Developing Story: The Trial That Dares to Say Cure with Dr. Lior Braunstein

We've always been told that metastatic breast cancer can't be cured, only managed. But what if that's no longer the whole story?

In this episode of Live from Stage 4, hosts Victoria Goldberg and Dr. Ellen Landsberger sit down with Dr. Lior Braunstein, a radiation oncologist at Memorial Sloan Kettering Cancer Center, to talk about the ARCHER trial, a first-of-its-kind clinical study asking a bold question: can surgery and radiation, added on top of standard HER2-targeted therapy, eradicate every last cancer cell in patients with oligometastatic HER2-positive breast cancer?

Dr. Braunstein breaks down what "oligometastatic" really means, why HER2-positive disease is uniquely positioned for this kind of approach, what ablative radiation to the liver or lungs actually involves, and why the word "cure" makes oncologists nervous, even when it might be warranted.

We also cover:

• What the ARCHER trial is looking for in eligible patients
• Why previous trials failed to answer this question
• How cancer develops resistance and why treating visible disease early may be the key
• The role of AI in matching patients to clinical trials
• What comes next if the trial succeeds

Who should listen: Anyone living with HER2-positive metastatic breast cancer, their caregivers, oncology professionals, and anyone who believes patients deserve to hear the hard questions asked out loud.

🔗 Find the ARCHER trial: search "ARCHER trial breast cancer" at clinicaltrials.gov
📝 Show notes and resources at https://www.livefromstage4.org/

Nothing in this episode constitutes medical advice. Please consult your own medical team before making any decisions about

Thanks for listening. If you enjoyed the episode, subscribe and leave a review — it really helps. Follow us on social media @livefromstage4 and visit our website at www.livefromstage4.org for show notes and links.

 Your support helps us continue to share important stories and advocate for those living with metastatic breast cancer.

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

Transcript

SPEAKER_04 0:10

Could if you are for cancer be close to the new thing. Welcome to Life from Stage 4, where MPC takes center stage as we talk to experts, share inspiring stories, break down science, and shine the spotlight on what matters most. Because when it comes down to it, the spot for us and by us is all about us. We have all been told the same thing. Once breast cancer becomes metastatic, the cancer cells remain in the body. The best we can do is treat active lesions, manage symptoms, and maintain status. There is no cure. And yet, we see people with no active disease for many years still on these toxic drugs, wondering what does that actually mean for them? Recently, the word cure has started appearing in scattered conversations among patients and oncologists, in opinion pieces, in the literature, quietly, carefully, but it's there. Today we're asking that question out loud. This is live from stage four. I'm Victoria Goldberg, and I'm joined by my friend and co-host, Dr. Ellen Landsberger. Ellen, take it away.

SPEAKER_03 1:47

Today we're excited to meet with Dr. Liora Bronstein, a radiation oncologist at Memorial Slunkettering Cancer Center in New York City, who's enrolling patients in a study with a new approach, an attempt to cure a subset of patients with HERCIP-positive MBC. Dr. Bronstein, thank you so much for joining us.

SPEAKER_00 2:09

Thanks for having me. It's a pleasure to be with you both and to talk about some of our work.

SPEAKER_03 2:14

So we know that you're a radiation oncologist at MSK. And before we talk about your study, we want to set the record straight. Many of us get confused between a radiation oncologist and a radiologist. So can you please explain the difference between the two?

SPEAKER_00 2:34

This is a great question. It's a very common source of confusion. Indeed, I am a radiation oncologist, and I still think that my mom thinks that I'm a radiologist.

SPEAKER_01 2:43

So thanks for letting me set the record straight. Typically, the source of confusion probably stems historically from the fact that our field, I think, did emerge from the field of radiology. So that's totally understandable, as actually many fields did, including things like interventional cardiology. But radiology typically is a diagnostic field. The radiologists evaluate images, read images, look at diagnostic studies like X-rays and CAT scans and mammograms, MRIs, things like this. And there's also a field of interventional radiology that's typically used to intervene in certain parts of the body using imaging. Radiation oncology is distinct in that we use radiation not for diagnostic purposes, but for therapeutic purposes, which is to say that we target radiation to specific areas, typically for oncologic use. So to destroy cancer in a particular area, cancer happens to be susceptible to radiation. Also, occasionally for benign conditions. And so there's a growing literature about using radiotherapy for benign autoimmune conditions or things like arthritis. And so that's the distinction. It's a diagnostic versus a therapeutic use of radiation.

SPEAKER_03 3:49

Okay, great. So that's another type of physician who treats cancer. We've got medical oncologists, surgical oncologists, and radiation oncologists.

SPEAKER_01 3:59

You got it. That's exactly right. So our surgical oncology colleagues, you know, pretty clearly do surgery to remove tumors or also to diagnose tumors. Medical oncologists use medications or chemotherapies, targeted agents, immunotherapies, anything that's a medicine. They're medicine doctors typically, and radiation oncologists use radiation to treat cancer. That's exactly right.

SPEAKER_03 4:19

How would you describe the role of radiation therapy in breast cancer in general and for metastatic breast cancer specifically?

