Radiation therapy has long been a mainstay of breast cancer treatment for many patients. Like other areas of cancer care, the goal is always to reduce risk as much as possible while still maintaining benefits. For patients undergoing radiation therapy, one key risk is unintended radiation exposure. In cases of breast cancer that occur in the left breast, for example, unintended radiation exposure to the heart can increase the risk of heart failure. So how could doctors limit this kind of damage?

Enter Dr. Rachel Jimenez and her research on proton beam radiation. Unlike traditional radiation, proton therapy radiation can target cancer cells specifically, sparing other healthy tissues from potential damage. Additionally, as part of her Conquer Cancer Foundation Advanced Clinical Research Award for Diversity and Inclusion, Dr. Jimenez and her colleagues are exploring whether proton beam radiation therapy could be delivered effectively in a shorter time span than traditional radiation, cutting down on the disruption to patients’ lives.

Dr. Jimenez is an assistant professor of radiation oncology at Harvard Medical School and the chair for quality and safety in the department of radiation oncology at Massachusetts General Hospital. Dr. Jimenez also serves on multiple national committees in oncology as well as various professional societies and patient advocacy organizations.

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Chris Riback: Dr. Jimenez, thank you for joining. I appreciate your time.

Dr. Rachel Jimenez: Thanks for having me.

Chris Riback: I thought we should start with your specialty: radiation oncology. Given the range of cancers, why did you choose to apply your specialty so significantly towards breast cancer? Why this discipline? Or by chance, do I have that wrong and you apply your time equally across all cancers?

Dr. Rachel Jimenez: You do have it right. So the majority of my time is spent caring for patients with breast cancer. And in the academic setting in which I practice that’s quite common. So academic physicians often will focus their practice on a specific type of cancer because it allows us to really delve deeply into the management of patients with that given cancer type. In my case, breast cancer. So we’re really thinking about how to care for those patients most carefully and are able to then lend our thoughts towards the creation of clinical trials and other types of research that we think are most likely to benefit those patients.

Chris Riback: And what drew you there?

Dr. Rachel Jimenez: As a trainee, as a resident, I really enjoyed caring for breast cancer patients. And while I enjoyed caring for many patients of many different types, I think the reason why I was drawn to breast cancer patients is because I feel like many of those patients are multi-hyphenate. They are mothers, they are wives, they are employees. They carry many, many different roles in their lives on top of managing their breast cancer and going through treatment. And I was really inspired by so many of the patients that I met, just seeing how many hats they wear despite the challenges. And it’s just a very inspiring group of patients to get to take care of.

Chris Riback: Which leads to my next question, which I wrote based on something I’ve read about you, but I feel maybe I chose slightly the wrong word. And my question is, what’s the role of compassion in what you do? And listening to you right now, maybe it’s not compassion, maybe it’s empathy, maybe it’s both. But in learning just a little bit about you, not a ton, it’s evident that that’s a key theme across who you are, how you engage with patients, how you think about your work. So tell me, if you would, how you think about compassion or empathy or any other word that you choose to throw in there?

Dr. Rachel Jimenez: Well, first of all, thank you. That’s very kind. I mean, I would like to think that all physicians go into medicine because they have an abiding empathy or compassion for the people that they care for. And I do think that it really is a privilege on our part to get to care for so many wonderful, impressive, steadfast, and dedicated patients. And I think that that’s the joy in what we get to do is to serve them in some small way on their journey to cure their cancer. So for me, I would like to think that that’s not a unique aspect of my practice, but I think it is the component of my practice that gives me the most satisfaction, which is really getting to know people as people—who they are, what they value, what’s important to them. And then be able to, again, in some small way care for them and to honor their values in the process.

Chris Riback: I love your use of the word dedicated, how dedicated the patients are. It’s such a multifaceted description and so accurate, and I haven’t heard it necessarily characterized that way, but it absolutely comes across in every conversation that I have with researchers, scientists, physicians, caregivers like you is the dedication. Because so many of the patients, yes, they are on a very, very challenging, to say the least, personal journey. And yet so many of them—and we’ll get to talk about this in a moment when we get into your clinical trials and your studies and your research—and I’ve heard it with other researchers, they are dedicated to the cause to other patients, to not just their journey so often, which has to be all-consuming, but also helping advance and discover and research for themselves but also for others.

That’s a really interesting and fantastic choice of words to describe their dedication, which it really is. It takes dedication to get through years of medical school and training, but it takes a different and really extreme type of dedication to be a patient. And that’s really thoughtful of you to recognize, of course.

Let’s move to the numbers. Approximately 60 percent, as I understand it, of breast cancer patients receive radiation therapy as part of their care. Why is that and how does that number compare historically? And I guess if I could pile on, in an age of increasing velocity of customized therapies and approaches to me as a lay person, an outsider, that 60 percent number feels high. So, talk to me about the 60 percent and how does it compare historically, please?

Dr. Rachel Jimenez: Sure. So the 60 percent may also be historical because we’re seeing so many advances in breast cancer therapy where we may be able to forego radiation, where patients don’t necessarily need to have radiation with a diagnosis of breast cancer. But to answer your question, historically, and I guess it depends on how far back we want to go, patients were treated quite radically even for very small early-stage breast cancers. And so many patients underwent mastectomy. And that mastectomy could be a fairly dramatic procedure with long-lasting morbidity for patients and cause a lot of side effects and really inhibit their quality of life.

And so there had been a number of clinical trials that explored the idea of instead of a radical mastectomy, doing a less aggressive procedure called the lumpectomy where we remove the cancer, but we preserve the breast of the breast tissue. And what we found was that adding radiation to the treatment, meaning delivering radiation to the intact breast after the patient had had the cancer removed, seemed to confer the same cure rates as doing a more radical mastectomy procedure.

So, when that data matured and we saw that the outcomes for those patients were just as good, the standard of care really began to limit the extent of surgery such that for early-stage breast cancer patients had a lumpectomy and radiation, and so they went hand in hand. That meant that many patients with early-stage breast cancer received radiotherapy. So, I think that’s where we’re getting that 60 percent number. And then there are other patients for whom the cancer may have left the breast but not traveled far away in the body, maybe into the lymph nodes underneath their arm, where they could still have curative surgery with a mastectomy and removal of some of those lymph nodes and might still benefit from radiation as a way to kill any small amounts of cancer that could be left behind even after a surgery like that.

So, the combination of both patients with early-stage breast cancer having a lumpectomy but preserving their breast and this other cohort of patients who may have still required a more aggressive surgery but could still benefit from radiation treatment afterwards gets us toward that 60 percent. Now, as I mentioned before, we’re starting to, I think, decrease that 60 percent number. There are patients who, as we learn more about breast cancer, have not very aggressive breast cancers. And so they may be adequately cured with surgery and some medication alone and they might not need to have radiation. And so now we’re seeing that older patients, patients with small cancers that are very favorable in their tumor biology, might be able to safely forego radiation treatment with still excellent cure rates.

Chris Riback: What is proton beam radiation?

Dr. Rachel Jimenez: Proton therapy is a type of radiotherapy. Typically, when we use radiation as a way to cure cancer, we’re using X-rays. And so those X-rays are the same X-rays that a patient might get when they go to the dentist and get an X-ray or when they have some other type of imaging if they break a bone. But we’re using the X-rays in a different manner. We’re using them at a higher energy as a way to damage the DNA of the cancer cell and prevent that cancer cell from growing.

With proton therapy, instead of using X-rays we’re actually accelerating subatomic particles called protons. And so those protons have a different physical property. The beam of the radiation behaves differently than X-rays do. And so the potential benefits of proton therapy is that we might be able to direct the radiation at the area that we think could be harboring cancer and that the radiation beam would stop after it treats that particular area, it doesn’t continue to travel through the rest of the body. This means that we’d be able to spare some normal tissue from getting exposed to radiation when we wouldn’t intend to give radiation to that area. But where X-ray therapy might still deliver X-rays, again, not intentionally, but because of the property of the X-ray that it may continue to travel through the body.

Chris Riback: And do I understand correctly, some of the tissue that people like you worry and have worried about with the X-ray form, let’s say, of radiation is particular to the heart? Is that correct?

Dr. Rachel Jimenez: That’s right. So for patients who have breast cancer, we’re always thinking about what are the parts of the body that are near the breast that might inadvertently get radiation that we don’t want to give radiation to? And so the heart is one of those.

The reason is because historically with radiation, we didn’t really have as many tools as we have available to us now. When we planned radiotherapy, it was pretty crude. So we would deliver the X-rays to the best of our ability using pretty limited anatomic knowledge of where things were in space. We could see the breast, but we really couldn’t see internally to understand where the heart was in relation to the breast. And in that era when we were delivering radiation in that manner, we saw that low doses of radiation to the heart did translate into a higher risk of heart disease for patients as they age. So we were curing breast cancer, but then we were finding that those patients were more susceptible to heart attacks and other things later. We were accomplishing the exact opposite thing of what we were trying to do, which is cure these patients and give them a great quality of life as they got older.

Now we have a lot more techniques that are available to us where we can visualize the internal parts of people’s bodies and see where their hearts and lungs are in relation to their breast. And we do that using CAT scans. And so most radiation planning these days uses a CAT scan so that we can actually see inside and try to avoid exposure of the heart and the lungs when we deliver the radiation. But there are some patients for whom even when we can see where everything is, there are some limitations to the technological delivery of the radiation that would still confer some radiation delivery to the heart and the lungs even when we didn’t want to, just because the techniques are limited to some degree. If the heart’s really close to the breast or to where the cancer is, it’s hard to avoid treating some of the heart with radiation.

So the potential benefits of proton therapy are that we might be able to better spare the heart, even in patients who have cancers where that is located very close to the heart. And so, I think that there’s a lot of interest and excitement about the ability to again, preserve the health of many of these patients who, aside from their cancer, are very healthy people that we’d like to see have great quality of life for many decades after we cure their cancer. And proton therapy may be a way to achieve that.

Chris Riback: There certainly is a lot of excitement around it. And some of that excitement is translated or has been translated into, I believe, funding or at least some type of support for a study that you and your team are undertaking. Tell me about the study around proton therapy. How will you do it? What will the research look like? What’s the current status?

Dr. Rachel Jimenez: Sure. I’ve been very fortunate that BCRF has funded the study that we’re looking at. My interests from a research perspective are always in trying to make treatments less burdensome and safer for patients. This particular study is really looking at both of those things together.

Just to provide a little bit of context, when patients receive radiation for breast cancer, often those patients that receive treatment need to have treatment daily Monday through Friday for a period of weeks. And again, historically it used to be that many patients required between five and seven weeks of daily radiation, which if you have a job and you have a family and you have other obligations can be quite burdensome. And radiation therapy is not something that we can just strap onto our back and bring to your door. So patients have to drive to a facility that has that capability, which means that many patients are driving quite a distance every day for multiple weeks to receive treatment.

So there has been a change over the last few decades to try to move towards shorter, more compressed treatment schedules for patients so that they don’t need to come in for such an extended period of time. That we could deliver radiation instead of over six or seven weeks that we could deliver that same radiation course over three to four weeks. And so we’ve seen that the treatment schedules have gotten shorter, which is much more convenient for patients. And so then the question becomes, how short can we go? How few treatments can we actually achieve safely?

