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Investigating Breast Cancer: Dr. Priscilla Brastianos
Mapping and understanding brain metastasis
Metastasis, when cancer cells leave the breast and spread to other sites in the body, is the major cause of mortality from breast cancer. The brain is one of the most common organs breast cancer invades, occurring in more than one-third of patients with advanced breast cancer, up to 300,000 patients a year. The prognosis of cancer patients who develop brain metastasis is poor, with only 20 percent of patients surviving at one year.
For Dr. Priscilla Brastianos, a BCRF investigator since 2017, this cause hits close to home. Both her mother and grandmother died of metastatic breast cancer. That’s why she has dedicated her career to better understanding brain metastasis. As the Director of the Central Nervous System Metastasis Program & Assistant Professor of Medicine at Harvard Medical School and Massachusetts General Hospital, her research focuses on understanding the mechanisms driving metastatic disease to the brain. She is currently conducting studies to characterize the genetic and molecular profiles of brain metastasis compared to primary breast cancer with the goal of identifying potential targets for therapy and strategies to improve response to existing therapies.
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Read the transcript below:
Intro: I’m Chris Riback. This is Investigating Breast Cancer, the podcast of the Breast Cancer Research Foundation and conversations with the world’s leading scientists studying breast cancer prevention, diagnosis, treatment, survivorship and metastasis… which just happens to be the topic of today’s conversation.
Metastasis, of course, is the process by which cancer cells move to different parts of the body. In other words, we might beat cancer in one place, only to have it show up – sometimes years later – in another place.
For breast cancer patients, the brain is one of the more common organs it invades. In fact, this occurs in more than a third of patients with advanced breast cancer, up to 300,000 patients year. And the prognosis of cancer patients who develop brain metastasis is poor, with only 20 percent of patients surviving at one year.
Which makes the work that Dr. Priscilla Brastianos leads so significant. Dr. Brastianos is Director of the Central Nervous System Metastasis Program & Assistant Professor of Medicine at Harvard Medical School and Massachusetts General Hospital. Dr. Brasitanos’ research focuses on understanding the mechanisms that drive metastatic disease to the brain, and she is conducting studies to characterize the genetic and molecular profiles of brain metastasis compared to primary breast cancer with the goal of identifying potential targets for therapy and strategies to improve response to existing therapies. She has been a BCRF Investigator since 2017.
But as you’ll hear, Dr. Brastianos’ work is not just urgent, it’s also personal. Her grandmother, as a 23-year-old medical student in Greece, was diagnosed with breast cancer. She passed away six years later from metastatic breast cancer. Then, more recently, Dr. Brastianos’ mother also passed away from metastatic breast cancer. As Dr. Brastianos has said, “We need to find better treatment options for patients with metastatic cancer.”
Chris Riback: Dr. Brastianos, thanks for joining me. I appreciate your time.
Dr. Priscilla Brastianos: Thank you for the invitation. Delighted to do this.
Chris Riback: So in this podcast, as you would expect, we talk in each episode about breast cancer. We also talk very frequently about metastasis, but people may not realize the brain is one of the more common organs that it invades. In fact, this occurs in more than a third of patients with advanced breast cancer and which I guess calculates to up to 300,000 patients a year. That is such a big number.
Dr. Priscilla Brastianos: Yes, unfortunately, breast cancer that's spread to the brain as a very common complication of cancer and it does occur, as you mentioned, in about 30 to 40 percent of patients with advanced breast cancer. And unfortunately, while advances in cancer therapies have dramatically improved our ability to control breast cancer outside of the brain, we still have a long way to go to develop better therapies for cancer that has spread to the brain.
Chris Riback: What makes the brain so vulnerable and what makes the brain itself so difficult to address?
Dr. Priscilla Brastianos: That's a fantastic question. So one reason the brain is so vulnerable is that many drugs that we use to treat breast cancer or other types of cancers don't get into the brain as well as other parts of the body. And that has to do with what's called the blood brain barrier, which is actually a protective barrier. It protects the brain from chemicals or other toxins. But that also means that drugs that could work for cancer outside of the brain don't work as well in the brain. So that's one reason.
