SPEAKER_02 1:06:54

Of course, of course.

SPEAKER_00 1:07:33

The trial is built around a radical idea that in a subset of patients with metastatic HER2-positive breast cancer, we may be able to achieve something that has never been the goal in the setting, a durable molecular complete response. Not just showing the disease, but potentially eradicating. To get there, the trial uses the two most powerful weapons currently approved for this disease, TDXD and the Cleopatra regimen, sequentially, not simultaneously, taking advantage of the fact that they work through completely different mechanisms and don't share resistance patterns. It tracks response not just through imaging, but through CT DNA, the liquid biopsy signal in the blood, as well as the CSF, the fluid surrounding the brain and spine, with regular MRIs to catch any CNS involvement early. Patients who achieve a molecular complete response move on to de-escalation phase, meaning less treatment, not more, and the trial is specifically designed to learn from every patient, including those whose cancer proves resistant to build the next iteration of this approach. The trial is currently open and enrolling at Memorial Sloan Kettering. It is aiming for 60 patients. If you or someone you love has heard too positive metastatic cancer and you want to know more, listen to this episode again. Share it with your care team and ask whether you might be eligible. All the details, including links to the trial, Dr. Razavi's contact information and resources mentioned in this episode are in the show notes at LifeFromstage4.org. And note before you go, nothing in this episode is medical advice. This conversation is for informational and educational purposes only. Every patient's situation is different, and any decision about the treatment or clinical trial participation should be made in close consultation with your oncology team. Please talk to your doctor. Thank you for listening to Life from Stage 4. If this episode helped you, share it. Someone out there needs to hear it.