So there has been a lot of interest in a one-week treatment schedule, and this has been explored in some large randomized clinical trials for early-stage breast cancer where they have found the same great local control rates, the same cure rates in these patients, and the same side effect rates in patients using a very compressed schedule over one week instead of these longer courses of treatment. So I think that is a big win for patients. And certainly if I were a patient and I had breast cancer, I’d like to think that I could get my cancer treated in one week and have minimal disruption to the rest of my life compared to having to commit to six or seven weeks.

And so in this particular study, what we’re doing is exploring this one-week regimen of treatment for patients who require breast radiotherapy, specifically those who require left-sided breast radiotherapy, where we’re worried about the heart. And we’re comparing proton therapy as we talked about and those potential benefits with regular radiation. We’re trying to determine if patients who receive proton therapy show less damage to the heart or less changes to the heart compared to those patients who receive regular radiation.

Chris Riback: And one, what’s the status of the study? I believe you might be in the stage where you’re securing patients, but maybe you’ve advanced beyond that. And two, for the older form of radiation, is the potential damage or when the damage does occur to the heart, is that evident immediately? Or when you’re doing this study, are you going to have to wait X years to see in column A, did the old form create damage and the new form did not?

Dr. Rachel Jimenez: Great question. So for most patients who have radiation, side effects do not appear right away. And so that’s been a real challenge for us because if radiation therapy is causing damage to the heart, but we don’t know it for 10 or 20 years, then it becomes very difficult to be proactive in caring for those patients and in telling patients very transparently when they get treatment what the real risks are to them. So we can look at a population of patients in a study and say, X number of patients have heart disease, but that doesn’t matter to the person in front of you. They want to know if that’s going to happen to them and what they need to do to take care of themselves.

So in this particular study, we’re utilizing an advanced cardiac imaging technique. We’re using a cardiac MRI. Looking at patient’s hearts with a cardiac MRI allows us to see if there are any subtle changes to the heart—things that we wouldn’t be able to pick up just by looking at someone or examining them in our office that would confer to us that this patient might have an increased risk later of a cardiac event.

And so using this kind of imaging gives us a tip-off that this is a patient that we should be thinking about more proactively and caring for more proactively from a cardiac perspective. And I’m excited about this because I think that oftentimes as radiation oncologists we sit on our hands and wait for side effects to happen. But what’s really compelling about being able to study patients in this manner is that we don’t have to wait, that we can actually communicate to patients that we don’t know for sure if you’re a patient who will have a cardiac event, but we can see on your imaging that you have some changes, and this makes us want to be more proactive about your survivorship care.

Chris Riback: Yes, I would assume that it’s fantastic for you in your role to know that, and it’s central to the patient and in their situation to know that. And so where are you in the study right now?

Dr. Rachel Jimenez: So we are actively accruing patients to this study. We’ve accrued about a quarter of the patients so far. It seems to be quite a popular study for reasons that I think we’ve spelled out, which is that patients are looking for ways to make treatment more convenient and safer for them. And so I’m excited to see how the rest of the accrual goes and to encourage our patients to think about participating if it’s something that has interest to them.

Chris Riback: How did you get into this? Let’s talk about you a little bit. I mean, going way back, where did you grow up? For you was it always science or were you this close to being an English professor?

Dr. Rachel Jimenez: Not super close to being an English professor. I grew up in Connecticut. My mom is a nurse, and I think the idea of taking care of patients was very present when I was a small kid. My mom was a pediatric nurse, and we used to spend time in the hospital with other kids who were hospitalized and didn’t have visitors. Sometimes she would bring kids to our home if they didn’t have family situations where people were visiting them. So from a young age, I really seemed to absorb from her the importance of caring for patients in a very personal way.

And while I did not know that I was going to be a doctor right away—it took me some time to figure that out—I think that I always was very interested in and engaged with people and what they valued and what was important to them. And I think cancer care has a very special way of providing that relationship between patient and physician. What patients go through is such a life-changing event. And so again, it’s such a privilege as a physician who’s caring for them in that context to be on that journey with them, to serve them in that way. And so I think cancer care really stood out for me pretty quickly when I started medical school. And I still believe that it is the best specialty and the one that I feel just truly privileged to get to be a part of.

Chris Riback: Well, obviously the compassion gene does not fall far from the tree. Is your mother still alive?

Dr. Rachel Jimenez: She is. Yep. She’s retired now.

Chris Riback: She’s retired now. Well, we need her back. What does she say about what you do?

Dr. Rachel Jimenez: Obviously, I think she’s proud of me. She’s proud of all her kids. And I think that it probably makes her feel some level of satisfaction to see that the field that she was so dedicated to for so long is something that continues in the next generation. I think that my family has had their own experiences with cancer over the years. My dad is a cancer survivor. Many of my family members are cancer survivors. And so I think that that adds an extra connection to cancer care, even though that was not her focus when she was in medicine.

Chris Riback: There’s one other area, if I’ve read about you correctly that I believe another aspect of cancer care—indeed medical care—that I believe is of interest to you, which is cultural diversity. Why are you focused there? What does it mean to you, and what actions or behaviors does it inspire?

Dr. Rachel Jimenez: I think from a cultural diversity standpoint, I am the product of cultural diversity. I come from a family that has roots and backgrounds in many places. And so I think that from a young age I knew or was aware of ways in which I was a bit different from other people in my community just based on my cultural, ethnic, and religious background. Coming from a family that is so rich in diversity, I think that I see not only myself reflected in conversations about diversity but also just recognize the value of different perspectives, different walks of life, different life exposures, and how important it is to honor those things and promote those things in medicine.

So my patient population tends to be relatively diverse in Boston, and I’m very gratified by that. I think it makes me very happy to see people from all different backgrounds and walks of life come through the door and make sure that when we are caring for them, we’re caring for them as well as we possibly can regardless of their circumstances in life. And I know that there’s been a lot of attention paid in medicine to reducing those disparities across the board, and I feel very passionately about doing my part to do the same.

Chris Riback: You certainly are doing that, it’s evident. To close out, I know you touched on it briefly before, but what role has BCRF played in your research?

Dr. Rachel Jimenez: I am just incredibly, incredibly grateful to BCRF because the research that we’ve talked about simply would not have been possible without them. I think one of the really special parts of BCRF is that they fund research that might not be readily fundable through other mechanisms simply because of the study design or the type of question that not all study sponsors would be supportive of that kind of work. So I’m just incredibly gratified that BCRF saw the value of this research and was willing to support it because it makes all of the difference, not just for me, but potentially for the advances that we can offer patients.

Chris Riback: Yes, I’m certain that it does. And Dr. Jimenez, thank you. Thank you for your time, of course. Thank you for the work that you do, the compassion, the empathy, but also the imagination and the care that it’s so evident that you give. Thank you.

Dr. Rachel Jimenez: Thanks so much, Chris. I appreciate it.

In October, at BCRF’s annual Symposium and Awards Luncheon, more than 250 esteemed BCRF-supported investigators were recognized for their achievements in breast cancer research and their devotion to ending breast cancer. The event also announced the Foundation’s research investment for the coming year.

This year’s program included an extraordinary symposium, “Three Decades of Innovation and Progress,” featuring an expert panel of BCRF investigators who discussed current breaking topics in breast cancer research and what’s new on the horizon.

The panel was co-moderated by BCRF Founding Scientific Director Dr. Larry Norton of Memorial Sloan Kettering Cancer Center and BCRF Scientific Director Dr. Judy E. Garber of Dana-Farber Cancer Institute and Harvard Medical School. Joining Drs. Norton and Garber were symposium panelists, Dr. Constance D. Lehman, Dr. Seema Khan, and Dr. Olufunmilayo I. Olopade, who received the 2023 Jill Rose Award for Scientific Excellence.

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Dr. Larry Norton: This is one of the most fun things that we do all year because this is our chance to speak about our work, to speak about breast cancer in general, to have contact with all of you who are obviously supporters, but also a chance for our array of investigators.

We have 150 in New York. We had a meeting yesterday to answer questions about their area of expertise and other questions that came up as well. So we have a sterling panel today. Of course, you see our scientific director, Judy Garber is sitting right there, and next to her is Funmi Olopade. I always have problems knowing where to put the accent. But it’s Connie Lehman and Seema Khan. I’m going to let themselves introduce themselves, their institution and their interests, and speak a little bit about their work.

We’ll start with Funmi—this is what we call her—who is the recipient of the Jill Rose Award this year, which is the highest honor that we give to an investigator every year, or to a scientist clinician who has made a very significant contribution to the field. And the list of contributions Funmi has made is so legion that again, it would eat up the entire time if we gave her a chance, if I started to roll through that. We’re very honored to have her here.

And then my other colleagues who are luminaries in their field will talk about their work, and then we’ll have a discussion, open up to your questions and discuss it among ourselves. I always like to think of this as very interactive and any questions you have, anything related to breast cancer, it doesn’t have to be the topics that we’re going to be talking about, is entirely appropriate to answer. And if I can’t answer the questions, Judy is here and she’s going to save me. So let’s take it away. Funmi, let’s start with you.

Dr. Olufunmilayo I. Olopade: Good morning, and thank you so much to the Scientific Advisory Board for naming me the Jill Rose Award winner for this year. And it’s always wonderful for me to come to New York because I live in Chicago. It was that second city, but now I’m even told it’s a third city because we’re always looking to be better than New York. And my work has actually gotten me to think about how we organize cities because I came to Chicago 40 years ago and our city is organized south, north, west, and east, and I live on the south side of Chicago, the best place to live on the planet. But also a place that’s segregated and a place where the University of Chicago has been working hard to make sure that every researcher, all research we do has global impact. And thinking about global impact of our work, I see patients who come to my clinic and they come in different shapes, sizes, colors. I work in genetics.

I was very fascinated about genetics and I happened to have married a man who is very concerned about the environment because our first daughter had asthma. And so every time we’re in the clinic and we’re seeing different types of patients, the question we ask is, “Are they having a severe form of asthma or breast cancer because they’re black or is it because we haven’t really had a good understanding of the root causes of every chronic illness?” And so we’re adult doctors, but our patients actually really teach us a lot. And so when I joined up with my colleagues who were looking to get a better understanding of the genetic basis of breast cancer, that’s when I ran into my amazing colleague Mary-Claire King. And we wanted to know, the families with breast cancer that come from different parts of the city of Chicago, what’s the origin of their breast cancer?

Why are they getting breast cancer at 30, at 25, at 21? And why do some old ladies on the south side of Chicago live with their breast cancer and they won’t show up to our emergency room until it’s coming out of their breast? And so I began to ask, “Is this America, and why is it so diverse in terms of the questions that we can ask?” So that’s why we began really thinking about who has BRCA1, BRCA2, and who doesn’t have a genetic reason for their breast cancer and how can we study the fundamental questions of why does a woman get breast cancer? And the answer is, the most important risk factor is you are a woman, and whether we know why you got the breast cancer or not, we ought to be able to treat you effectively. So that’s why I then started asking why are some people living and doing really well, surviving with great quality of life, and some don’t even make it to one year after a diagnosis of breast cancer?

So I’ve joined up with a lot of amazing people to ask those questions. What should we do to treat every patient successfully so that not only do they survive, but they thrive after a diagnosis of breast cancer? And my work is taking me to Nigeria and back and the lessons I’ve learned, it’s really been powerful to be able to think about all of us and the promise of precision medicine. So in a nutshell, that’s what I do and I’m passionate about it and I can’t thank all of you who support BCRF enough for giving us the idea to ask any question and to be creative with our research. Thank you.

Dr. Norton: Connie.

