BCRF investigator Dr. Nancy U. Lin talks about the urgent need for metastatic breast cancer treatments and potential breakthroughs on the horizon.

As the largest private funder of metastatic breast cancer research (MBC), BCRF is passionate about supporting the most bold and innovative researchers who are seeking new treatments for this incurable form of the disease. While current therapies are helping those with MBC live longer than ever, there are a limited number available and, unfortunately, they eventually stop working. 

To mark Metastatic Breast Cancer Awareness Day, BCRF spoke to Dr. Nancy U. Lin of the Dana-Farber Cancer Institute—a BCRF investigator since 2007—about the vital work that could lead to new treatment options for people living with MBC.

Watch the full video above or read an edited version of their conversation below.

Jen Feinberg: Hello, welcome to BCRFs behind the breakthrough series. I'm Jen Feinberg, mother of two and a BCRF fundraiser living with metastatic breast cancer [MBC]. Five years ago, I was diagnosed with stage 0 DCIS, and two years later I learned that it had progressed to stage IV because it spread to my lungs, liver, bones, and brain. My subtype is HER2-positive. I lost track, but I think I'm on my fourth or fifth line of therapy. I fully appreciate that I would not be here today, if not for the advances in science that have made my treatments possible.

I've committed to fundraising for BCRF to help support the cause. Fundraising has also proven to be a great coping mechanism. To date, my community has raised over $860,000 for research, and we're still going. Our fundraising is currently supporting the work of BCRF investigator Dr. Nancy Lin, who I'm thrilled to be joined by today. Dr. Lin is an expert in HER2-positive breast cancer and brain metastases and works at the Dana Farber Cancer Institute in Boston. We're going to talk about MBC and her research today. In full disclosure, Dr. Lin is part of my amazing care team. But this is the first opportunity that we've had to talk about her BCRF-supported research. Dr. Lin, thank you for joining me. And to start, could you please introduce yourself to the audience?

Dr. Nancy Lin: My name is Nancy Lin and I'm a medical oncologist based in Dana-Farber Cancer Institute in Boston, Massachusetts. I run our EMBRACE [Ending Metastatic Breast Cancer for Everyone] program, as well as our program for patients with breast cancer brain metastases.

JF: Can you tell us about your BCRF-supported research? I'm frequently asked this question, and I think you'll do a much better job of explaining it.

NL: I've been very fortunate to have been funded by BCRF since 2007. And even before I was officially funded by BCRF, some of the projects that I worked on with my mentor, Dr. Eric Winer, he provided some of the BCRF funding for my projects. So even before I was officially named, I have been the recipient of enormous donations from BCRF to really advance the research. And the research area that I've been most focused on is the problem of brain metastases, which is cancer from the breast that ultimately spreads to the brain. And the reason this is such a big problem is because, obviously, the brain is a very important part of your body and controls important functions. But also because, historically, patients who have had cancer that went to the brain were not included in clinical trials—unless they were clinical trials of, say, radiation therapy for brain metastases. And that left a big void for patients as far as the treatments that we could offer.

BCRF funded the very first trial of HER2 targeted therapy with lapatinib, which we don't even really use so much anymore. But that was the first HER2-targeted trial ever tried in patients with brain metastases, and that trial would not have been possible without the funding from BCRF. And since then, we've gone on to develop a number of other regimens, including neratinib based-combinations, including tucatinib-based combinations and now trastuzumab deruxtecan like Enhertu. And we're excited to study additional regimens as well, which we can talk a little bit more about. This has been a major focus of my BCRF work. 

The other part of the work that BCRF funded is the creation of a database and collection of tissue and blood samples from patients with MBC to try to understand disease resistance. That is when treatments stopped working…why do they stop working? And so that's another area that BCRF has been very, very helpful in. It’s not so hard to find granting mechanisms, the competitive grant mechanisms to pay for “I have all the samples, now will you let me sequence and analyze them.” It's essentially impossible for granting mechanisms to grant you money to collect the samples in the first place, or the clinical data, which is what you need to do all this work. And so BCRF has been incredibly instrumental in providing the funds to allow us to do really important work on questions that we see relevant to the clinic every day.