SPEAKER_01 4:27

Yeah, it's a good question. So generally, for breast cancer, radiation has been used as something called an adjuvant. And the term adjuvant stems from the fact that cancer historically has been a surgical disease. Before we had good chemotherapies or targeted agents or even knew about radiation, cancers were removed surgically. And then anything that you wanted to add on top of surgery, be it a medication, be it radiation, be it a supplement of some variety, that would all be called an adjuvant. And so radiation has typically been used as an adjuvant in breast cancer, beginning almost probably about a century ago, I would say. Some of the very first treatments in oncology with radiation started right after the X-ray was discovered in 1895. And then in 1896, people started using the X-ray to try to treat breast cancer. Of course, at that time, the breast cancers that were treated were all rather evident. Mammograms didn't exist. When a patient showed up with breast cancer, it was typically something that was clearly evident. It was probably superficial because you could see it, meaning that some of the tumor was involving the skin or actually grossly visible. And then radiation at that time was very effective because you could treat very superficial things using very low energy x-rays because you didn't have to get to too much depth in the tissue. And then the field has evolved, as you might imagine, quite considerably over the past slightly more than a century. And in metastatic disease, the role of radiotherapy in many forms of metastatic disease, you could say probably in most, the role has been rather palliative. Meaning if a patient is having a symptom in a particular area and that symptom may be not responding to their oncologic medication, their chemotherapy, their targeted therapy, or things are progressing in a certain area where they might cause some symptoms or they might be dangerous, for example. One of the emergencies that we have in radiation oncology is occasionally patients sadly come to the emergency room with neurologic symptoms because maybe a tumor has grown to the point where it's pressing on the spinal cord. And these are situations that we consider in radiation oncology to be emergencies where you need to intervene quickly in order to protect the spinal cord.

SPEAKER_04 6:36

Just to put that in context, spinal cord compression from a tumor is a true medical emergency. When the tumor presses on the spinal cord, it can cause rapid and sometimes permanent paralysis, loss of bladder, and bowel control or numbness. Every hour matters. Radiation can be started within hours, which is why radiation oncologists are called in urgently, sometimes in the middle of the night. It's one of the situations where radiation isn't just helpful, it's the fastest tool available to protect function.

SPEAKER_01 7:12

And radiation is fortunately one such intervention where you can give the treatment within a matter of hours rather than waiting days or weeks for medications to work. Occasionally surgery is used in those situations as well. But generally speaking, radiation in the metastatic setting has been used for palliation of symptoms to make someone feel better or alleviate a symptom or to prevent some imminent injury that's about to happen if the tumor continues to progress in a particular area.

SPEAKER_03 7:39

So let's get to your study. Let's hear about this Archer trial.

SPEAKER_01 7:44

Yeah, so the Archer trial is a pretty new study. It's just opened in the past few months. It's very multidisciplinary. There's input from surgeons and medical oncologists and radiation oncologists. And we're very fortunate as well to have the tremendous input of patient advocates like yourself, Alan. You've been instrumental in the design of this trial as well to make sure that what we're really focused on is what patients want us to focus on and that we're bringing them an option that they're actually interested in rather than an option that we as scientists have cooked up that maybe nobody else is interested in. So the study, it's called Archer. Archer stands for the ablation and resection for the consolidation of HER2-positive breast cancer.

SPEAKER_04 8:22

I can't believe that you actually remember that and you didn't look it up somewhere.

SPEAKER_01 8:26

It's a mouthful, but these are words that we use every day in our practices. It's not that bad. So ablation is what we are attempting to do with the radiation to actually ablate sites of tumor. Resection refers to the surgery. We're also trying to remove the area in the breast where the tumor originated. And consolidation, that word essentially refers to getting over the finish line with a treatment. So consolidation typically means there's usually a standard treatment. And then we want to really make the effect permanent and get the patient or the disease over the finish line, which in this case means trying to eradicate every last focus of cancer that we can, in an attempt to manifest what we call durable long-term control of the disease, which is to say we don't see the disease come back or rear its head in the future.

SPEAKER_04 9:20

So let's pause to recap those three terms in plain language. Ablation means destroying the tumor cells in place using radiation. Think of it like burning them out. Resection is the surgical removal of the original tumor side in the breast. And consolidation means finishing the job, making sure there is nothing left behind that could eventually develop resistance and come back. Together, these three steps form the backbone of what makes the Archer trial different from standard care.

SPEAKER_01 9:57

And so what the trial is looking at essentially is that building on the current standard of care. So as your listeners may know, and as is pretty common in the solid tumor space, typically when disease is considered stage four or metastatic, the main treatment is a systemic treatment, something that treats the whole body. And that treatment typically continues indefinitely, as it does for stage four breast cancer. So patients with this disease typically start on a chemotherapy and some targeted therapy for HER2-positive breast cancer. And that continues for as long as it'll work and there's no stopping date. That's the current standard of care. Sometimes additional medications are added, sometimes medications are removed based on what's going on, but the stopping date is not predefined. What we're looking to do is introduce an opportunity to also add surgery and radiation to this treatment plan in an attempt to improve the outcomes that we see essentially with just the systemic therapy. So what we know is that in HER2-positive breast cancer, there are very effective treatments as a consequence of our profound understanding of the biology of HER2-positive breast cancer. This is one of very few types of cancers that we understand very, very deeply in terms of what's driving the cancer and what its susceptibility is, so that we can interfere with what's driving it and stop the cancer from proceeding along its normal course. And that has to do with the name of the cancer. The HER2 protein in that cancer is what's driving it. It's the main problem that makes it a cancer. And so we have a lot of agents that interrupt the HER2 protein and interrupt the signaling that comes from the HER2 protein. And that renders the treatment very effective. But unfortunately, it's not universally effective. There are patients who, after a period of time on this treatment, their cancer continues to grow, and there's a lot of reasons for that. The overarching theme of why that happens is the emergence of resistance. Cancers are unfortunately very tricky. They have a lot of problems with their DNA that allow them to shape shift over time.

SPEAKER_04 11:58

Let's pause and explain another way. Cancer learns to work around the drug. Think of it like a lock and key. The drug is designed to fit a specific lock on the cancer cell and shut it down. But over time, some cells mutate and change the lock slightly, so the key no longer fits. Those resistant cells survive, multiply, and eventually drive the cancer to grow again. This is why even highly effective targeted therapies like the HER2-directed drugs eventually stop working for some patients. And it's the core problem the Archer trial is trying to address.