Dr. Constance D. Lehman: Good morning. I’m Connie Lehman. I’m just delighted to be here. I’m a breast imager in Boston at Mass General and Harvard, and I am so grateful for the Breast Cancer Research Foundation’s willingness to fund and support high-risk, cutting edge, future-thinking research. And nothing could be more true than in the area of artificial intelligence. There are many groups when they hear AI, it actually raises more of a sense of fear, particularly in the healthcare domain. Can we trust this? It’s a black box. We won’t understand it. The BCRF support of myself, of Regina Barzilay, of Adam Yala, really they’re standing by their commitment to push the field forward for a paradigm shift. I’m so excited about it because in my entire career as a breast imager, I’ve seen the limitations of how we screen. We had screening mammography in the late 1960s in the US. Not a lot has changed.

We’re still making recommendations for how women should be screened mainly based on their age and breast density when we have so much data about women where we could be more precise, more effective, and save more lives. We also have a lot of work to do in early detection, to have it more equitable and to have not only access more equitable, but also the outcomes. It’s not just about people being engaged, but about reaching the right people with the right tests at the right time. So probably 25 years ago, I was studying my grandmother’s CAD, old school cad. That was machine learning. And you may all have had mammograms where you know that it was interpreted with CAD, an older technology of-

Dr. Norton: Explain what CAD is.

Dr. Constance D. Lehman: Machine learning. Computer-aided detection or computer-aided diagnosis. So computers assisting radiologists isn’t new. We’ve been working on this area going back to the 70s and 80s.

The FDA approved the first CAD product to interpret mammograms in 1998, but we found with the Breast Cancer Surveillance Consortium that it wasn’t translating to improved mammographic interpretations. And that was a hard lesson, but one we’ve carried forward to today as we’re now studying the next level of computer data detection about that. So we’re now going from CAD to deep learning. And what was probably one of the more exciting times in the field was around 2010 or so when computer vision really started to show promise in being able to use neural networks so that computers could separate out different types of images.

So then we realized all of the images in healthcare, whether it’s a lesion on the skin, an image of the body, an MRI, an ultrasound, a CT, a mammogram, the back of your retina, all of these images we can use with these big databases to train AI models, machine learning and deep learning models to be able to read these images independently, either to assist the physician or in some domains we are going to have examples where we can replace the physician. I think what I became most excited about when I first met with Regina Barzilay and we started talking about the potential of this was to leverage AI to do things that humans are not doing. We’re not terrible at finding present cancers on a mammogram, but we could certainly do better. But what we can’t do is look at a mammogram and judge a woman’s future risk of breast cancer, but we can with AI.

So that is the area that’s particularly exciting and where our work comes together. If we want to have prevention methods, wouldn’t it be great if we had a tool that could assess if that intervention is decreasing a woman’s risk? Many of my friends that have gone through breast cancer and are then put on risk-reduction strategies, and I find out after a few years that they just don’t stay engaged. There’s other side effects or problems, but I really believe that if they saw the impact it was having on their risk, it would give them an incentive. And if it wasn’t having an impact on their risk as assessed by the AI mammogram, to shift to a different type of intervention. Whether we’re working in obesity or hypertension or diabetes, we can give patients feedback about the interventions and how they’re influencing their risk. I think in the future, we’re going to do that with breast cancer as well and it really opens up so many different areas.

The last thing I’ll say before passing on to Seema is what was very exciting as Regina and Adam Yala and I were studying the outcomes of these tools in our clinical populations, we’re seeing that there is equity across diverse populations. We haven’t had that with our other risk tools, and we’re very excited about that possibility to provide accessible, affordable, and equitable care to more women in assessing their risk, intervening early, and preventing cancer. So thank you for your support, and I look forward to our questions and answer.

Dr. Seema Khan: Thank you, Connie. So I too would like to thank BCRF and all the support that they have provided to myself and other researchers like me who are focused on breast cancer prevention mainly. But the avenue to effective prevention is actually identifying women who are at risk for breast cancer and estimating that risk. So a lot of what I’m going to say is going to relate to what Connie Lehman has just told you, but I’m a breast surgeon at Northwestern University in Chicago, and I’ve been interested in breast cancer risk and prevention since early in my career. If you remember, this whole field was actually started by a surgeon. So a good role model, Dr. Bernie Fisher led the first prevention trial testing the value of tamoxifen for risk reduction, and this was published in the late 1990s.

There was a lot of excitement at the time because tamoxifen appeared to reduce the risk of breast cancer in women at increased risk by 50 percent, so halving the risk of breast cancer, and there was real anticipation that this intervention would make a difference in the occurrence of breast cancer and help women who were at increased risk. Unfortunately, over the next decade or so, we realized that what was anticipated to be a safe and tolerable intervention treatment for high-risk women turned out to be not so tolerable. And it was not perceived as safe enough for high-risk women to use when they were healthy if breast cancer hadn’t happened yet. So since then, over the past decade, I think there’s been a lot of attention paid to this question of how we can take an effective medication and reduce the risk of toxicity and increase the tolerance so that women who would benefit from such intervention would accept it.

There are many people who worked on this. Dr. Jack Cuzick is here, Dr. Andrea De Censi, and people from my institution. We’ve all been approaching it from different directions. The tech that we chose initially was to try to develop a gel formulation that would be applied to the skin of the breast, would concentrate in the breast, but have very low circulating levels. So this would deliver the benefit of the medication to the breast, but would avoid side effects. So with BCRF support, we were able to work on this for some time. This is a process in development at the moment. The initial data are encouraging, but more work needs to be done. And again, we really appreciate the support of the BCRF and of all the BCRF supporters as well.

The newer tech is low-dose tamoxifen, and that is something that we are pursuing in the next phase of work based on trials done by Dr. De Censi. So we think of this as a renaissance in tamoxifen use and in medical prevention, because obviously the alternative is surgical prevention, which is effective, but is also a big burden for women who are considering it. So we have to strike the right balance and offer the right intervention to women who need it.

Dr. Norton: Thank you. I would just say that it is such a shift in the kinds of discussions that we’ve had here in front of you, I don’t know how many years we’ve been doing this, but a whole lot of years in terms of contact, from some of the issues that we were discussing back in the beginning to where we are now. If you just think how remarkable it is, we have among our panelists, an expert in genetic in things you inherited from your mother or your father that may give you risk, ancestry in terms of geographical ancestry, social determinants of cancer, and an expert in breast imaging.

We always think of breast imaging as you find a cancer so you can go and take care of it. But now we’re getting into the area of actually looking at a breast that is normal and saying, “Gee, this is at higher risk,” and we have to take into account social determinants and geographical ancestry andusing the most modern tool that we have in analyzing complex data sets, which is artificial intelligence and machine learning. And an expert, a surgeon who’s trying to put herself out of business by preventing breast cancer in the first place. So she has nothing to operate on. And then she and I are going to open a bakery together. That’s our ultimate plan.

And this is a prevention strategy that is so benign that everybody could take advantage of it and without fear of side effects. So we’re talking about identifying people at high risk, we’re talking about not only detecting cancer, but finding by a mammographic image the probability of developing cancer and intervention strategies. It was inconceivable when we started this that we’d be talking about prevention to this degree and in this way, and especially with these advanced tools that we’re talking about. Aa\nd genetic analysis is very complicated, very detailed, very hard to do. Obviously mammograms have so much information in it that you need computers to help you interpret it, and pharmacological advances, advances in medicinal chemistry that allow us to deliver these drugs. I’m just blown away by this. We also have another expert here happens to be in genetics, and I’m going to pass the baton over to Judy to have further discussion on this topic.

Dr. Garber: Well thanks, Larry. And I have to say Funmi has been a colleague on the genetics journey all my career. And there are many others in this room who are expert. But I think genetics fits in. If we’re thinking about how do we find women at highest risk, some of them have genetic risk, some of them have no family history, no genetic risk, they get breast cancer anyway. Are there subtle genes that are still less powerful but able to help us identify who’s at risk? And we could say if we could figure out who is at risk, however we do it, we might be able to have a much more efficient system.

Connie talks about risk-based mammographic screening, so we wouldn’t all have to go sign up at 40 or 50, depending where you live, every year, every other year. If we had more sophisticated risk estimation, we could stratify who needs to be screened frequently or less frequently, like we do for colonoscopy. And if Seema is able to give us really effective, acceptable prevention strategies and we work on those things too, then great. We wouldn’t all be as afraid of this as we are. And then we could come back to Funmi and ask Funmi, you covered so many things, you’ve had so many interests in your time. Where do you think are our greatest opportunities for moving forward now? Thinking the way you do so broadly, so globally, how can we make the biggest difference?

Dr. Olopade: Yes, thanks Judy. When we started really mapping genes one gene at a time, we had a promise that we can map the entire human genome. And I remember when we got the good news that Congress was going to give us $5 billion dollars to map the human genome. And it was a bipartisan congress that gave us $5 billion. It seemed like a lot of money. And we talk about the fact that it took $1 billion and $5 billion to find the first map of the human genome, and now we can actually do it for less than a thousand dollars. How powerful is that? And Larry’s always talked about mathematics because he’s a genius. He thinks mathematically.

Dr. Norton: It’s true. It’s totally true.

Dr. Olopade: And we had at our symposium yesterday a talk about mathematics in medicine. Who would’ve thought? If I knew mathematics was going to come back to medicine, maybe I wouldn’t have been a doctor. Because what you need is data, and you need technology. And some of us are concerned about data, about whether the internet and people are fixated on social media, and that’s bad for us. But there’s technology for public good. And one of the amazing things that we are doing now is getting data from all over the world. Women get breast cancer in every country and in every neighborhood, and we can actually map where the worst survivorship for breast cancer is in this country because from 1975 till now we’ve been recording cancer as a reportable disease. It’s the only disease that you actually must report from every hospital. So imagine if we can pinpoint where the most vulnerable patients are.

And by the way, my husband is in the audience, and he tells me we don’t need to do breast cancer research. We only need to fix the environment. And so between the environment and genetics, we have this tension in my family because I think we have a foundation. We’re born with the genes we’re born with and then life happens. So what are those lifestyle trajectories that we can actually intercept? So I’m very excited at this moment that we are finally having the tools to pull all of it together so that we can do cancer interception. We cannot wait until people walk into our door with advanced cancer to treat them. We can monitor them, we can check them, we can tell them to exercise.

I ran the marathon last year. Why? Because everybody told me I have to increase my metabolism. I shouldn’t gain weight after menopause. Those are all important things to help us change our lifestyle. So I’m very optimistic that it’s not whether we do this or that. It’s like we’ve all to come together in solidarity to use the evidence we have now and keep building on it. And luckily we have young men like Dr. Yala, who as a graduate student working with Connie at MIT, was thinking about women with breast cancer and about developing tools that those of us who never knew mathematics can actually press the button and then it gives us the answer. How amazing is that?

Dr. Larry Norton: Connie? Do you think AI is going to help sort out all of the complexity of the data that Funmi is talking about?

Dr. Lehman: I think it’s certainly going to be huge. It’s so fortuitous that at the same time, we had diagnostic methods that were collecting more and more volumes of data, whether it’s genomics or radiomics, the imaging data, at the same time we were having computers have such increased speed to be able to process and manage that data. Many of us in healthcare were worried that we were getting so much more data out of our patients that we could possibly process. And that’s where I think AI is really going to influence every domain of breast cancer.