And then the second reason is, and this is, and I'll touch upon this later in the interview too, the second reason is, and this is a lot of my research that we're currently doing, is that brain metastases do differ genetically from the primary tumors. So targets that work for the primary tumors may not necessarily work for the brain metastases.
Chris Riback: And that's-
Dr. Priscilla Brastianos: And I can touch-
Chris Riback: Yes, sorry, I'm sure that you will. No, no, I know you will touch on that because that's the core of, if not all of your study, a significant area of the study that you're doing. So, let's get into that. You're conducting studies to characterize the genetic and molecular profiles of brain metastasis compared to the primary breast cancer, which you just explained, with the goal of identifying potential targets for therapy and strategies to improve response to existing therapies.
So I take that to mean either to find new therapies, find new strategies and tried to improve the approaches that are currently underway. So, let's break that down. First, tell me if you would, about the studies themselves, how do they work and how far into them are you?
Dr. Priscilla Brastianos: Yes, so that's a great question. That's actually dear to my heart and to what my lab does. So I do want to start by saying that historically a lot of clinical trials have excluded patients with brain metastases. And that has to do with...
Chris Riback: Why?
Dr. Priscilla Brastianos: Yes, it's a great question. One reason is because patients with brain metastases often do worse than other patients. So unfortunately, drug companies are often hesitant to want to have their drugs investigated in patients with brain metastases, and that is unfortunate and terrible. And so a common exclusion criteria in clinical trials throughout the US has been the presence of brain metastases and us in a number of other investigators are really trying to change that. So we're really trying to change the attitude that we should be excluding patients, that in fact we should be studying patients with brain metastasis because we need to find better treatment options for patients.
And so that is actually the crux of why we do what we do is we're trying to find better treatments for patients with brain metastasis. And how we do that is we try to understand the molecular underpinnings of metastatic disease that goes to the brain. So, what does that mean? So, cancer is caused by changes in DNA and often these changes can be targeted. So targeted therapy or personalized medicine has revolutionized how we manage many different types of cancers. Even in breast cancer, for example, overexpression of the marker HER-2 is associated to responses to HER-2 therapy, so anti HER-2 therapy.
So what my lab has focused on in the last few years is trying to understand are the therapeutic targets in the brain the same as the primary tumor? So often what we see, so I'm also a clinician, so I'm a physician scientist. So, I treat patients with brain metastasis, but I also run a lab focusing in this area. And often what we see is that patients with brain metastases will often progress in the brain and not outside of their brain. So that's not an uncommon clinical scenario.
And so the question is, is it because there's new genetic changes in the brain that we don't necessarily see in the primary tumor? And over the last several years, my lab has been focusing on trying to answer that specific question. So we have been collecting and analyzing the genetics of brain metastases and comparing them to the primary tumors and then seeing if these genetic changes are potentially therapeutic targets.
So, in one of our initial studies that we published a few years ago, we had taken patient samples from about a 100 patients and that included not just breast cancer patients but other histologies, meaning other types of cancers such as lung cancer, renal cell cancers, as there are other cancers that go to the brain also. And in that initial study we did find that brain metastases have new genetic changes or new therapeutic targets that are not detected in the original primary sample.
So what does that mean? It means that if we are only targeting what we see in the primary tumor, we might miss potentially clinically significant alterations that are in the brain metastasis.
Chris Riback: In reading about your work and listening to you now, tell me if this is wrong, it's almost like you're creating a Google Map of how the cancer moved, of how it metastasized from the initial tumor location to the brain. You're trying to determine, wait, where did this thing make a wrong turn and not just where did that occur, but what happened to the vehicle to make it make that wrong turn? Is that, obviously hyper basic understanding, but is that something of a description of what you're after? Are you doing something way beyond Google Maps?
Dr. Priscilla Brastianos: That's a fantastic description. And in fact, the other way we like to describe it. So are you familiar with the term the Cancer Genome Atlas?
Chris Riback: Yes.