SPEAKER_01 12:37

And what typically would happen then is someone will start on a medication and then after a given period of time, for some people it's months. Fortunately, for many people, it's many years, at some point the cancer on the next scan shows us that it's growing or progressing. And the thinking is that it's found a way to elude the medication, it evades the initial susceptibility that it had and it found another way to grow that goes around the medication. Our thinking is that if at the very earliest stages, for people who don't have very much metastatic disease that's there, there are probably just a few cells that are left that have somehow survived the chemotherapy or the HER2-targeted therapy. And the most likely place that those cells are to live, and this is a hypothesis that we have, this isn't proven, but we think that the most likely place that these cells exist are in places where tumors were visible on scans. So either where the tumor originated in the breast or in a metastatic site. These are places that had the most cancer cells, so many that you could see them, in fact. It wasn't a microscopic amount of disease. And these are the places where we think the resistance may emerge from. There might be one or two cells in there that have the ability to elude the chemotherapy, and these are the spots that are of most concern. And we have a little bit of evidence to support this as well. And so the purpose of the trial essentially is to look at these specific places where the resistance might be emerging from. And before resistance emerges, before we see something progressing on a scan, to treat that exact spot. And so in the breast, what that means is removing the tumor bed, removing the area where the tumor originated in the breast. And for all of the other metastatic sites, if there's a lesion in a bone on a scan or a lesion somewhere else in the body, we look at that spot very carefully with imaging, and then we treat it with radiation to a dose that's considered ablative, meaning that if there are cancer cells there, they should be destroyed by the radiation. And by adding that surgical component and the radiation component, our goal is to ostensibly eradicate every last cancer cell that might be there, certainly every last one that we can see, and then evaluate patients over time, follow people to see how they do after this treatment, and ideally to increase the duration before we see any additional progression.

SPEAKER_04 15:00

So you said the bones, which in the HERTU positive disease is not the most common. So when you start talking about ablating your liver or ablating your lungs, the first thought that most of us have, oh no, oh no, no, no, no. So can you talk a little bit about that?

SPEAKER_01 15:31

It's a very good point. So you made one really interesting distinction between triple positive and HER2-positive disease. Both are eligible for this trial. So triple positive refers to estrogen receptor, progesterone receptor, and HER2. So these are patients who benefit from both endocrine therapy, anti-estrogen therapy, and HER2-targeted therapy. And then there's also estrogen receptor negative disease that's still HER2-positive that still benefits from HER2-directed therapy. So these are both subgroups of breast cancer that are eligible for this study because both of these types of cancer are susceptible, as we said before, to HER2-targeted therapy, and they tend to do quite well in the trials of systemic therapy for HER2-positive disease. The other question about location is also a good one. There are rules. Different subtypes of breast cancer have different propensities to go to different places in the body when they become metastatic. The borders of these rules are fuzzy. You can see almost any subtype of breast cancer with a brain met or a bone met or a liver met, and just the proportion of these sort of varies by subtype. You're absolutely right. The point is well taken. You know, radiation, a blade of radiation to something that you might deem as sensitive as the liver sounds scary. Fortunately, the field of radiation oncology has developed to a point where we routinely treat many different spots in the body and we can do it safely. And we have a lot of expertise and evidence that supports these sorts of treatments. So you can imagine there are patients with primary liver tumors. Breast cancer is one kind of cancer, but certainly patients can have liver cancer that starts in the liver. And for such patients, sometimes radiation therapy is exactly the treatment that they receive, and we've learned to do that safely and effectively. There are many other kinds of cancer that also have propensity to go to the liver. And when they get there, sometimes they cause their own problems. They can obstruct the bile ducts, they can create liver issues, they can back up the blood flow. And these are tumors that we sometimes also treat with radiation in a palliative way. And we have techniques for doing that. So that's just the liver. Other sites that we think about routinely, the lung is another typical site. It's fertile soil for metastatic disease of many varieties because it's very vascularized. There's a lot of nutrients and oxygen there, and also it's a very large organ. And so just by size, it's a place where sometimes things go, particularly because it filters the entire circulatory system. There are certainly techniques for treating ablatively in the lung as well, and doing so safely and effectively for all different areas in the lung. Of course, when we're closer to the heart, we have to be more careful. When we're closer to what we call the mediastinum, the central structures, there's a lot more sensitive tissue and organs there. And so we have techniques for handling that. But again, to take the analogy from primary lung disease, there are patients who have lung tumors that are early stage that can show up anywhere in the lung. And in many cases, we can cure those early stage lung tumors just with a blade of radiation, and we can do so safely. And so it's a well-taken point. But I think that for people who have radiation in mind and concerns about different kinds of radiation, I think a discussion with a radiation oncologist who practices using contemporary technology and has experience treating a particular part of the body can be very reassuring because there are a lot of novel techniques and positions that we can get patients in to make things more comfortable and also safer.

SPEAKER_04 18:56

Thank you so much. So, as a follow-up, you mentioned another body part that I actually hadn't thought about and I should have the brain. That's another area that seems to be very popular with the HER2-positive disease. So I read in the description that the CNS meth are excluded from your trial. Can we talk a little bit about that?