Dr. Norton: You said something that sent a chill down my spine, is maybe we can eliminate doctors, Connie. That’s a terrifying thought for many of us in the room. No, I’m just joking. Actually, I am impressed even to this day by how much information I can get while I’m talking to a patient just by taking my smartphone out and asking a question and getting some further information in that regard. So this interface I think is one of the really important areas. You have a comment on that?

Dr. Lehman: Absolutely. And I am so grateful. Many of you in the audience are also helping spread the word of these paradigms that are shifting. So depending on our age, we’re either extremely comfortable with computers being a part of our lives, how we feel about a self-driving car, whatever our experiences are, AI is permeating so many different facets of our life. It can be a little bit fear inducing to think about it in your healthcare. Many of my patients will say, “I trust you as my doctor. How can I trust a computer?” But that’s where we in the medical environment are going to be educating ourselves and educating others on how this is really enhancing our jobs.

My friends that are breast imagers, we cannot wait until we can take some of the tasks that we do that we know computers can do better and offload those onto the computer so we have more time to spend with our patients, to provide greater access, to be much more refined in our conversations and discussions about the best personalized screening strategy, the best personalized diagnostic pathway for the patient in front of us. So hematologists aren’t looking under a microscope counting red blood cells anymore. We pass that off to computers. There are a lot of domains where it was a change, but we were all very excited about that transition.

And the same will happen with interpreting images. We have the FDA involved because the regulatory process is extremely important in AI. The FDA has already approved a new domain for AI, which is triage to take exams, whether it’s a scan of the brain looking for a stroke or early signs of a stroke or a mammogram, to scan them and say, “This really doesn’t have anything remarkable. Let’s put this at the bottom of the list. These others need extra attention.” So we’re already seeing the FDA engage in this process to move the field forward, and we’re going to continue to see that trend.

Dr. Norton: How is this influencing cancer surgery? What are the changes that we’re seeing in approaches to cancer surgery that are happening with this data revolution and other things that we’ve been talking about?

Dr. Khan: Well, surgery, as we all know, is the oldest treatment for cancer. So it has stood the test of time and it is an integral part of cancer treatment today and will remain so for some time, I believe. The way that AI advances are influencing cancer surgery will probably not be totally apparent for some time. I think where the information that Connie is talking about does influence us is in risk estimation. So again, as I’ve said, surgeons are very interested in preventing cancer as well.

And so many of us counsel high-risk women about interventions, and it’s a partnership between the breast imagers and the breast surgeons counseling women about the appropriate imaging strategy for them. And that’s where AI is likely to make a difference in the near future. The longer-term effect on cancer surgery might have to do with predicting a response to neoadjuvant therapy, for instance, which is increasingly used, as you probably know. Somewhere around half of women are now being considered for medical treatment prior-

Dr. Norton: That’s using drugs before we operate to shrink the tumor down and make it disappear.

Dr. Khan: Right. Medical treatment prior to surgery to try to shrink the tumor and get some information about the effectiveness of the medical treatment, the chemotherapy for that particular tumor in that particular woman. So that information is very useful both in planning surgery and also in planning downstream medical therapy. And that’s where these kinds of algorithms may fit in to help the surgeon decide on the appropriate surgical recommendation. But at the moment, it’s in detection and risk estimation that AI is having the biggest impact, I think.

Dr. Norton: Very good.

Dr. Garber: So Larry, I’m going to take what could be the last AI question. We may have to cover some other things, but this is really for you. How do you see the future of clinical trials? How can AI better inform drug discovery?

Dr. Norton: Well, there’s two questions there. The future clinical trials and the question of AI going forward in that regard. Clinical trials are absolutely essential. I differ from a lot of my colleagues in one important respect. I still think strongly that randomized clinical trials going forward are the way that we get clear answers, and that’s when somebody who’s a candidate for the trial can get one treatment or the other or can get standard therapy versus other therapy rather than just trying something and seeing how it works and comparing it to historical experience. But that is happening as well. And we can debate it and we can argue it. I think that the big transformation that has to occur is that we have to democratize the clinical trial process. We have to get clinical trials out for everybody, certainly in the United States, maybe even the world, that has a certain disease that’s a candidate for the clinical trial and bring the clinical trial to them.

One of the really painful things that I have to deal with all the time is getting phone calls from somebody who  has advanced disease, metastatic disease, that has the potential of being helped by an experimental drug that is coming down the pipe that looks very promising., And we may even have early evidence that the drug works but we’re not be able to get that drug to them because they don’t have access to the clinical trials where the drug could be provided by geography or by economics or by inclination because of past experiences for themselves or their family or even their cultural group. So I think that one of the major things that we have to do is we have to make clinical trials available for everybody. And I think that’s really one of the most important things that we have to address. All right, and that’s the last question I hope I’m going to have to answer.

Dr. Garber: You’re not going to do the AI question?

Dr. Olopade: Actually I can maybe help my colleague because there’s something that’s actually fascinating with AI in every area of our life, and I’ll give you the example of what happened to me this summer. We had students in the college coming to do experiments in the lab. And because we have mapped all the genes, all the proteins, and we know how the proteins are configured, and you can just go to the computer and say, “If this mutation occurs in a breast cancer cell, how can we drug it?” And these literally third-year college kids came back and said, “This is where we can drug this because the protein is being mapped.”

So AI will influence how we even begin to test which drug we should go after. And there are lots of ways in which we do chemical screening—there’s what is called now chemical biology, computer biology, so that we are all looking at a way to accelerate and make things happen faster. Some of the work that BCRF has funded is I-SPY, where we want to get a biomarker to the right patient at the right time. And lastly, you take wedding photographs using drones. Imagine if we can deliver drugs to somebody’s doorstep with a drone. It’s going to happen.

Dr. Norton: Connie?

Dr. Lehman: I love your out-of-the box thinking. And also I think in the specific domain of drug development, we’ve seen some examples in the past where drugs—especially those designed to prevent a cancer occurrence—where it’s been very difficult to do those trials and wait to see who gets cancer and who doesn’t get cancer. So some groups have said, “Well, could we impact the breast density? Could we look at surrogate markers of risk?” And those have shown some interesting results. But AI on the mammogram, if it’s showing us risk and it’s showing modifiable risk factors that will change that risk on the mammogram, you could have an earlier indicator of promise in certain drugs versus others.

The second domain is we know, and it’s so frustrating when you see drug trials where it helped some women so much and didn’t help others. In the domain of precision medicine, can AI help us identify those that will benefit from that drug and move out the subgroups? The same thing with mammography. Mammography is a great tool for a lot of women, and it’s a really poor tool for others. Can we start to be more precise because of the AI power to help us categorize women more effectively and look for changes in risk with different drug trials and interventions?

Dr. Norton: Seema?

Dr. Khan: So yes, I just want to add that what Connie has been mentioning is actually going to be tested in our BCRF-supported clinical trial that will begin soon, hopefully in a few months, where we’ll be starting premenopausal women on low-dose tamoxifen five milligrams a day based on Dr. De Censi’s work, and then testing their response in terms of breast density. So breast density is known to be reduced in many women by the use of tamoxifen, and we will be following their tamoxifen response using breast density and also assessing their risk reduction with the AI tools that we’ve been talking about. So this new generation of trials will be putting these concepts into practice, at least at the level of clinical trial testing.

Dr. Norton: Yes, I can’t help but jump in with a couple thoughts in this regard. The thing that really is impressive about AI is that the way science has been done in large data sets—the way science has been done for centuries—is you have to have a hypothesis. You have to have an idea, and then you have to design an experiment to test that idea. By looking at a tremendous amount of information now using these modern electronic tools, the idea can come from the data rather than having the idea first and then looking for data to support the idea.

Look how many centuries it took us to figure out that cigarette smoking caused lung cancer. It would take an AI tool a few milliseconds to make that observation, People do a lot of things, of which smoking is only one of the thousand things that people do, and if you actually had the data, it would find it instantaneously and then you could also test it going forward. The other point I want to make is yes, I’m a mathematician, and we have other mathematicians researchers that are all arrayed around you in this regard. I think the interface between machine learning and AI and mathematics still is an area of great potential of development. AI is a tool for looking at large data and finding patterns and discerning them.

I’m reminded of the analogy I always use in this regard, which is that you can look at the night sky forever and collect all the data about the stars, but actually making sense of the motions of the planetary bodies can only happen when you have a mathematical hypothesis, which is the theory of universal gravitation and the mathematics of calculus, then it all makes sense. But you can’t develop calculus and the theory of universal gravitation unless you have the data and unless you’re able to analyze the data. And that’s why it took so many centuries to actually figure this thing out.

Had we had computers at the time of Kepler, for example, Copernicus, it all would’ve sorted out extremely quickly because you could test a lot of ideas about the way the planets interact very, very quickly by looking at the data. So we really are in a different world. This is one of those quantum leaps, I think, of human intelligence where the data itself can generate the hypotheses that we can look at, and where it’s all going to lead is really exciting—alittle frightening but actually profoundly exciting moving forward. We have a question from the audience there.

Dr. Garber: We do, and I would just add one thing, which is that AI is a fabulous tool, but as everyone said, it’s a tool. It has to help us be smarter and we’ll still need clinical trials to prove that what we think is the right tool is actually predicting correctly and that the ways that we modify actually work. So I don’t think we’re finished yet.

Okay, so we’ll shift gears a little bit. Here’s a question, maybe Seema, you might want to start this one, which is about breast cancer in men. So breast cancer in men is a little better understood than before. We’re recognizing that breast cancer in men certainly happens. We’ve known that. What are we learning from women that might inform our ability to take care of men?

Dr. Khan: Breast cancer in men, of course, happens much more rarely. It’s about 1 percent of the rate that breast cancer happens in women. But we have learned over the past decade or more that there are some genetic susceptibilities that increase the risk of breast cancer in men, BRCA2 being the most prominent, but also some others including BRCA1. And so the one thing we’ve learned when we see a man with breast cancer is that this is an indication for testing of that man as well as his family members if his cancer proves to be related to a genetic inherited mutation. And then those men are also at increased risk for prostate cancer. So that sets in place the whole sequence of other considerations that apply to people with genetic susceptibility.

In terms of the actual treatment of breast cancer in men, it seems to be fairly frequently hormone sensitive that is responding to anti-estrogen medications, and those are used regularly in men. The surgical treatment is mainly similar to that of women. Typically in a man’s breast, a breast cancer occupies enough space and there isn’t enough breast tissue to really think about breast conservation. So most men with breast cancer are treated with mastectomy, and then the follow-up treatment is really based on the characteristics of the tumor. But again, many times endocrine therapy, anti-estrogen therapy is very effective. One other issue about breast cancer in a man, the risk is increased after hematologic malignancies. So the data from the surveillance and results reporting from the big database that’s maintained by the NCI suggests that breast cancer as second malignancies is also more frequent in men.

Dr. Norton: Do you have other thoughts to add to that?

Dr. Olopade: Well, she’s covered everything.

Dr. Norton: All right. A question for you, Connie. We’ve been talking about mammograms. What about MRIs? People out there are being recommended to get MRIs. Some of them are getting an MRI every year, some of them are getting mammograms every year, but other countries recommend mammograms less frequently than that. What are your thoughts about that and how it relates to your work?