JF: Actually, just to put a finer point on it—can I ask, does the research that you're doing help inform treatment decisions for somebody like me who may have progressed on standard therapies?

NL: BCRF has in fact funded the research efforts and parts of the trials. Not the entire trial, we have many ways to cobble together funding for trials of lapatinib, for trials of neratinib, for trials of neratinib in combination with T-DM1, for example, for trials of tucatinib. And so I think especially in the HER2-positive space, it's been very fruitful. In patients who have HER2-negative breast cancer brain metastases, we've seen fewer successes, although we're very hopeful that we will start to see more. And we have a trial that is being partly funded by BCRF looking at a drug called Dato-DXd [datopotamab deruxtecan], which will enroll HER2-negative patients with brain metastases as well as patients with leptomeningeal disease. We're excited to hopefully get that open before the end of this year. I think the research we do definitely translates into the clinic. We've been very interested in research that is very close to that sort of translational lab clinical interface so that it's not 10 years before something gets to the clinic but sooner.

JF: It's clear that more research dollars are urgently needed for all subtypes of breast cancer. I happen to be particularly focused on HER2, because that's the kind I have. Can you explain what HER2 is and what it means to have HER2-positive breast cancer? 

NL: Cancers have all different ways that they become cancers. They become dependent on pathways that allow them to divide and grow. One of those pathways is HER2. So when we say that a cancer is HER2-positive, we mean that there are too many copies of the HER2 gene in the cell. And those copies of genes create too much protein on the cell surface. And then what that does, it's kind of like a growth factor. And it promotes the cells to grow, divide, and survive. So if we target HER2, we can target the so-called driver of the cancer. And it turns out that when you target HER2 and you add even a little bit of chemo, it actually makes those other treatments work tremendously better. 

And so that's why you'll see, for example, in the HER2 CLIMB regimen with tucatinib, it’s not just the HER2 drugs of tucatinib and trastuzumab or Herceptin, but also there's a little bit of chemotherapy thrown in as well. And those kinds of combinations tend to be very effective. HER2-positive breast cancer makes up about 15% of breast cancers, so it's not the most common type of breast cancer. But it's one where I think we've made some of the most astounding progress. And we are very hopeful that one day we'll be at a point where we might even be able to cure people with metastatic disease. We’re not there yet—I don't want to make false promises. But I think it's the first subtype we’re probably going to figure out.

JF: I've described it to friends as a blessing and a curse. It's nice that there's targeted treatments, although it's a very aggressive form. When I was diagnosed with an early stage breast cancer, I thought I was lucky because we had caught it early. I did not appreciate the potential for metastases. Can you explain what it means to have metastatic breast cancer and why it's such an important area of research study?

NL: Metastatic breast cancer is cancer that originated in the breast, but then at some point in time went to other parts of the body outside of the breast and the nearby lymph nodes—the bone, liver, lung, brain. Those would be common locations. Most people who have early stage HER2-positive breast cancer will not have a recurrence and will be cured of their cancer. But most is not all.

In addition, there are patients whose cancer is metastatic from the get go—not because they didn't have screening or not because they didn't do everything right, but just because the cancer is by nature aggressive. And the reason why I think it's so important to figure out metastatic breast cancer and why I have devoted my career to trying to sort it out is because if we want to eliminate breast cancer deaths, we need to be able to figure out how to deal with metastatic breast cancer. Because even if we cured every single patient with early stage breast cancer, there will still be patients who, when they first come see us, have metastatic breast cancer. And the reality is that I'm not sure we're ever going to get to a place where we cure every patient with early stage breast cancer. So if we really want to reduce deaths from breast cancer, we really have to pay attention to treating metastatic breast cancer patients with more effective therapies and developing those therapies for patients. 

JF: You have a somewhat unique specialty in that you have this focus on brain metastases, and I always wanted to ask you how you came to focus on this area. 