SPEAKER_01 19:22

Yeah, that's a question that's come up a fair amount and garnered a lot of discussion when we were designing this study, and we can talk a little bit about why some of these decisions were made. But essentially, this is a study for oligometastatic breast cancer, which means there are only five or fewer metastases, and they can all be safely treated with radiation. That's another sort of determination that the consenting clinician would have to make before enrolling on this study. And then the other criterion that you brought up was the study unfortunately excludes patients who have brain metastases. And the reason for that is because there's a fair amount of literature and many studies that show that some of these targeted HER2-directed treatments just work differently in the brain than they do in the rest of the body. And we didn't want to start asking too many questions of this trial where it could become complicated to understand what the outcomes were if we had too many different types of patients. I certainly think that if this trial succeeds, the next iteration should look at patients with brain metastases. That's definitely one of the next steps. But for this particular iteration, we're very meticulous about the kinds of patients who can enroll. As a clinical trialist, I've been involved in a number of clinical trials over the course of my career where clinical trials don't succeed, where too many questions are being asked at once, and then you end up not being able to answer anything because you've spread yourself too thin. With this trial specifically, we're focused on a very, very narrow question so that once we get that answer, it becomes clear where to go next versus going to all this trouble and then not really being sure if we were able to address anything at all.

SPEAKER_04 21:03

So if you're listening and wondering whether you or someone you know might be eligible for the RCA trial, here is a quick summary of the key criteria. You need to have HER2 positive metastatic breast cancer, five or fewer metastatic sites, no brain metastasis, and this needs to be a first diagnosis of breast cancer, not a recurrence from an earlier stage. All sites of disease need to be safely treatable with radiation, and you would continue on your standard systemic therapy throughout. As always, talk to your oncologist, and we'll link to the trial in our show notes.

SPEAKER_03 21:43

That's really important. I think as patients, we question the exclusion criteria because we want to have the opportunity, and we want our friends to have the opportunity to have these new potentially terrific treatments. But that's a really important point for us. To understand that you're getting an answer and then you can build on that rather than spending a lot of time and effort and money and not coming up with any solutions. That's helpful for us to think about.

SPEAKER_01 22:14

Yeah, and I appreciate that. And when we're designing trials, that can be a very controversial point. Oftentimes, you know, even clinicians and patients alike, they want to push for everybody to be eligible for these trials so that everyone can try this exciting new therapy. But I think ultimately it's important to be scientifically rigorous about asking these questions so that we don't shoot ourselves in the foot and go through this whole project and then realize after the fact that, oh, we actually cast too wide of a net. We're asking too many questions, and now we can't answer any of them, and we have to start over and essentially ask the exact question that we're looking for. In fact, this is a little bit building on a trial that asked a very similar question across all breast cancers. There was a trial called Energy Beer 002 that asked a very similar question looking at ablating all sites of oligometastatic disease and breast cancer. It was a trial that didn't show benefit to that approach, but it was also a trial that looked at all subtypes of breast cancer, essentially. And when you allow all subtypes of breast cancer, what you learn quickly is that HER2-positive disease is not the most common type. And this trial accrued very low numbers of patients with HER2-positive disease. And so effectively, this question hasn't really been asked in HER2-positive disease, where we think we have the most effective systemic therapies.

SPEAKER_04 23:44

And here is the story. Some breast cancer patients have what doctors call oligometastatic disease, meaning the cancer has spread but only to a handful of spots. Maybe two, maybe three, four at most. And for years, oncologists had this idea. What if we just destroyed every single one of those spots? Zap them with high precision radiation, cut them out, wipe the slate clean, and then let the drugs do the rest. It made sense. It was logical, it was hopeful, and it did not work. The trial tested exactly that approach in a randomized control study, and when the results came in, there was no meaningful difference. Patients who had those metastasis targeted with radiation or surgery did not live longer. Their cancer did not stay away longer. The numbers were almost identical to the patients who just received standard drug therapy on its own. The trial was stopped early, it won't move forward to a larger phase three study. But here is the thing about a negative trial. It's not a failure, it's an answer. And in medicine, knowing what doesn't work is just as valuable as knowing what does. It is an important lesson in how to read cancer research. The trial included all subtypes of breast cancer, not just HER2 positive. Since HER2 positive disease is only about 15 to 20 percent of breast cancers, there simply weren't enough HER2-positive patients in that trial to detect a benefit specific to them. It's not that the approach failed, it's that the question was never really answered for this particular group. That's exactly why the RTA trial is focused exclusively on HER2-positive disease. The whole notion of a legal metastatic disease is still kind of controversial, right? I mean, there are conversations about whether it has its own biology, and it's not exactly the same as just saying that this is a cancer that just has fewer metastatic sites.

SPEAKER_01 25:58

You're absolutely right. And this is one of my first slides when I present this talk to my colleagues and to other centers that are interested in opening the study. One of the very first slides says that essentially not all stage four disease is the same. As we pointed out a moment ago, there are patients who present with stage four disease with a brain metastasis. There are patients who present with a liver or a lung or a bone, and there are different quantities of stage four disease as well. And what the literature shows that lower amounts of disease tend to do better. This is what we see from the literature. Whether that's a function of just the overall burden of disease, meaning the number of cells that have the potential to develop resistance, that's probably one reason. Another reason is probably just organ function generally. The more disease there is, probably the more compromised the organs are, and the body might have a little more difficulty handling that burden of disease. And the question here with oligometastatic disease, as you say, is it a distinct biological entity? Is it actually behaving differently from disease that comes to attention when there's already several dozen sites of disease? If someone on a scan has just three sites of disease and you looked at their cells from the disease specifically, would they look different from someone who had several dozen sites of disease? And the answer to that in terms of how we treat them is that we treat them as if they're identical because they've already spread beyond their initial site of origin, which in this case is the breast and the lymph nodes near the breast. But it might be that they behave very differently and should be treated differently. And that's one of the questions of this study is can we basically address these few sites of disease and have an outcome that's different from other stage four outcomes, essentially.

SPEAKER_04 27:49

I would also pose a hypothesis, which is based on being uh a total layperson, but it could also be that the disease itself is not as aggressive. And that's why there are fewer sites.