Dr. Priscilla Brastianos: Or TCGA? So TCGA has its genome atlas in all kinds of different cancers, lung cancers, breast cancers, have been studied in TCGA. So it's an atlas of the genetics of specific tumors. And most of these samples or most of the samples analyzed are primary tumor samples, very few of these are our brain metastatic samples. So essentially we like to say we're creating an atlas of brain metastases genetics. And I do like the idea of the Google Map, essentially that's exactly right. We're trying to pinpoint what are the key alterations that drive metastasis, and can we understand why that cancer metastasized? Why did it go to the brain? And that's one of the key questions we're trying to answer.
Chris Riback: And what's your hypothesis, and I don't know exactly, you can fill me in, is there initial feedback or insights from which you can extrapolate? What are you learning about the genetic and molecular profiles of brain metastasis compared to the primary breast cancer? Are there connections, and if you're not fully there yet, the data just aren't sufficient. What's your hypothesis?
Dr. Priscilla Brastianos: We're knee deep in the analysis now. With our initial sequencing data, we are finding that the brain metastases do have new driver mutations that we're not seeing in the primary tumor. And in fact, we see that there are commonalities across many samples. So there are certain pathways that seemed, or molecular pathways that seem to be common in the brain metastases across many brain metastases.
And there are some pathways that seem to be very common and that's already led to a clinical trial in patients with brain metastases. So we actually just activated a clinical trial mid-August that is a national clinical trial, where we're actually going to be treating patients with brain metastases based on the genetic alterations that are found in the brain metastasis. And that's a different paradigm to how we've traditionally been treating patients with brain metastases in the past.
And if I can go a little bit more into how brain metastases patients were commonly treated. In the last several decades, brain metastases patients almost always got whole brain radiation and that was just standard. And now as patients are living longer, we're seeing that there are a lot of toxicities to whole brain radiation. And there's still a role to whole brain radiation in a select group of patients.
But we're trying to now create a more personalized approach to patients with brain metastases, whereby we can try to understand what are the molecular drivers in this particular patient with the brain metastasis and can we target that patient. And that piece is still a work in progress. We're actively now investigating in this national trial that we're doing and we're hoping that this will lead to better clinical outcomes for patients with brain metastases.
Chris Riback: And from my understanding, when you talk about these patients and the folks in the trial for brain metastasis or with brain metastasis, did they all originate from breast cancer or are these, as you mentioned earlier, patients who have gotten cancer and it has metastasized to the brain, but it originated out of multiple forms of cancer?
Dr. Priscilla Brastianos: We're actually allowing all histologies, so we're allowing lung cancer patients, renal cell, melanoma to go onto this study because we're finding some of these same patterns that we're studying in breast cancer are actually emerging in other cancers also. So we're hoping that we'll be able to help not just breast cancer patients, but other cancers also. But we do have breast specific arms of the study, where we're specifically going to be treating or looking at the breast cancer population, but we are allowing other histology. Then we'll be analyzing those separately, if that makes sense.
Chris Riback: And it makes total sense and it hits on truly one of the most interesting things that I have learned in these conversations is how leading researchers like you connect work across cancers. I mean, you're like the ultimate investigators finding clues. Maybe it's, in some cases, from one part of the body. Certain folks that I've talked to or certain types of cancer and then defining how they may or may not be applied to other parts of the body or other types of cancer. I assume that that's part of your approach as well as trying to understand the similarities, differences across these various types of cancers in terms of how they metastasize to the brain?
Dr. Priscilla Brastianos: That's exactly right. That's exactly right. So we're looking at how breast cancer differs from lung cancer in the brain, but then we're also looking at the similarities, because one can learn a lot from each of the different cancers.
Chris Riback: Yes, I hear that frequently and it's a really interesting part of all the study that goes on. Tell me about the brain metastasis tumor bank. I understand that you are in fact working with an international network on this. How do those logistics work?
Dr. Priscilla Brastianos: Yes, so I am so grateful at this group of national international collaborators that we have. So we have established a number of collaborations, both within the US and nationally, and we are receiving samples from, we've received samples from Spain, from Poland, from Toronto, from Korea, and then from a number of institutions in the US and a number of others also. And we're collaborating to try to create the largest resource we can to study brain metastases and one cannot do great science in isolation.