NL: It's a little bit of a random story. I really enjoyed my neurology rotation when I was a medical student, I thought it was very interesting. But I also thought that oncology was much more sort of interesting from a science, drug development, etc., standpoint. Like things were really moving, it was the place to be. And I really enjoy taking care of people with breast cancer. I just think that the level of conversation and the patient's input into everything is just…there's something very special about it that I love. But when I met with Dr. Eric Winer, who was my mentor when I first started my fellowship, he suggested that I might think about HER2-positive breast cancer. And then sort of in passing discussed that there's this problem that they've been seeing that patients are developing cancer in the brain because the treatments are getting so much better in the body, that we're starting to see this problem. And he said, do you want to maybe start working on it. And I said okay, so I did. But I think what is appealing to me is that I kind of like hard problems. And it was a place where as a fellow starting out, I could actually make an impact. There weren't like 1,000 people working on the same thing. And it was really a void, right, and that's where one could really make the biggest difference, I think.

And I think the other part that I like about it is I like the multidisciplinary aspect of it. It's not something that I’m treating patients “on my own,” it's really a team-based approach. We involve the radiation oncologist, sometimes we bring in the surgeons, the neuro-oncologists, etc. But most of all, I think it's really that it's, in a way, the last frontier. If we're going to go back to this idea of HER2-positive breast cancer, if we’re going to eliminate death from HER2-positive breast cancer, you cannot ignore the brain. It's a place that for patients who have early stage disease, as you have experienced, it can come back in the brain. It's a place if patients have metastatic breast cancer, about half of patients with metastatic HER2-positive breast cancer eventually will have cancer in the brain. So if we ignore it, and we don't try to do better, we're just not going to make the kind of progress that we need to make.

JF: On that note, in recent years, we've made a lot of progress in the treatment of brain metastases. So I'm hoping to talk about what's improved over the last few years. I know there's been a lot of new drugs. How have they impacted treatment?

NL: One of the drugs that we've been involved in developing is this drug called tucatinib. And it's not a miracle drug. Sometimes it doesn't work. It doesn't work forever, even when it does work. But the trial that looked at tucatinib was called HER2CLIMB. And in the trial, patients with or without brain metastases were given Herceptin, chemotherapy, and then either they did or did not get tucatinib. And the striking findings from the trial is that patients survived longer if they received the tucatinib. And in patients who had brain metastases, they survived almost twice as long. I mean, it was a really dramatic improvement. But it’s still not as long as I want it to be, and it still doesn't work for everybody. And it still stops working. I mean, it’s not a perfect drug. But I think that the real breakthrough is the idea that a systemically given treatment, not radiation treatment, not some sort of surgery, but a systemically given treatment has the potential to dramatically impact the survival of a patient who has cancer that spread to the brain. And I hope that it's the first in many drugs to be able to show this effect.

JF: I hope so. What are the biggest challenges right now? Like you said, it doesn't work for everybody. Why is that? And what are the biggest hurdles to overcome?

NL: I think one of the biggest hurdles to overcome is trying to overcome resistance. Because there are some patients who have exceptional responses, there are patients who are on Herceptin for 15 years. For metastatic disease, there are patients who have these amazing responses. But for the majority of patients, cancer eventually gets through, it figures out how to get past the first line of therapy and figures out how to get past the second line of therapy and we switch from one to another—and we don't have unlimited numbers of things to switch to. And I think that the better we can understand what drives these resistance pathways from what's causing the resistance, the better we can develop drugs and trials to try to prevent the resistance from happening in the first place. Also, the more options there will be for patients whose cancers become resistant. Because it's one thing, thinking about a diagnosis or living with a diagnosis of metastatic breast cancer, if you know you have unlimited numbers of things that you can switch to that will eventually work, versus there's a finite number of treatments that will eventually work. And the longer we can make that list, the better, and the longer lives people can live even with the diagnosis of metastatic disease. 

So I think those two things go hand in hand: understanding resistance, developing new therapies. And I think one of the challenges for HER2-positive breast cancer is that it becomes harder to run the trials now than it was before. Why do I say that? Because if there are fewer patients who have recurrence of their breast cancer, then there are fewer patients with metastatic HER2-positive breast cancer that could go on a trial. And then if patients live longer, it means you have to wait longer to see if there's a difference between the new treatment and the old treatment. It's actually faster to develop new drugs in diseases where people do very badly, because you don't have to wait as long. I mean, it sounds very morbid, but that's true. 