Dr. Lehman: We have so much good data that tells us one thing. If we want to find more cancers above and beyond what we can see on mammography, we need to do vascular imaging. I’m not saying contrast-enhanced MRI, I’m saying vascular imaging. Contrast-enhanced mammography—which BCRF is supporting via a fabulous trial with Chris Comstock and GE and the American College of Radiology—appears to have the same power of contrast-enhanced MRI, but at a fraction of the cost, and it’s globally accessible. If you have a modern mammography unit, you can upgrade that mammography unit and then inject a contrast agent and get the same power that you get from MRI. So I’m a huge proponent, huge fan of vascular imaging, and I hope in my lifetime we shift from MRI to contrast-enhanced mammography, as the globally accessible, very powerful way to find cancers that are hidden on a regular mammogram.

Dr. Khan: Hear, hear.

Dr. Garber: Amen.

Dr. Olopade: Maybe I can offer another example of why we’re talking about precision. When you have a problem, you want to make sure that we are working on the best tools to actually find that cancer. I talked to a lot of physicists and they’re telling us now that we can actually find the smallest molecules that are becoming deranged to cause cancer. So it’s not just about imaging to find cancer early. Yesterday we heard about early detection, multi-cancer analytes, things that are shared by the earliest signs of cancer that we can get from a blood test. Now when I say it’s coming, the same thing about the human genome, we thought it would never cost a thousand dollars. Phones will never cost a fraction, but the science keeps getting better. And what we want is what’s going to work. In the meantime, we did an experiment with Dr. Comstock in Chicago when he was younger.

What Dr. Comstock wanted to do at that time was to have me get my patients with BRCA1 mutation who will get breast cancer at the age of 30 . There’s no recommendation for how you find cancer in a 30-year-old or a 25-year-old. And that technology has matured to the point that those women will come to us now and they can get an MRI, they can get it faster, cheaper than when we first started, that in four minutes we can actually image their breasts. So these women can have babies, can do whatever they want, and at the time that they’re done having their children, they can make a decision whether they want to have surgery, go to my friend to go and have their breast off, or just keep screening. That experiment started in 2004, and guess what? We’re no longer in 2004, we’ve gotten it faster, and cheaper because the technology allows us to reassure these young women that “Yes, you were born with a BRCA1 mutation, but come to us, we’ll take care of you.”

And what we learned by doing that study was their anxiety level went way down. They had their babies, they breastfed their babies, and they’re going on with their lives. That’s the power of integrating science and technology so that every woman has a chance to get the right treatment at the right time for the right disease. And so for us, we’re now testing this study nationally, and that’s what WISDOM study is about. Let’s find the highes- risk women. Have you all done your risk assessment? I’ve done mine because one size doesn’t fit all. I want to know, it’s a bell curve, am I on the extreme of risk or am I on the extreme of I don’t have any risk, or am I a little to the right? And I happen to be a little to the right, so I’m going to do something to reduce my risk.

That’s what precision prevention is about, and it gives us an opportunity to lower risk and catch cancer early. So we continue to do the research because we don’t know what’s going to be better in the future. And that’s why BCRF brings us together and we can test a lot of different ideas so we can finally begin to think about how to get it right for every woman. Because right now we don’t know enough on who’s going to get cancer and when they’re going to get cancer. And if we can make sure that they never die prematurely from breast cancer. That’s the goal.

Dr. Norton: That’s where we’re at. Dr. Comstock, are you here? Tell them about BCRF’s supported study.

Dr. Christopher Comstock: Larry refers patients, and he sees the power, as Connie mentioned, in vascular-based screening. And our biggest, I think our quickest, fix to lowering mortality because too many women still die of breast cancer each year is that mammographic. Our current gold standard of 3D mammography is maybe 30 percent sensitive. And so we have twice as many cancers walk out the door that we find after looking through all those images, and vascular-based screening can significantly, by two and a half fold, increase our sensitivity. As Connie mentioned, it’s very accessible and it can be done on most systems throughout the country by just a modification and then giving contrast. So it’s vascular-based screening and it’s not affected by breast density. So that’s the problem with mammographic screening. The more dense breast tissue, the harder it is to find cancer.

And these tools, MRI and contrast mammography, overcome that limitation, reducing sensitivity. So with BCRF, along with GE and the ACR, we’ve just launched our trial at four sites. We hope to have 10 sites up and running soon. The trial is looking at contrast mammography as a new paradigm for women to have screening if they have dense breast tissue. We couldn’t have done this without Larry and BCRF. As Connie mentioned, I have a slide of pictures of different aspects of society from mobile phones to computers. And in the 50s, when mammographic screening started, a 5MB hard drive was two and a half tons, a massive piece of equipment, and now it’s a little card in your phone that holds a terabyte.

But mammographic screening is just improved slightly with, we went from analog to digital, added tomosynthesis. I call it the art car phenomenon. On the West Coast, San Francisco, you see these pictures of cars where they’ve glued on all these different ornaments and statues and they’ve made it fancy. But the problem is that’s mammography. It’s this art car phenomenon where we’ve added all these little increments but we haven’t compared them to the rest of society. And now with AI, we’ve got a whole other model of doing screening, and hopefully with this trial BCRF will usher that in.

Dr. Norton: Thank you.

Dr. Garber: I was just going to point out that we hear all of this. It’s so exciting, it’s so promising, but you have to prove it. Before you have the country decide that we’re going to invest in upgrading all of our mammography machines, we have to prove they work. That’s why there’s research. That’s why there are trials, because of course we’re all excited about things that sound new, but we have to do the rigorous work to prove that they’re better before we change practice in the world.

Dr. Lehman: And we’ve learned again and again and again that where we had the excitement, the enthusiasm, the ideas, the creativity, rigorous scientific trials showed us we needed to go in a different direction.

Dr. Norton: You asked me the question before is a well-designed clinical trial, whatever the outcome is, is going to be important information going forward. And so that’s the art of clinical trial design, which we have many people here that do it moving forward. Judy?

Dr. Garber: So I have a great question, but it’s also for somebody not on the stage. Dr. Finn, would you speak to research being done on breast cancer vaccines? Dr. Olivera Finn is at the University of Pittsburgh, and she has spent her career in immunology working on vaccines in colon cancer, but we’ve enticed her to work on breast cancer.

Dr. Olivera Finn: Thank you very much, Judy, and thank you for the question. This is my very first BCRF event, because I’m your new grantee, but I’m really excited. It’s also the 30th anniversary event, because exactly 30 years ago, in 1993 December, I started the very first clinical trial in a cancer vaccine in patients with advanced colon, pancreatic, and breast cancer. And my very first patient was a breast cancer patient who was basically dying of breast cancer and she signed up for the vaccine and she told me, “I know this is not going to do anything for me, but I really don’t want anybody to live through this through what I’ve just lived through.”

So the same vaccine with slight tweaks is now what BCRF is funding for breast cancer prevention. And we have spent 30 years showing that it is safe, that it can be effective and more effective if the woman is not suffering from advanced cancer because we have learned that in the setting of advanced tumor, not only our vaccine but all cancer vaccines—and there have been many tested in clinical trials—are very strongly impaired and compromised in their effectiveness by the immune suppressive environment of the cancer. So it is much better if we can use them early. And you know, vaccines have saved the world many times before against infectious disease. The latest example is our COVID-19 vaccine.

So the same way we are preventing infectious disease, we are going to prevent cancer. And we are doing this in baby steps because as Judy pointed out, we have to prove that this works. And the baby steps are not taking a seven-year-old and giving her a vaccine or a 15-year-old girl and giving her a vaccine, but taking women at very high risk, however we define the risk, and we had the whole discussion on that. So, we have to work on this together. Right now, what we are doing for my trial, our trial in Pittsburgh as well as several trials going on all around the country, one at the University of Pennsylvania for the BRCA 1 and 2 mutations, is to diagnose pre-malignant disease. Judy mentioned our colon cancer work. We actually vaccinated people with a history of advanced polyps that are immediate precursors to colon cancer. And those polyps are removed via colonoscopy, but over 60 percent of people who have those polyps can recur with other polyps one to three years later. So, we vaccinated right after the polyp removal, and then we observed for five years, and in people who responded well to the vaccine (because even at that level there’s some level of suppression at that stage), there’s some level of suppression, but we had a lot of responders. Those who were vaccinated had a 38 percent reduction in polyp recurrence and (are still polyp-free). Which means that there is a 38 percent reduction in your risk of developing new polyps that can progress to colon cancer.

The breast cancer equivalent here now in what we are trying to do is women with DCIS, ductal carcinoma in situ. You all know that is not a cancer. However, we don’t know what the risk for the woman with DCIS is for progressing to cancer, so it’s surgically removed, otherwise other times differently treated. We are going to vaccinate women newly diagnosed with DCIS with our vaccine. The vaccine is expressed on all breast tumors and on DCIS, and we are going to measure their ability to respond to generate a very strong immune response. And then the women will have standard of care—those who want surgery will have surgery and we will have tissue to compare the initial biopsy with the tissue post-vaccination.

If we see that we have one, induced a very strong immune response to our vaccine and two, that we have brought all the immune cells to the site of DCIS before it was taken out, we might in the next phase of our trial just wait because the immune system should have the capacity to get rid of that lesion without having surgery. And it should also protect the woman in the future from developing new lesions. As you know, that can happen in the other breast, et cetera. So, we are very excited about that. Similarly, in the study at Penn, they are using a very similar vaccine but in carriers in BRCA 1 and 2 carriers. Would you like to comment on that?

Dr. Laura Esserman: Yes, I’m presenting at San Diego at AACR on Saturday. We have been doing a phase one study using a Moderna mRNA with a cocktail. I’ve been working on this for several years. BCRF actually funded a lot of the work that led to this. So if you directly inject into the DCIS and let the DCIS be its own vaccine so you can organize it, you can bring the immune system cells in great numbers. Now most DCIS are slow-growing and hormone-driven. They’re not immune-driven, but there’s about 10 to 20 percent that are, and they can be these very big lesions, but we used to think those were the worst DCIS. But you have to ask how is the body already containing them? And it’s probably the immune system that’s keeping them intact. So we now have, when we combine pembrolizumab ( Keytruda), one of the drugs that takes the brakes off the immune system.

But again, you don’t want to give it to the whole body when someone’s got pre-cancer. You want to just give it locally. And then we added this mRNA cocktail to our 10 patients. Eight of the 10 patients had the big immune cells in their DCIS already. And all of them responded. Four of them went away completely, and three of those patients have not had surgery and they’re now over a year out without anything left. I think we’ve already shown that this is possible now and we’re expanding it. And it’s another way of saying we don’t have to know. It’s as if you were injecting the polyp right there, we can inject the DCIS right there and have it go away.

For the hormone-driven DCIS, we’ve also shown that if you give endocrine risk-reducing agents, these are the people who are the most at risk for ER-positive disease that maybe 60, 70 percent of people will never progress. And we of course use MRI as a way to measure this and to really look at who’s got endocrine-sensitive and endocrine-insensitive disease. We’re starting a study across the country called RECAST where we are testing new endocrine types of agents, testosterone, looking at endoxifen, which is the active agent for tamoxifen.

Dr. Norton: I have to ask this question and the right person to ask this is Dorraya El-Ashry, the chief scientific officer from BCRF. One of the things we’re hearing about here is the interactive-ness of the various scientists and the various collaborators that we have. Once we start on a topic, essentially anybody could stand up and talk about how they’re related to this topic. Do you have data on how interactive we are as an organization?