So before, I would say 2010, 2011, the largest study to comprehensively characterize a brain metastasis from breast cancer. And that's using the genomic tools that we're using now, had one patient sample. So you can't do much with one patient sample. So now we have in our bank more than 1500 brain metastases from all histologies. That includes breast cancer, lung cancers, melanoma, renal cell, carcinoma, and we're now systematically analyzing these samples to try to see, again, what's unique to each histology and then what's common across all histologies and how can we take this data to clinical trial. And the beauty of this collaboration is that we share data back to our collaborators and each collaborator can then run with that data and investigate the analysis in their labs too.
Chris Riback: Yes, yes. I don't know if it's kind of a combination, it sounds like between democratizing but also exponentially growing the amount of data and the insights that various scientists and researchers can get out of the inputs.
Dr. Priscilla Brastianos: That's exactly right. And I do have to say that we've benefited a lot from philanthropic support, and I am grateful for that. So we've received funding from places like Breast Cancer Research Foundation and other foundations to help with a lot of these efforts. And that's been tremendously rewarding.
Chris Riback: Yes, I am sure. Kind of maybe a final question on this part of what you do, in thinking about the potential outcomes and benefits and therapies and strategy that you hope and others hope might come out. What might an improved strategy to the existing therapies look like? What could that entail?
Dr. Priscilla Brastianos: An improved strategy is personalized medicine for each patient with a brain metastasis. So taking each patient, studying the tumor for each individual patient and finding what the right targets and what the right treatment approach may be. And I've talked a lot about precision medicine and targeted therapy. Right now, immunotherapy is also quite hot and is being looked at and has revolutionized many different types of cancers. We're still trying to figure out what the best roles for it in breast cancer.
However, again, in the future what I hope is that we'll be able to predict from analyzing a tumor sample what is the best treatment for this patient? Should we give this particular targeted treatment, should we be giving this patient immunotherapy or chemotherapy and individualized treatment will be I think the future for these patients.
Chris Riback: As I am listening to you, I'm also aware of course of all the directions that studying metastasis in the central nervous system can go and you have studied it in a number of areas and of all the connections it might have to other medical conditions. For you personally, it's not by accident that you've been inspired to explore at least in part its connection to breast cancer. Is it?
Dr. Priscilla Brastianos: Yes. I have a very personal connection to breast cancer and yes, my personal story is that my grandmother was diagnosed with breast cancer at the age of 23 and she at that time was one of the only females in her medical school class. And she palpated a breast mass while learning how to perform physical examinations and she diagnosed herself with breast cancer and she went on to graduate from medical school and she unfortunately passed away in her late 20s from metastatic breast cancer. And she left behind my mom who was six at the time.
And I grew up hearing my grandmother's story and my grandmother for the short life that she had made an impact on her patients even in those few years where she practiced medicine. And I remember hearing her story and knowing I wanted to become a medical doctor like my grandmother, but I knew I wanted to study cancer.
And then unfortunately, 40 years later my mom was diagnosed with breast cancer and at that time I was in medical school and so we started her journey of mastectomy, radiation, chemotherapy. And together we live through the trepidation of awaiting scan results, trips to the ER, side effects of her chemotherapies and it's these two women and their stories woven into my life that really inspired me to become a medical oncologist and scientist and look for treatments that metastasize.
And unfortunately, my mom passed away just a few years ago from metastatic breast cancer and when she was alive, I felt like I was racing against the clock to try to delve into the research that could potentially help her. I was not able to do so unfortunately. And before she passed away, she made me and my brother promise that we were going to dedicate our lives to this pursuit. And we're doing that, and I miss my mom every day and that's what drives me every day. I really want to find better treatments for patients with metastatic cancer. And I made that promise and I hear her every day and I'm determined to do that.