SPEAKER_01 28:05

That's exactly right. Yeah, that's the exact underlying hypothesis of the biology being different, is that maybe the fact that you've only found a few sites means that the disease is moving more slowly, or that it doesn't have the ability to go into other places that it hasn't gone yet. So that's exactly right.

SPEAKER_04 28:23

I also wanted to ask you, and I don't know if I saw this in the description of the trial. You limit it to the number of distinct mets, but what about the sizes of the metastasis themselves?

SPEAKER_01 28:37

The size, we're agnostic about the size, so long as it can be safely treated with the ablative therapy that we're planning. Okay. So in the breast, we work closely with breast surgeons. What we're trying to do is recapitulate early stage breast cancer as much as we can and basically treat with the same sort of intent as early stage disease, which means in the breast, if it's a larger tumor, it might necessitate a mastectomy. If it's a smaller tumor, it might be adequately managed with a lumpectomy. And we leave that to the discretion of the surgeon who's doing the operation in terms of what they can do safely and effectively and in discussion with the patient and what their desires are. And in terms of the metastatic sites, if the treating radiation oncologist determines that they can ablate this safely with our latest ablative radiation techniques, then there's really no size limitation per se. You can imagine that the size limitation is probably different in every part of the body depending on what can be done safely.

SPEAKER_03 29:36

So essentially, you're taking patients with a limited amount of disease, oligometastatic disease, less than five lesions, you're offering them the same treatment in terms of the chemotherapy and targeted therapy, and then you're adding a surgical component and a radiation component to see if they can get better outcomes. And you've described it as long-term durable treatment, and you have avoided the word cure. So, first I want to ask am I summarizing the treatment properly? And then if you can comment on the language.

SPEAKER_01 30:18

Yeah, you summarize the treatment beautifully. So that's exactly right. The standard of care remains. So nobody on this trial is getting less than their current treatment. They continue on their chemotherapy and their HER2 targeted therapy. And what we add on top is the surgery and radiation component, and then they go back to their standard chemotherapy and targeted HER2 therapy. That's also a moving target, by the way. As new drugs are being developed, the standard of care is probably going to change in the near future to more effective treatments. And there is still a long pipeline of treatments in development. And so we're not going to change that because that's effective and it works, and everyone's very optimistic about the outcomes with those agents.

SPEAKER_04 30:59

Has already, right? The uh the first line has already changed. That's exactly right from the Cleopatra protocol of perception project and a taxane to a to an antibody drug conjugate.

SPEAKER_01 31:11

And Cleopatra itself built upon the point. This march of progress will continue and it's only accelerating. So that's exactly right. And then Ellen's other question: you see physicians in the field of oncology shying away from using the word cure. And I think that's a reaction to how it was used in the past. If you look at the older literature, a lot of studies and a lot of pontifications by physicians would have said, you know, if you're five years out from your treatment and nothing's happened, you're probably cured. And that was the end of it. And then what we learned from trials that had longer and longer follow-up was that actually events, unfortunately, could still happen beyond five years.

SPEAKER_04 31:51

You're actually talking to the two people who are in that particular case.

SPEAKER_01 31:55

Thank goodness. Thank goodness. And there are more and more people in cases where the longer people are around, the longer we know that events can show up, unfortunately. And we're in a position now with HER2 positive breast cancer where people are around for decades, and yet still there's no time point beyond which we can say nothing's going to happen. You know, as time goes on, there's less likelihood that things will happen in a lot of situations. But we've become a little bit gun shy about using that word because you don't really know if you've cured someone unless they've lived out their natural life expectancy and you've proven that nothing has happened. And so as the field has learned this in many different kinds of cancers, we talk about long-term durable control. That's not to say people are not cured. We see people cured all the time. And in many cases, and in many subtypes of breast cancer and in many presentations of breast cancer, we see a majority of people being cured. But we don't use that word because it doesn't convey exactly what we're trying to say, which is that we don't know for sure. Even in cases where outcomes are really, really excellent in early stage disease and breast cancer, where you can expect a more than 90 or 95% chance that nothing will happen as a consequence of this early stage tumor over the person's lifetime, we still hesitate to use the word cure. Part of that is cultural. Part of that is we're just being maybe overly cautious about providing a picture that doesn't exactly represent what we expect. But it's a fair point and it's a controversial one that comes up a lot. The word cure is very loaded in the oncology space, and we want to be very careful about what we're presenting to patients.

SPEAKER_03 33:38

I just really appreciate your honesty with that because as patients, we're sort of the five-year mark is this magical time where everything changes, and supposedly many people think that we're cured, and we would like to feel that way. But then the reality is that for many of us, this we know that 30% of people with early stage disease are gonna go on to get metastatic disease. That's an enormously high number. So I think it's false reassurance. Not that we would need to live our lives thinking it's gonna come back any day, but there's a reality to it. And I think being honest is the best way of dealing with this. I want to ask about two areas. When you're adding the surgery and the radiation, that's going against the common thinking now, which is there's no reason to treat someone like a de novo stage four patient with breast cancer to do surgery on the tumor because we're told there's no long-term survival benefit. But it makes sense to me to decrease the tumor burden. And the same thing with the radiation. I think there was a study that showed that radiation for specific lesions also did not do better than the chemotherapy. But going against the traditional thinking, that's what I did for my treatment. And I found with oligometastatic bone disease, I had very good outcome with the SBRT.

SPEAKER_04 35:11

Ellen just mentioned SBRT. That stands for stereotactic body radiation therapy. It's a highly precise form of radiation that delivers a very high dose to a small specific target, like a single bone mat. In just a few sessions, sometimes even one, because it's so focused, the surrounding healthy tissue is largely spared. It's a key tool in the RHI trial for treating metastatic sites outside the breast.