Dr. Olivera Finn: Larry, I’ll just add that everybody who I talked to at this meeting about our trial asked how many patients are involvedand can they also contribute? So that’s the other thing, that all BCRF investigators here who, including Seema, I was sitting next to her last night, said, “If you have slow accrual, get in touch with us.” Beth Mittendorf offered. So this is a community that immediately can form these sorts of-

Dr. Garber: Interactions.

Dr. Norton: Absolutely.

Dr. Garber: Thank you.

Dr. Laura Esserman: And Larry, I just wanted to say, the WISDOM study. Anyone here who hasn’t had cancer can participate.

Dr. Garber: One more take.

Dr. Laura Esserman: Wisdomstudy.org. Thank you. Dorraya?

Dr. Dorraya El-Ashry: Good morning, everyone. You’ve been hearing about the most impactful and tremendous progress that is being made in the fields of disparities and prevention this morning. But what I also hope you’ve heard, and what Larry mentioned, is how much of this is being done in a collaborative way, and that this is the future of taking great ideas forward. And BCRF has had as its hallmark fostering collaboration. In fact, as we do our five-year impact reviews and reports, we pull together this data on collaborations of BCRF investigators, both with other BCRF investigators that are fostered at events we hold, like the research retreat we had yesterday as well as at many think tanks as well as with outside investigators, which only extends the impact and reach of BCRF funding.

From a cohort that we have looked at and from each of these years, BCRF investigators collaborate on average with three other BCRF investigators and with clinical trial groups that we support at a tremendous rate, and at a rate of five to six times non-BCRF investigators. And so the amount of collaboration that is both fostered by BCRF, but also because all of these investigators know that the way we move things forward is through team science, has just been tremendous.

Dr. Garber: Funmi, there are some communities that have a very high incidence of young, advanced disease women with metastatic breast cancer. Are there environmental factors or social factors that you think might contribute to this particular problem?

Dr. Olopade: Yes, thank you for asking that question, and I hope some of the epidemiologists in the audience—and there are many of them here—would chime in. When I started my introduction, I talked about the south side of Chicago. One of the areas that we’ve really been focused on is environmental justice. Dumps and every toxic chemical is put in poor neighborhoods. And we have been very concerned about not just environmental pollution that you see outdoors, but household air pollution. About three million women and children die globally from household air pollution because they burn dirty fuels.

Just this morning we were talking about the PM 2.4, particulate matters that we may think don’t matter. We’ve spent a lot of our time looking for genetics. What are the genetic causes of breast cancer? And we’re now actually also funded by BCRF to look at the epigenetics. As we are all sitting here, mutations occur. Most of us have the immune system to wipe away the mutations, but somehow some mutations cause derangement of other genes, and you have this cascade going on that then leads to advanced metastatic breast cancer. Globally, the fastest-growing breast cancer community are premenopausal women. It’s become an epidemic, and the World Health Organization has actually put in a call to say, “Why are young women everywhere getting breast cancer before the age of 50?” What’s in the environment? What’s in our lifestyle? My mother had six children and breastfed for 21 years. Who does that anymore?

Dr. Garber: More recovery.

Dr. Olopade: Right. So, it’s a women’s health issue because we don’t know what’s happening to the modern woman and what’s happening to our environment, and I think this is where we need political action to have more support for women in the workforce, more support to diagnose cancer if you’re going to get it before the age of 50. And of course, to always really think about environmental justice, because it is true that when we map the areas with the most disparity, where people are most likely to die from breast cancer, it’s also the communities that are most affected by environmental injustice. And we all have to really do something about that.

Dr. Norton: Yes. Connie, you’ve done some fantastic work on differences—I call it geographical ancestry— in terms of AI and risk prediction using your models. Do you want to talk about that a little bit and then maybe answer the question that I handed to you?

Dr. Lehman: Sure. So many of us have heard of the domains with AI where errors were made because the trials used predominantly light-skinned patients. So for example, some of the dermatology AI tools cannot accurately diagnose disease in people with dark skin, and that was extremely concerning because we have a long, long history of racially biased research and clinical care around the world. We were delighted to find with the AI applied to interpreting the mammogram for a future breast cancer event, that it was equitable across races. We studied this carefully at Mass General, populations across Hispanic, Asian, African American, and Caucasian, and in other domains in other centers as well. So I think one of the reasons is because the model can learn from the image itself how all these differences are being expressed and displayed, whether it is the endocrine challenges that a woman has gone through during her life or different factors and features of race, et cetera.

So we were very enthusiastic about that, but think it is imperative, as Judy points out, that we continue to rigorously test. We now have, and this gets to one of the questions that I was asked here, “Well, is this available?” Right now there are about four or five different risk assessment AI-type tools that are being used. The FDA has made it very clear that these will need to be regulated by the FDA, so that’s a murky area right now. Vignesh Arasu at Kaiser studied and presented with a single database with known five-year outcome of cancer outcomes in a cohort of patient— both the clinical Breast Cancer Surveillance Consortium, a clinical risk assessment method that is more traditional of how many family members have breast cancer, how many children did you have, did you breastfeed, et cetera—and compared that to these different AI tools. He found that the AI tools that have been developed at multiple different centers, including NYU, including some different companies, performed significantly better than the clinical approach.

That study was fantastic because it also uncovered that some of these tools are actually finding cancers that are probably present at the time on the mammogram and the computer vision is identifying it, but it was missed by the radiologist that was reading the exam. So that’s why the clinical research is so important. We’re still early in understanding how this is working. The question was also are there prospective trials of MRI? This is a tricky area. The direct answer is there is not a prospective trial seeing the impact of MRI in clinic, that would take a minimum of five years if we wanted to see the prediction of a future breast cancer. And these models are evolving rapidly, so that’s a little challenging. What we’re doing in our very large Mass General cohort is looking to see how did MRI distinguish from those women that were undergoing screening with a high cancer burden and a lower cancer burden.

We can use registry data for that. We have done that and shown that we are better at identifying patients with cancer who undergo screening MRI, and we can identify those patients that probably didn’t benefit at all from the MRI. The same with more intensive mammographic screening and less intensive mammographic screening. We look to our mathematicians, our epidemiologists, our biostatisticians, for creative ways to develop and evaluate these risk prediction tools to try to set prospective trials with five or six years needed to see what the impact is as they’re developing so rapidly, and it’s going to be challenging.

Dr. Norton: Excellent, thank you. There was a lot of interest out there and I got a lot of questions about this, is the idea of getting tamoxifen out as a prevention strategy. What are the toxicities of tamoxifen that you’re trying to reduce by your methods?

Dr. Khan: What we know about the toxicity of tamoxifen is based almost entirely on the standard 20 milligram dose. And that dose was developed in cancer treatment trials. It was initially used in women with more advanced cancer and then as additional treatment after surgery in women with earlier cancer. In these cases, tamoxifen is very well-established for improving cancer outcomes. What we’re discussing here now is tamoxifen for prevention, and the calculus, the effect of toxicity in women who have had cancer and are offered a treatment for that compared to women who’ve never had cancer and are offered a drug for prevention of cancer in the future. That’s a different calculation. So, the toxicities that are very acceptable in women who are being treated are not so acceptable in women who have never had cancer. But I think it’s useful to divide those side effects of tamoxifen even among healthy women into two categories.

One is the quality-of-life side effects, and they are more common. So menopausal effects like hot flashes and sometimes sexual problems and vaginal dryness, those things happen more frequently. They’re ’tolerated variably by different women depending on their motivation. The serious side effects of tamoxifen are mainly twofold. One is that it results in a small increase in uterine cancer risk, and the other is that it may cause an increase in risk of blood clots. Those are seen mostly in older women. So for premenopausal women, those risks are really quite low and not that different from women who are not taking tamoxifen.

But for postmenopausal women, and particularly women in their sixties and older, those are serious considerations. Fortunately for that group of high-risk women, we do have alternative medications that don’t have these side effects. They have other side effects, of course. So as a general principle, the idea that we have to find the minimal effective dose rather than just doses that have been borrowed from treatment trials is a very valid principle, and that’s what many of us are working on. But yes, the tamoxifen risks are mainly quality of life, as I mentioned, and the uterine and clot risk.

Dr. Larry Norton: Judy?

Dr. Judy E. Garber: So I can’t believe it, but it’s time for the last question, which is about circulating tumor cells, circulating cell-free DNA. Last year, Funmi mentioned that among all this technology progress is the possibility that we could use a blood test to find cancer and, no offense Connie, skip the mammograms altogether. Where do we stand with that now? Does anybody want to comment on progress in blood detection?

Dr. Lehman: I hope it happens. I’m going to have you talk about how you think it’s going to happen, but as an imager, I hope it happens and it would be fantastic. We imagers have a lot of work to do in a lot of different domains, and if we have a simple blood test that can replace the mammogram, it would be fantastic.

Dr. Norton: Yes, I think it’s going to be an interactive, and I think there’s no “yes or no” answer on all of this. There are some already tools out there that look very, very promising because cancer is caused by abnormalities in DNA almost exclusively. Some of that DNA is spread into the blood, and by doing a blood test—and again, the technology has improved enormously about finding these abnormalities—it is possible you can find a piece of abnormal DNA and that might indicate that there is a tiny invisible cancer brewing somewhere. We’re still going to need imaging tests to find out where it is, I think. So I think there’s going to be an interaction in that nature. The other thing, which is not apparent—and we’re getting into a big topic when we have no time—is that as you get older, you’re going to get abnormalities in your DNA anyway, despite the fact that you don’t have cancer.

There’s something called clonal hematopoiesis, where you have actually mutations in your white blood cells that occurred as a function of age, and it actually does predispose you to developing things like leukemia. But most people have these abnormalities, and their blood cells don’t develop leukemia. And so when we actually measure DNA abnormalities in the blood, we’re identifying a lot of normal individuals who are never going to get cancer. And I think that even though they have those abnormalities, it’s just part of natural aging, so we’re going to have to be very careful that we don’t over-diagnose. And I think that all of our panelists have touched on some aspect of this, which again, the interactive-ness of the science, BCRF. If you have a known predisposition, if you have risk factors and you have a profile that suggests a higher risk and you have an abnormal piece of DNA, that’s going to have different meaning than somebody who doesn’t have that, for example.

If you have an abnormality that suggests, “Well, it’s most likely coming from the breast,” but very sophisticated imaging tools don’t show anything, then it may require further imaging tests or other tests in the future to follow that individual. But it also may indicate an opportunity for chemo prevention, cancer prevention with drugs. You have an abnormality, we can’t find it, but we have an approach to reduce your risk, and then we can follow that blood test and see if it disappears. And often with our cancer therapies, when patients have abnormal DNA in their blood, our cancer therapies make those abnormalities go down or disappear entirely. So it’s not any one thing. I’ll end with my favorite cliche. People ask, “What’s the most important part of what you’re doing?” And I say, “I’ll answer that question if you tell me what is the most important part of the airplane.”

Is it the left wing or is it the right wing? Is it the landing apparatus? Is it the navigation so that you land in Dubai and not in some other place where there’s a war going on? Which happened to me recently. The fact of the matter is it’s all important. What makes the airplane work is that all the parts work and they all work together. And that’s what BCRF is all about. We are developing all parts, everything that we can think of, everything that comes from the extraordinary intelligence of our investigators, everything that we learned from the field. We study the entire airplane, and we also want to make all the parts work together. And that’s why I am incredibly appreciative of this panel for bringing forward their ideas, for talking about their own work, for talking about the interactive-ness of it, and my colleagues in the room who are doing it as well. Please join me in thanking our session.     