And so it's one of these kind of situations where sometimes we have to argue that No, we really, really do need more later-line treatments for patients with HER2-positive disease. We don't just need the first four treatments, we need more. And we definitely need more for patients who have cancer in the brain because the number of treatments that we know that work there is even more limited than in cancer outside of the brain. And so I think some of the challenge is we're just successful enough to make it maybe not as interesting to study, but not successful enough that it's really good enough for patients. And that's again, where BCRF really comes in. Because we really can't take our foot off the pedal. This is the time to really go because I think we can make transformative changes. If we don't, we don't accept the status quo.

JF: You're proving my theory. This is the whole reason I started doing targeted fundraising for HER2, because I had worried that the landscape had been so developed already, that researchers would turn their attention elsewhere and say we've done enough here. But I know that enough is not enough for everybody.

NL: That's exactly right. Enough is not enough for everybody. And I don't think it's enough until people don’t die of metastatic breast cancer. It's not enough to have four lines of therapy that are pretty good. And I think, again, this is where BCRF is so helpful because it helps us not take the foot off the gas pedal. It helps us find new directions that then could become new drugs someday. It helps us develop the preliminary data that can lead to large phase three trials that you know, BCRF is not necessarily funding the large phase three trials, sometimes they do. But those preliminary studies allow us to then go to companies with data in hand to say, Look you want to really do this study. And then those big studies get done, but they would never have happened without the early work.

JF: What do you think are the most promising areas of research right now in breast cancer?

NL: There’s still a lot of room left to optimize antibody-drug conjugates, called ADCs. Antibody-drug conjugate examples are Trodelvy, Enhertu, Kadcyla. These are antibodies that find some target on the cancer cell, and then there's usually a chemotherapy attached to it. And they have proven to be very effective delivery devices for treatments. And there's many other targets that could be targeted, and many other so-called payloads or chemotherapy, other molecules that are attached. It's kind of like a mix and match. And there are many, many companies developing ADCs. I think that over time, we'll see more and more use of ADCs and less and less use of regular chemo.

Another area is immunotherapy. We only use immunotherapy in selected patients with triple-negative breast cancer subtype at this point and that's only a small proportion of all breast cancers. And even for triple-negative, we know there must be ways to make immunotherapy work better than the current immunotherapies that are available. So I think, How can we make immunotherapy work better for triple-negative breast cancer? And how can we figure out how to make immunotherapy work at all for the patients who have ER-positive or HER2-positive breast cancer, because the immune system is really different than the drugs we give. The immune system can evolve over time. So Herceptin, when we give it, it's the exact same structure every time we give it, it doesn't change when the cancer changes. But if we can train people's immune systems to evolve with the cancer, then if the cancer tries to become resistant, your immune system can evolve with it. I think there's a lot of promise in immunotherapy in terms of long-term responses, but we haven't really figured it out in breast cancer the way it's been a little bit more figured out in melanoma or other kinds of cancers. 

And then finally, this idea of personalized therapy. In other words, when cancers become resistant to treatment. In some cancers, it's always one way. But in breast cancer, what we've learned is that that's not so simple. And that when cancers become resistant to treatment, the cancer could have taken multiple paths to get there. So maybe like 5 percent do it this way, and 10 percent do it this way, and another 8 percent do it this way. Then it becomes an issue of one size doesn't fit all. And we're not used to developing drugs or trials where there’s lots of different pathways people can go down. And then how do you develop a trial and a strategy where one day, we could in fact, do some sort of molecular test and then say, of these eight treatments, this is the one you should go on next. We're not at that point yet, for the most part. But I think that is one of the ways that treatment of metastatic breast cancer could go. To really try to personalize the treatment to what's going on in the patient at that moment in time.

JF: That's not happened. Is that in a trial context? Where is personalized medicine right now? 