SPEAKER_03 35:42

So I'm a proponent of this radiation treatment, and I'm a proponent of having the surgery. So I love this trial. But where did you come to think about this and to go against the grain of the current treatment?

SPEAKER_01 35:55

Yeah, you're exactly right. The literature in this field is very, very mixed, both in terms of the role of surgery and the role of radiation. There was a study that came out just a few years ago by the E.Cog Akron group that looked exactly at what you were describing, which is surgery for the breast in the case of stage four disease. Prior to that study, there it was a bit of a mixture of what other scientists had discovered. There was a very famous study out of India that actually showed that it was beneficial. And there was a series of other studies that showed that it was not beneficial. It turns out that the reason those studies were so mixed is because they were not forward-looking randomized trials. They were hospitals looking at their own prior experience of patients with stage four disease who had surgery. And when you do something like that that's not randomized and not forward-looking, you end up with a problem called confounding. You also end up with some selection biases.

SPEAKER_04 36:52

Two terms worth unpacking. Confounding is when a third factor you didn't account for is actually what's driving the result you're seeing. So you think treatment X caused outcome Y, but really it was a factor Z all along. Selection bias is when the patients who ended up in one group aren't really comparable to the other group. Not because of the treatment, but because of who they were to begin with. In this case, the patients healthy enough to get surgery were already in a better position than those who didn't. So the surgery looked like it helped, but it may have just been that those patients were healthier from the start.

SPEAKER_01 37:36

What you can imagine happens is that it is the healthiest, most informed, most well-resourced patients who end up having the surgery. And maybe if you're a hospital and you look at who had surgery, you're now looking at only those patients in the most favorable position. And consequently, you're comparing them to patients in a less favorable position that has nothing to do with the surgery itself. It has to do with how informed the patient was and how healthy they were and their opportunity to even get to the operating room. And so that led to this E.Cog Akron 2108 study, which basically looked at surgery for patients in this position, but in a randomized way, meaning a patient, just like the Archer trial is randomized, which is important to highlight, not everyone who signs up for the trial ultimately gets this more intensified treatment. Some people continue on the standard of care so that we have a reasonable comparator group. But basically, on this surgical study that was randomized, what we learned is that the surgery didn't make a difference in the setting of stage four disease. The key to that trial, and one of the distinctions with what we're trying to do now, is that that study didn't address all of the metastatic sites. It only addressed the primary tumor. It answered a very specific question for us, which is does treating just the primary tumor, to your point, Ellen, about just reducing the amount of cancer in the body using surgery to the primary cancer, does that make a difference? It turns out that as far as long-term survival, it doesn't. And the hypothesis there might be that because the metastatic sites weren't addressed, there might still be little cells in those metastatic sites that ultimately develop resistance. And that's what ultimately could cause progression in the future. And to your other point, just treating a few of those sites and not treating all of them on some other studies also showed no benefit. And that's the reason that we're taking such a comprehensive approach here. So that's where this all emerged and why we're looking specifically at oligometastatic disease, just at HER2-positive cancer, and looking to treat all the sites where we know the disease is, because the underpinning of the whole approach is to say, can we try to eradicate every last cell that might emerge with resistance? We hope that answer is yes. And then as a consequence, you end up with longer, what we call progression-free survival, meaning a longer duration without progression after the treatment.

SPEAKER_04 39:54

And so once the active treatment period ends, you will be monitoring people for three years, right? Did you say it's three years of active treatment?

SPEAKER_01 40:05

That's right. So the active treatment actually doesn't end.

SPEAKER_04 40:08

But the active surgical and local treatment.

SPEAKER_01 40:11

That's right. The intensified treatment for this trial, as you point out, is very periodic. It's a surgery and radiation, and then back to standard of care. And so that's exactly right. Patients are then monitored for three years. There will be plenty of patients who haven't had progression at three years, even just by standard of care. Yes. But the way that we look at the statistics now and at designing the trial, we can surmise whether it worked or not by about three years. In an ideal world with unlimited resources, we would follow everyone for 20 years and then we'd know what happened in the very, very long term. But given these things are very expensive and we're also very cognizant of the burden on patients, there's time points where we need to collect imaging, where we need to collect questionnaires, there's some laboratory tests that need to be done over the course of a patient's treatment throughout all of this. And so rather than burdening folks beyond the time at which we've been able to answer our question, we're stopping at three years essentially.

SPEAKER_03 41:10

How would somebody sign up for this?

SPEAKER_01 41:13

So the study is open. It's openly findable online. Just look for the Archer trial and breast cancer. And there's one other Archer trial out there looking at bladder cancer. Actually, a colleague of mine is running that, and we just had a fun discussion about how we both came to our names concurrently. So no one had dibs on that name, essentially. But Google is a perfectly fine place to find our study.

SPEAKER_04 41:35

Well, yours is an acronym. Is your colleague's an acronym as well?

SPEAKER_01 41:40

It is too. You pointed out that mine was a mouthful. I won't even begin to figure out what his is about.

SPEAKER_03 41:46

We have shown notes and a website to go along with this. So I'll be happy to include the information in that.

SPEAKER_01 41:52

Fantastic. I appreciate that.

SPEAKER_04 41:53

How many sites do you expect to be recruiting for this?

SPEAKER_01 41:57

We have the ability to open a number more sites right now. It's early days, so we don't know where it'll end up, but we're very hopeful that it'll be available in many different regions across the country for people who are interested.

SPEAKER_04 42:07

Right. And how many people would you like to uh recruit for this?

SPEAKER_01 42:13

So overall trial is designed for 162 people.

SPEAKER_04 42:17

And that's doable, right? Even though I have to remind people that the HERD2 subtype is about 15% of the whole population. So it's not as many people as you might think.