That was BCRF’s 2023 NY Symposium and a special Investigating Breast Cancer podcast. Thanks for listening. To learn more about breast cancer research or to subscribe to our podcast, go to BCRF.org/podcasts.

Breast cancer is a profoundly personal disease, and blanket approaches may not work for all patients. In fact, some can avoid particular therapies or treatments altogether. BCRF investigators have played a significant role in developing precision medicine and individualized therapies, improving treatment efficacy, and limiting side effects.

This is the area where Dr. Roisin Connolly’s work is centered. Her research is focused on investigating new and innovative biomarkers to support more individualized treatment plans for triple-negative breast cancer (TNBC), which has fewer treatment options than other types of breast cancer. Upcoming work seeks to identify promising biomarkers in blood samples and tumor biopsies from patients who have received chemotherapy with or without immunotherapy. She and her colleagues will examine the tissue environment and breast cancer microbiome to develop further treatment options. 

A BCRF investigator since 2022, Dr. Connolly is the Director and Professor Gerald O’Sullivan Chair in cancer research at the University of College Cork and Cork University Hospital in Ireland. Dr. Connolly previously served as an associate professor of medical oncology at Johns Hopkins University. She has also recently received an Irish Cancer Society grant to support a Women’s Cancer Survivorship Clinic in Cork in collaboration with national and international teams.

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Read the transcript below: 

Chris Riback: Dr. Connolly, thank you for joining me. I appreciate your time.

I thought we might start with the phrase that’s associated with your work. On the surface, it seems like an obvious term, but the more I thought about it, I wondered how much complexity might lie below the surface. The phrase is “individualized treatment.” And we hear it so often, particularly with breast cancer and other types of cancer. But what does individualized treatment look like? I understand, of course, what the words mean, but what exactly might it involve? What are the permutations or potential areas for individualization?

Dr. Roisin Connolly: That’s a really great question, and I suppose we need to think back to the history of cancer treatment when we’re considering this term. I’m a breast cancer physician, so I’m discussing treatment options with my patients in the clinic, and I’m telling them that we are where we are because of decades of clinical trials and clinical research. But as the decades have passed, breast cancer is no longer seen as one disease. It’s been divided and divided into smaller cohorts. And as we do that, we realize that our almost blanket treatment decisions that we might have made in the past may not be suitable for everybody.

So for example, in the past, the majority of women with breast cancer who were coming to see a physician after surgery may have been recommended chemotherapy. And that became a standard of care. What we have learned over the last 15, 20 years is that there are tools we can use that can help us determine which patient may benefit more from chemotherapy. And what we’re doing in many cases is we’re actually omitting or avoiding chemotherapy in many of our patients, which we’re very happy with. And of course, the patients are very happy when they don’t have to go through that.

So I suppose the individualized question is, for the patient sitting in front of you, if you look at all of the tools that you have available to treat the cancer, which one is more relevant for that patient? And it might be in the future that we get even smarter than we are now, and we could do something like a simple blood test and say, “Well, the test that we had available to us already suggests that you are probably going to benefit from chemotherapy.But now I have a blood test that refines this even more to tell me that you specifically may be one of the 10 patients who really is going to get that benefit, and so it’s going to be more worth it for that patient to receive the treatment.

That’s just one example where, again, in the past, we used more chemotherapy than we do now, but we also can make those decisions if we consider other targets in breast cancer, like HER2 or the estrogen receptor. And we are now using those routinely in the clinic to make decisions. But we want to delve even deeper. We want to see even more. Can we choose who needs what therapy, who needs more chemo versus less chemotherapy, who needs none at all? That’s the general sense of individualized therapy, if it makes sense to you.

Chris Riback: It does. And I love that phrase that we will hopefully get smarter in the future. Thanks to work from folks like you, we are exponentially smarter today than we were 5, 10, 20 years ago. And as that continues, those advancements in the ability to then individualize the treatment is really remarkable.

What are immune checkpoints, and how might some cancers evade an immune response by simulating these proteins? We’re getting closer to the heart of the work that you’re actually doing.

Dr. Roisin Connolly: Yes. So I suppose, in general terms, we know that cancers are smart, and they can grow over time to be only a cell at the beginning to be a palpable lump. And they grow because they learn how to, I suppose, live and grow in our human bodies. Some of the mechanisms whereby they have been able to do this is because they have developed ways of evading or avoiding the immune system. And our immune system is very clever. It can fight infections. It can fight cancer and other insults to our body. And there’s probably many cancer cells that are killed or taken away by our immune system, but others learn to evade it.

And that’s where these immune checkpoints come in. They are, as you said, proteins that can be present on a cancer cell or a normal cell that help it to evade the immune system by it interacting with a partner protein on one of the immune cells. And so scientists have realized that this is a potential mechanism for cancer cells to avoid being killed by our immune system, which is constantly searching for these insults in our body. That is where a new generation of medications has been developed to break down that connection between those proteins and allow the immune system to then fight the cancer.

Chris Riback: And is that next generation? Are those the immunology agents, or is that something else?

Dr. Roisin Connolly: Well, there are medications we call immune checkpoint inhibitors that are specifically targeting those proteins. Some of them are called PD-1 or PD-L1, PD-L2, and they’re sitting between the tumor cells, the normal cells, and the immune cells and interacting. So, the new generation of medications that we’ve heard a lot about over the last few years that have been approved in certain cancers earlier on, approved in melanomas, really revolutionizing their management, approved in lung cancer and other diseases. And then, more recently, there have been approvals in the breast cancer space specifically, TNBC, which is the area that I’ve been working on recently.

Chris Riback: Let’s get into your work, and with that context established, you’re focused, as I understand it, on identifying biomarkers that can help determine which patients would benefit from a combination of adding an immune checkpoint inhibitor to chemotherapy in  early stage TNBC. I assume that among the key aspects of that, key qualifiers of that, is early stage. And so maybe we’ll talk about why you’re focused on early stage and the differences between coming in at that opportunity, as opposed to, unfortunately, if one comes in at a later stage.

My first question in thinking about your work is why is that combination not viable or effective for everyone? And maybe that goes back to what you talked about at the beginning around individualized approaches. And what helps determine who might benefit from the combination approach?

And lastly—because there’s no question that I wouldn’t want to just pile onto—, for those who might not benefit as much, is it a question of tumor reduction effectiveness, or is it a question around highly desirable side effects? So, which aspect of outcomes is what drives some of that decision-making? So a lot there. To the extent that I offered you something convoluted, I fully expect that you will straighten it all out and give me nice, clear answers.

Dr. Roisin Connolly: Exactly. So I think what we’ll do is we might go back to the original conversation, about how over time we have developed strategies to treat a certain type of cancer or a certain stage of cancer. And oftentimes, those strategies have built on the past. So, there is a combination of chemotherapy and immunotherapy that is now approved for use in TNBC. And by adding this immune checkpoint inhibitor to the type of combination chemotherapy approach that we’ve had available to us for a long time, the results are better. So, we have added on what we’ve learned in the past, and now we’re in a situation whereby we have a regimen that is really quite effective in terms of preventing the cancer from coming back down the line and saving lives of a proportion of women.

But what we’ve realized is that we are likely not benefitting everybody that we give that regimen to. We, in our heart of hearts, know that there’s probably some women within the triple-negative group that are really going to benefit from that, and others who may not have needed that extra treatment approach, may need two chemotherapies versus three. And so, now that we’ve not quite maxed out on efficacy, but getting closer to that in TNBC with these new combinations, now the community is thinking, “Okay, we have this effective regimen. It’s been given regulatory approval. We’re using it in the clinic. But can we start to tease out now who may benefit more or less from that approach so we can make those individualized decisions?”

Another part of your question was about who could be benefitting from these treatments and who may not benefit from them. And what we think about TNBC and breast cancers is they were not traditionally felt to be as sensitive to these immune agents as other cancers, like, again, the melanoma, the lung cancer, et cetera, possibly because the environment around the cancers was a bit hostile to that effect. And that term has been used to describe sort of a cold environment, whereby maybe the surrounds of the tumor were not so amenable to using these immune checkpoints, or the tumor microenvironment, which is a term that’s used a lot these days.

And so, a lot of efforts have been initiated to see, “Well, can we be more smart with the medications we use with the approaches to almost make triple-negative more hot or more amenable to these immune checkpoint inhibitors?” And so, there’s been a sense that we both need to do better where people aren’t responding, and for people who are going to respond, pick them out so that we’re making sure that we give the treatment to them versus other people who may not benefit as much.

An area that is of interest to mine is looking at this tumor microenvironment, the tumor itself and the microenvironment around it, so we can learn more about what’s happening there as these medications are given so we can, in the future, again, be smarter about the choices that we make, so identify these biomarkers or signals that can tell me that one patient is going to do better than another. So I hope that gives a general answer to your question.

Chris Riback: It certainly does. And what I appreciate so much about the characterization, what’s more personal than cancer, than what an individual is going through? I mean, anyone who goes through it obviously knows she or he are not the first ones in history to have gone through it, and yet, it surely feels, for that person, like, “I am the first one,”. I mean, it’s the most personal.

And so, the work that you’re describing to personalize, individualize the evaluation and then obviously, the approach and what gets done to help that patient, the ability to personalize or individualize that, to me, is a line moving towards the reality that that individual is feeling, that this is highly personal, highly individualized, so, “Doc, could you please tell me what I need, not what the general population needs? Could you tell me what I need?” And in listening to you, that’s what you, and others, are really striving towards. So, describe for me, then, if you would, please, your study, the work that you’re actively under right now. What is your hypothesis? What’s the status? What happens next?

Dr. Roisin Connolly: The reason that this area is so important to me is because I am prescribing these medications in the clinic. And when patients are experiencing side effects, either from the chemotherapy or the immunotherapy, that disappoints us to have to put patients through that if we don’t need to, and balancing, again, the benefits and the risks. So, this idea that some patients as well as maybe the immune system attacking the cancer cell, the immune checkpoint agents might also be causing these unwanted side effects. And that’s a whole other area of research, is the immune-related adverse events. So, my research in TNBC and other cancers in other projects is to try and, again, maximize efficacy and minimize toxicity, that balance. So for this specific project, we’re deciding to focus on the tumor microenvironment and explore it further.

One of the main areas of interest is a very topical scientific area in oncology right now, and that’s the area of the microbiome. There’s been a lot of interest in bacteria that are living in us that might actually be influencing how we are responding to treatments given to us. And there’s been a lot of work done in the gut microbiome, so the bacteria that are living in our guts that might then be passed in our stool. There is some evidence that these bacteria may influence response or side effects from immunotherapy.

Some collaborators of mine here in Cork in Ireland have gone a little bit beyond the stool microbiome. They have a particular interest in what’s happening in the tumor itself, and they have identified that bacteria are also residing in the tumor.

So how do we best identify them and determine what’s tumor-related bacteria versus normal bacteria that might just be there because of contamination or living in other tissue? And we need to look at whether those bacteria might be able to influence response to treatment and the drugs that might be present treating the cancer, and how they interact with the surrounding immune system.

So, we are going to try to tease this out in this project in a number of different ways. One is by using samples that are already available that have been stored in a biobank, a breast cancer biobank, and looking at those samples. And how do we look at the bacteria in those stored samples? How are they interfacing with immune cells locally, and is there a better way to identify those bacteria in other ways? And so we have not only taken a look at samples that are already in the lab that have been taken with patient consent but also developing a new protocol, whereby we’re looking to see if there are better ways to identify these bacteria and to link them with both the local immune cells and immune environment. And then in an early sense, what is the association between those and how the patient is doing in regards to the response to the treatment, which we call the pathological response, and also their survival outcomes?