NL: Where it is right now, I think, it’s probably the furthest along in patients who have estrogen receptor positive metastatic breast cancer, because there we have approved drugs that are targeted to specific changes. And an example is, the estrogen receptor can mutate in cancers. In early stage breast cancer, it’s mutated less than 1 percent of the time. When somebody has a first diagnosis of metastatic breast cancer, it's mutated around 10 percent or 15 percent of the time. And then when the cancer has gone through endocrine therapy and the cancer has gotten worse through it, then it can be up to 40 percent or 50 percent of the time that the gene is mutated. There are many drugs in development and one FDA-approved drug, which is being looked at specifically targeted to people who have the ESR1 mutations. So that's an example of something where if you just tested the tumor, the original diagnosis of early stage disease, you're going to miss a lot of patients who could benefit from it later. So it’sthis idea of continually retesting and personalizing based on what we see. But we don't have too many examples of that right now in breast cancer. But I do think that's where some of the targeted treatments are going.

JF: Just in the time that I've been living with breast cancer, so much has happened in the last even three years. I can't imagine what the next three years will hold. So I find that very exciting. I know you collaborate closely with patient advocates in your work. Why is that so important?

NL: I think that patient advocates help to really contextualize everything in a way that is…we can get very stuck in our own sort of world. And one example of this is there are two ways of looking at people with brain metastases prognosis. Which is that in the “old days” everybody was told you have six months. That's the average and very few people went beyond that. And now I take care of patients who are living years even after brain metastases diagnosis. But it is not 20 years, and it's not 40 years. And what seems like so much better to somebody who has seen a lot of bad things happen over time is not really what somebody coming in as a patient who otherwise previously had a normal life wants. And I think that working with patient advocates always helps to remind me of that. Yes, we've made a lot of progress but it is just not enough. 

I've been very fortunate to work with incredible patient advocates. Liz Frank is somebody who I worked with for many years, and she helped basically us to conceive and put the EMBRACE metastatic program together that we have at Dana-Farber that's this clinical research, wraparound program for patients with metastatic disease. And it was really Liz's vision in terms of the patient-facing components. We have webinars, we do educational materials. And she really spearheaded so much of this, really thinking about from a patient perspective, what would she want to hear about? What would she want to learn about? What are the gaps? And that has been incredibly important as we developed our program. And then the research as well has been incredibly useful. We run clinical trial designs by patient advocates all the time. Is this going to be something that's doable from a patient standpoint? Does this seem palatable and okay from a patient standpoint? Does the science sound exciting or not? To really have an outside look at it. And finally, from the standpoint of clinical care, I think it's really useful to have perspectives from people who are both in the know but not directly invested, because it's not happening to them at that moment of time. In other words, we have had patient advocates sometimes attend our brain tumor board, for example. Because I think it's very useful to have a patient perspective on clinical care. And it really helps us become better doctors.

JF: So glad to hear it. I've actually found a lot of support from people who I think serve as patient advocates, but they also provide support to the patients, which has been really helpful. You've already done this a little bit, but could you talk about why BCRF funding is so important to your work?

NL: I think it's very hard to underestimate the impact of BCRF. I think that what is sort of inscrutable to people outside of academic medicine is the very strange way that our lives are structured. Which is that the default is that I would see patients 100 percent of my time, and that any research time that I have I need to pay for essentially. What BCRF has done is to allow me protected time to do research and to devote a good chunk of my time to focusing on the problems that we just spoke about and funding the work itself. It's in addition to funding the coordinators and the research staff that make the work happen, as well as any reagents and lab supplies and all of that. It also is a very unique funding mechanism, because it allows us the freedom to have this area of passion and pursue it with all we have in a way that is quite distinct from normal granting mechanisms. And then finally, I think what BCRF has really done is allow people to develop data, preliminary data, that then can become practice-changing studies. But you need to start somewhere. And it allows us to build really important foundational elementsas well as look at areas that are “out there” or different. You know, when we started this first brain metastases trialthat had some BCRF support, no one else had done a trial like that, ever. We weren't going to get a major grant to do a study like this. And so I think it's these kinds of investments in some amount of risky science and concepts really pay off.

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