SPEAKER_01 42:31

That's right. It's not the most common. Unfortunately, breast cancer is the most common cancer. So even a small segment of the breast cancer community ends up being a fair number of people, unfortunately. Um, but we do think that it's doable. It will be challenging and we'll have to work hard to find 162 participants. But we're on our way, I should say, since we've started.

SPEAKER_04 42:54

I think, especially since more younger people are being diagnosed with this disease. And her too tends to be more common with the younger population. And the younger population does tend to be diagnosed at a later stage.

SPEAKER_01 43:11

It's a little bit mixed. Unfortunately, you're right. And I think people have seen this in the news that younger and younger populations are starting to be affected by cancers for some reasons that are explicable and others that we don't yet have good answers for. But you're right. There are some patients who are very young, unfortunately, with HER2-positive breast cancer. And a lot of us in many different fields are working to understand why and to develop more aggressive treatments like this for situations where the outcomes are not as good as we would like them to be.

SPEAKER_04 43:40

I'm a person living with the triple positive disease since 2004, actually. And I have seen how my subtype went from the worst to the best. And it's good, and it's really heartwarming for me to see that the curative approaches are. Uh, being considered for people with my subtype.

SPEAKER_01 44:03

They're being studied in great depth. And we've been talking a lot about HER2-positive breast cancer today and what it means and the biology behind it. And I should say that it's a paradigm in oncology. I may have alluded to this a little bit in the beginning that we understand it very well. And it's one of only a few cancers that we understand to this degree. It's probably one of only a few cancers that are driven by one specific molecular pathway to this degree, where cancer can be very complicated. In this case, it is complicated, but it's also quite well characterized and understood and has a susceptibility that we can target. We wish we had such a target for all other cancers. And what you've seen over the past 20 years is the development of drugs that treat this target that have enabled us to have patients who present with stage four cancer and we can take care of them for decades. Whereas in the 90s and prior to that would have been unheard of.

SPEAKER_04 45:03

Yeah, it is incredible. So what's next? Say you've accrued your 100 people and the trial is successful, and three years later, everybody's still doing great. What's next?

SPEAKER_01 45:17

Yeah. Fantastic question. This is the question that should come up for every study that we think about. What comes next? Because we should always be forward-looking and anticipate next steps as we're completing our current work. Say this trial is successful, which is what we all hope. The next steps, we pointed out that this trial is very meticulous in terms of the types of people that we're looking for. The next steps are to expand the approach to patients who might not have been eligible for this study, to patients whose presentations might not be as so meticulously favorable as we've selected here to see if they might also benefit from this. So we talked about brain metastasis is one other place to look, potentially other subtypes of breast cancer, potentially more than just oligometastatic disease. There are many ways that you can envision broadening this. Right now, it's also a study important to point out that it's only for people where this is their first diagnosis of breast cancer. It's more challenging to study someone who's been treated for breast cancer and then develops metastatic disease a few years later because the biology may have changed in that interim. So this study is looking particularly at people who, at their first diagnosis, have this oligometastatic disease. But the next step really should be to look at patients who are treated for early stage disease and then unfortunately have a metastatic recurrence. That's a place where I think there was a lot of discussion about even including patients like that on this study. And then ultimately, again, we focused in on a very narrow window so that we could be sure to answer the question we were looking for. But the next step might be to broaden that window. Absolutely.

SPEAKER_04 46:50

Hopefully, you will not find anybody in that group going forward. Hopefully, those early stage people will have been cured by their early stage treatments, but we don't know.

SPEAKER_01 47:01

And I'll project into the very long term and say that hopefully in my lifetime, there really is no role for surgery and radiation at some point, that these medications become so good at keeping things under control that really they do the whole job on their own, and that we don't need to intervene on any particular site because at some point resistance can't emerge because the medications are so good. And I hope we're approaching that point.

SPEAKER_04 47:28

Well, this is a great way to end, isn't it? One thing I wanted to ask you. Ellen doesn't like me to ask that question, but I'm really, really curious about this because when somebody decides to become a medical oncologist, that seems to be clear. How does one decide? Oh, you know what? I want to become a radiation oncologist when I grow up. How does one decide to do that? Is that interest in physics that makes you go into that or not wanting to be around people too much, although radiation oncologists do?

SPEAKER_01 48:05

That's funny. That's funny. No, I love being around people. I think it's a it's a different answer. You'll find a different answer for every type of physician that's out there. And I'll say that I came to this field a little bit late. I can't say that I ever uttered the words I want to be a radiation oncologist when I grow up. I probably never said that because I didn't know what it was really until I encountered it in medical school. It's a pretty niche field. It's not one of the standard rotations for people training in medicine. But I knew based on some of the research that I had done in the laboratory, that I wanted to work in one of the cancer fields. And then ultimately I just spent time in all of them. And I picked the one that felt most comfortable and spoke to me the most and where I thought I could make the biggest difference. So to your point, physics was always a deep interest of mine, and computational methods for treatment and analysis and things like that were always very appealing to me. So that was one of the reasons I chose radiation oncology. But I'll tell you the primary reason. And when young people ask me for advice about which specialty to choose, I tell them to find their people. So every specialty has its own culture, it has its own setup, its own way that you balance the rest of your life around the culture of that specialty. And the most important thing is to find people who are like-minded and with whom you get along, and people that you can see yourself spending the rest of your career with. And when I rotated in the radiation oncology department at Dana Farber and at Mass General in Boston, those are some of the greatest people I've ever encountered in my career. And I thought that I'd be giving up a very valuable thing if I didn't go into radiation oncology with that group of people.

SPEAKER_03 49:36

That's wonderful. It's that same advice about people for I'm an obstetrician. And it's like if you like hanging out on labor and delivery, and these are your people, that's a great feel for you. If you don't like us, don't do it. You're not going to have fun.