Chris Riback: I'm sure that you are and you are doing it, and obviously, and in learning about your story and thinking about it, there were two aspects of it that really hit me. One is you must connect so directly with what I assume is one of the main concerns of anybody with an illness like that, which is the pressure of time, the stress of time, the limitation of time. How does that affect either your work or maybe your connection to the mentality, mindset, that's really the word I'm looking for, the mindset of patients. How does the question of time play into what you do?
Dr. Priscilla Brastianos: So my experience with my mom has made me a better doctor. I can understand the patient and family and the anxiety that goes with a diagnosis of metastatic breast cancer because you don't know how much time you have. And we lived through that. So, and that inspires me in my work because I'm constantly trying to find better treatments so that we can give patients more time. Median survival is still not great for patients that have brain metastases and I want to try to extend that.
Chris Riback: The other part that struck me is your role. I mean, my belief is that you are still on the young side as well. Your grandmother was very young and made incredible impact, it sounds like, and from what I've read, I don't know what your mother did, but obviously in a very young as well, how do you think about that part of your role specifically engaging with or encouraging young women to take on such enormous challenge? I mean, you personally have met great success and maybe more importantly or as importantly, incredible responsibility at a relatively young age. How do you think about this? Do you think about this in terms of engaging with or encouraging young women to take on challenges like you've taken on?
Dr. Priscilla Brastianos: What I tell young women is that if they have a passion, they should absolutely pursue it. And in my role as a physician scientist, I take great joy in mentoring young women. So I have young women in my lab and also I work with residents and fellows and I try to guide them, and I try to inspire them in some ways so that they're not afraid to take on big challenges and ask big questions and then pursue their goals.
Chris Riback: And you indicated earlier that you kind of decided at a very young age that for you it would be science. Was that the case? Was there ever a second option or was it just, it was always science and it was always math and becoming a fiction novelist just was never really going to be in the cards?
Dr. Priscilla Brastianos: Yes. I enjoy writing and I actually write poetry on the side, but I-
Chris Riback: So, maybe that is where this is going to go.
Dr. Priscilla Brastianos: Oh, I enjoy the humanity of medicine too. So there's an art of medicine too, so I love that, the artistic side of medicine. So, obviously I knew from a young age I wanted to pursue medicine and help people in some way, and I loved science. But I do love writing and I do creative writing on the side.
Chris Riback: Well, excellent. We'll have to check out the... Find if there's a website out there, even if you haven't done it yet, maybe you've got a nom de plume that'll have to be... Anything you want to talk about? Anything you want to reveal right now?
Dr. Priscilla Brastianos: Not yet.
Chris Riback: Okay, well-
Dr. Priscilla Brastianos: Not yet. Maybe if I decide to retire at the age of 80 or 85, I can start publishing poetry.
Chris Riback: Well, the world isn't going to wait until then for your poetry. So you're going to have to come up with another plan. Dr. Brastianos, just to close up, two questions. One, you mentioned earlier the incredible role that organizations play in funding work and helping create opportunity, I guess, and there are a number of them, the Breast Cancer Research Foundation, what role have they been able to play in your research?
Dr. Priscilla Brastianos: I am so grateful for the support that Breast Cancer Research Foundation has provided. So they have provided support for us to be able to create this tumor bank of samples and to genomically characterize the breast cancer-brain metastases samples and the work has already leading to clinical trials. So I'm incredibly grateful for their support.
Chris Riback: And of course not to appear ungrateful in any way, but people, of course are going to want to know what's next? Is it really focusing on finishing these clinical trials and the current study? How do you define what's next in terms of the science?
Dr. Priscilla Brastianos: Well, we still have a long way to go to understand the genomics of brain metastases. So our goal is to identify the genetic drivers that are specific to the development of brain metastases and we're still not there yet. And so that's one goal.
And then the second is to take this work to more clinical trials. So we need to find more effective targeted treatments. Not just target treatments, but treatments for brain metastases patients, and that's going to be my life goal. We need to find better treatments for patients with brain metastases.
Chris Riback: We certainly do. Dr. Brastianos, thank you. Thank you for your time, and thank you, obviously, for the work that you do.
Dr. Priscilla Brastianos: Thank you very much.