SPEAKER_01 49:52

Absolutely. And it's not a piece of advice that you can appreciate until you've arrived in medical school and are approaching the time when you need to make that decision. Because before medical school, doctors are doctors. They all seem, you know, pretty capable. They've all worked hard. They all have lives that maybe don't look too different. But once you're really in the weeds of it, things are very, very different.

SPEAKER_04 50:14

Yes. Before we wrap up, we asked Dr. Bronstein about something we've been asking a lot lately. The role of artificial intelligence and medicine. It's a topic that's impossible to ignore right now. And in radiation oncology specifically, the implications are significant. Okay, so I have the last question. So, what is your thinking on AI and what is the future of AI, especially in your field?

SPEAKER_01 50:43

It's a very timely question. It's one that we discuss multiple times a day. What would a conversation be without someone mentioning AI these days? I'm glad you brought it up. I mean, the role of AI is very interesting in a lot of our practices. Some medical specialties lend themselves more to assistance from AI than others, for sure. In our field specifically, in radiation oncology, what we're learning is that the AI is very good at interpreting the images that we have and helping us to segment or contour the images. So, you know, when we look at a CAT scan, as physicians, we can see the lungs and the kidney and the heart. And when we're treating a tumor, we can see the tumor as well. And what we have to do is physically go into the scan and outline all of these structures to tell the computer these are the lungs, this is the tumor, this is the heart. And then we calculate where the radiation is going to go, and we can estimate the amounts of radiation to each of these structures so that we make it safe and then we make it effective by getting the highest dose of radiation on the tumor or the target, as we call it. That used to be a lot of time for us where we would sit with each scan and go piece by piece and physically, like with a pen, just draw out all the different areas on the scan, like a map. And now the computer can do that on its own for a lot of structures and do so very reliably. So that used to be a big part of my day, and now it's a smaller part of my day. The other place where AI is becoming very helpful, and our group is pioneering some work right now, is in helping to match patients to the correct clinical trials.

SPEAKER_02 52:17

Yes.

SPEAKER_01 52:18

As your listeners may know, and as you may have encountered, there are thousands of trials going on at any given time. And our ability to accrue to all of these trials is limited. A lot of trials stop early because they can't find enough patients. Maybe patients are out there, but they can't be matched in an effective way. Even in our own clinics, I'm very fortunate to work in a place where our portfolio of clinical trials is hundreds or even a few thousand trials deep. And at any given time, I may be sitting with a patient who has maybe a dozen trials available to them. And if I don't have all those trials in mind, and if I'm not motivated in that moment to cognitively match the patient to the trial, I won't say anything, and then the patient will never know, and the trial will have missed an opportunity to present their information to a suitable candidate, let's say, who might have benefited. And so with AI now, we actually started building something like this before AI came online, or before this particular type of AI came online. We were trying to build tools to help us match the right people to the right trials, and they were pretty rudimentary and they didn't work very well. But now with these new technologies, our goal is for every time we see a patient in the clinic, we want to have a comprehensive assessment of what trials they might they be eligible for so that it's not on the clinician during a busy clinic day where they're running around managing a lot of medical issues and they have a lot of priorities before the clinical trial. It's not on them to stop everything and think about what might be out there and put that on themselves because that's another burden. And what you'd rather have is clinicians focusing on practicing medicine. Rather, you serve it to them so that it's available, it's easily accessible. And when they see a patient, they can just look at a quick report and say, oh, this trial is very interesting. If you're interested in more information, we can talk about that, or I can refer you to the people running this trial. And hopefully that will make some better matches and help to drive the whole research enterprise by making some of these trials that take a very long time to accrue to, maybe accelerating them a little bit or even finding pockets of patients that we might not have considered otherwise. So that's another place where people are pretty excited about this. You know, we could talk for hours about the different roles for AI and the practice of medicine.

SPEAKER_04 54:30

Excellent. Would you like to come back and talk for hours about that?

SPEAKER_01 54:33

I'd be delighted.

SPEAKER_04 54:34

Particularly with a glass of wine.

SPEAKER_01 54:36

Round two of the podcast. That sounds great.

SPEAKER_04 54:38

That's right. That's right. Well, thank you so very much. I don't want to keep you any longer than I have to, which I'm sorry to say I would love to. But thank you. This was wonderful.

SPEAKER_01 54:49

You know, it was absolutely a pleasure, and thanks for your interest and thanks for your time. It's great to share some of this information. And I always learn something when we have these conversations. It was a two-way street today.

SPEAKER_04 54:59

I'm so glad. As I said, we can ensure more teachable moments for you if you come back.

SPEAKER_01 55:05

That sounds like a plan. You got it.

SPEAKER_04 55:07

Thank you. Take care. That's a wrap on today's episode of Life from Stage 4. I want to thank my co-host, Dr. Allen Landsberger, for bringing her characteristic warmth, her sharp questions, and as always, her lived experience to this conversation. Ellen, this show wouldn't be what it is without you. And a tremendous thank you to Dr. Leo Or Bronstein for his time, his clarity, and his genuine commitment to asking the questions that matter most to patients. The Archer trial is enrolling now. We have linked everything you need in the show notes. If today's episode moved you, challenged you, or gave you something to bring to your next oncology appointment, please share it. Share it with your care team, your community, your fellow patients. The more people who hear these conversations, the more people who might benefit from them. If you haven't already, subscribe wherever you listen to podcasts so you never miss an episode. And if you have a moment, leave us a review. It helps more patients find us. One important note before we go Ellen and I are patients and patient advocates, not physicians. Well, Ellen is, but she's not an oncologist. Nothing in this podcast constitutes medical advice. Please always consult your own medical team before making any decisions about your care. Until next time, keep asking the hard questions. This is Life from Stage 4.