This very topical area really has potential to influence our decisions if we can follow through on this, and may also be a way for usto identify new treatments, like treatments that might actually target those bacteria if they’re not helping us in treating cancer by virtue of how they’re acting in the tumor.

Chris Riback: Is your work focusing on all of those different stages—first IDing what bacteria are in there, but then also testing the impact of that bacteria, and then  testing the pathological response of that bacteria to various, I guess medications is what one might say? Are you investigating all, let’s just call it three or four of those stages? It looks like you are. And then, if so, what’s your status? Where are you now? And do those happen in parallel path, or do you have to take it stage by stage?

Dr. Roisin Connolly: Yes,we are doing this in what we’re calling a careful step-wise approach to looking at these potential biomarkers, because if we’re going to use something to make a treatment decision, there’s a very clear and careful pathway that we have to follow.. We would never want to use a biomarker or assay unless we were very sure that we knew exactly how it was behaving, exactly how we should identify it, exactly how it associated with response.

Where we are right now is we’re doing this in parallel, not sequentially. So we have access. We’ve identified the samples that are linked to these patients with a history of TNBC who’ve received these treatments. And, at the moment, they’re on their way to the laboratory. And then, in parallel, we’re working out the final details of the new protocol that will enroll new patients. And those patients will consent. Then they’ll have their blood sampling, their tissue sampling. We’ll be collecting their clinical data. And so, it is a parallel effort to look at a variety of ways of measuring these bacteria and the tumor microenvironment. And, we believe that then adding this information together will strengthen what we can learn about the field.

Chris Riback: This might be just a hyper-naive question, but you mentioned earlier the potential around the blood testing. I know there’s work being done around that. If you do this work and are able to identify which bacteria might be creating or affecting what aspects of cancer and, perhaps as well, what medication or treatments might work against those, is there then a simple test for bacteria? Or is the ultimate outcome something that is potentially as uninvasive as a blood test in terms of testing? Or no, I’m thinking about it wrong, that testing blood is very, very different than bacteria because you have to see if the bacteria in the tumor, et cetera? So I might be conflating things, but I’m wondering if that’s potentially a direction where you’re headed.

Dr. Roisin Connolly: I think it’s a really good question. I think it will be most ideal if down the line, we can do a simple, non-invasive test to make these decisions. There is certainly some interest in the idea of picking up these bacteria in the blood. That is not a focus of our project right now, but certainly that is where the future may go.

We are actually collecting blood in our current project for a different interesting area, which is called the area of tumor exosomes. So these are little vesicles that can be secreted out of cancer cells and maybe float in the blood. And that’s another very novel potential area. We’ve heard a lot about circulating tumor DNA, plasma tumor DNA, circulating tumor cells. There’s been a lot of research over a long period of time trying to look and see whether these help us predict response to treatment and help us make treatment decisions. They haven’t quite reached the clinic yet in breast cancer, but another area that is being explored is these extracellular vesicles.

So oftentimes, when we’re doing these projects where we are collecting biospecimens, we’re thinking, “How can we maximize what we can learn in this project?” And we may be working with scientists in different fields, but then, the benefit is that we can look at that data in aggregate when we have the final numbers.

Chris Riback: And, of course, we want to offer eternal patience in waiting for your results, but at the same time, we’re all just a little bit anxious. So, where would you say you are and what’s next?

Dr. Roisin Connolly: In the next few months we’re going to be actively collecting these samples from new patients coming in the door. And I hope that towards the end of next year, we’ll have some early readout from those patients. In terms of correlation with the clinical outcomes, that’s going to take a little bit longer. And then, for the samples that are already available, I hope that early next year we’ll have some early readout on that and we will have the clinical data available. But again, this is a step-wise approach, and our hope is that once we have information from these two sort of parallel cohorts, we’ll be designing larger studies that will really move us towards the point whereby we can use these in the clinic for patients. But that does take some time.

Chris Riback: You indicated a couple of times that this is very current work. What’s pushing it in that direction? Is it new hypotheses? Why are you characterizing it in that way?

Dr. Roisin Connolly: Some of what we do as clinical trialists is we move things along that pathway towards the patient. And we may have projects at different stages. For example, another area that I’ve got some interest in is imaging with PET scans and other modalities to help make better choices. I have a new large clinical trial that has opened in the US which is at a later stage, whereby we have decided that this biomarker or potential biomarker in HER2-positive breast cancer is at the point where we can do a larger study and try to get more definitive answers for patients.

In the triple-negative stage, immunotherapy is so new that we’re trying to figure out these best biomarkers. And as a clinical researcher, I need to work with the best laboratory scientists to make these new findings relevant. With all of the interest in the area of the microbiome, this is a space that has a lot of excitement, but there is a lot more work to do. It’s at a very early time point. So I am just very happy that I work with folks in Cork who have a slightly different spin on this and can bring something novel, and similarly in the blood phase.

We want to take better developed biomarkers to the final stages, where we can be closer to impacting patients. And then, for new, emerging technologies, they need to go through the step-wise fashion. For the triple-negative group of patients, that’s where the focus is at the moment for me.

Chris Riback: Interesting. So, you indicated earlier something about the fact that colleagues of yours, in Cork, I believe you had said, had been doing some work with bacteria. So, when you just said a moment ago, very fortunate to be working with these folks, am I interpreting you correctly that you are kind of sitting a little bit in the, maybe not the only center of the universe, but close to the center of the universe for this kind of work?Or is it being done in a number of places, and you just happen to be in one of the solar systems, let’s say?

Dr. Roisin Connolly: I think from the perspective of the actual tumor itself and the presence of the bacteria in breast tumors, I would have to say that we’re one of the few areas in the world that is doing this level of research. The gut microbiome has been extensively investigated now by many, and so many have developed expertise in that area. But from a tumor microbiome perspective, I believe my colleagues here are really at the cutting edge.

Chris Riback: That’s got to be incredibly exciting. I mean, for someone who has dedicated her life to the type of work that you have, to get to be affiliated with that type of energy and excitement has got to be very inspiring I should say.

Dr. Roisin Connolly: I would see huge potential, again, for trying to individualize in the setting of immunotherapy, because it really has revolutionized many other cancer types. It’s developing its space in the breast cancer arena, mainly the TNBC. But as a clinician, half of my job is helping to make these treatment decisions and half of it is the research. I really want us to be in a situation whereby we are making those right choices for patients. So it’s that partnership between the clinical need and the great science that’s happening in the labs.

Chris Riback: Yes, the translational aspect of medicine is one of great learnings that I’ve had in these conversations. That and speaking to many people like you who have learned so much from cancer type A and have then made hypotheses and then advancements in cancer type B—all those cross-pollinization opportunities and the way people like you have both the opportunity and then the responsibility to think and bring learnings from one environment to another. It’s always really interesting to hear about.

Quickly, if you would, tell me about you. Was it always it was  evident that you were going to be a scientist? Was there ever the potential that we could have lost you to creative writing or anything else in your life?

Dr. Roisin Connolly: I’m the only physician in my family, and I made the decision to go down this pathway early when I was a child. I had a history of childhood asthma and spent a lot of time in hospital at one point. And it was a place that I actually felt very happy, actually.

Chris Riback: Wow.

Dr. Roisin Connolly: I loved being in the hospital. I loved going to school in the hospital—hey had a little school—and I loved talking to the nurses. And I just actually really loved that environment, which isn’t everybody’s experience. So I knew pretty early on that I wanted to go down the medical route. Initially, I thought I might want to be a pediatrician and then changed to adult medicine. In medical school, I had the experience of working with the oncology service in one of our training hospitals and I suppose I just recognized the real, unique relationship that an oncologist has with their patients, to be supporting them through a really difficult time.

I worked with very inspiring attendings at that time, and so I then made the decision to go down the oncology route and did some of my training in Ireland. But then I was lucky enough to start the fellowship program as well at Johns Hopkins subsequently. And that’s where I was more exposed to the academic side of oncology and really enjoyed, “growing up” to some degree in the breast cancer program with absolutely amazing physicians, and then being able to interact with experts in cancer immunotherapy and other scientific areas, the imaging side of things as well. And that opened my eyes to the importance of research in cancer medicine.

My position now is a little similar to my position at Hopkins, whereby I have the clinical component to my work and then the protected time for research. It allows me to maintain my academic interests, to collaborate with pathologists, laboratory scientists, biostatisticians not only in Ireland but in the US and Europe. And so, it is very, very exciting, and it’s probably what keeps me going week to week, is all the new changes and trying to develop new ideas and working with this multidisciplinary group of people who all want to make things better, ultimately, for patients with cancer.

Chris Riback: That’s quite a pathway. And two thoughts are coming to mind. One is incredible, great credit to the doctors and nurses and administrators who ran a child school in the hospital that gave us you in this field now and didn’t turn you off of that. I’m also just slightly curious, if you’re the only one in your family who took this path, what is their reaction to you today? Do they think you’re crazy and whacked out and talking about all sorts of things that aren’t top of mind for them, or I assume that they’re also extremely excited and proud. What’s the family reaction you get today?

Dr. Roisin Connolly: I think they’ve always been very happy with me being happy in my career choice, and obviously proud. It’s an honor to have trained and worked at an internationally recognized center like Johns Hopkins. So I think my family are proud of me, but they probably don’t really understand a lot of what I do. They’re in very different fields but recognize the importance of it.

Chris Riback: Well, maybe they’ll listen to this, and you explained everything so extremely clearly that maybe this will help. Lastly, what role has BCRF played in your research?

Dr. Roisin Connolly: I’ve been so grateful to have been taken on as a BCRF investigator. I feel it’s hugely important for me as well, having moved institutions and having moved countries. BCRF is supporting investigators all over the world, and their support is really giving me the kickstart and the seed funding to get this type of exciting project up and running in a new location with new collaborators and a new patient cohort. And that, to me, has been the most important benefit here. So I’m really grateful to them for believing in what I’m doing, believing in me, and enabling this work. Getting this off the ground would not have been possible without them. And I hope that it spurs on additional support from other places when the early readouts are seen.  I think we can probably make BCRF continuously excited about this type of work, as well as other funders and donors.

Chris Riback: Wow, that’s terrific, and I’m sure that they and others will feel similarly. Dr. Connolly, thank you. Thank you for your time, and thank you for the work that you do every day.

Dr. Roisin Connolly: Thank you so much, Chris, nice to speak to you today.

Chris Riback: That was my conversation with Dr. Roisin Connolly. My thanks to Dr. Connolly for joining – and you for listening. To learn more about breast cancer research or to subscribe to our podcast, go to BCRF.org/podcasts.

It all started 30 years ago at Evelyn H. Lauder’s kitchen table. Evelyn recognized that the major obstacle to achieving a cure for breast cancer was funding for research. Together with the guidance and support of her dear friend and revered medical oncologist Dr. Larry Norton, they launched BCRF in 1993.

Since then, remarkable advances in breast cancer prevention, diagnosis, treatment, survivorship, and metastasis have been made. But there is still critical work to be done. The Foundation is moving faster and closer than ever to achieving its mission to prevent and cure breast cancer by advancing the world’s most promising research. 

BCRF co-founder and Founding Scientific Director, Dr. Larry Norton, has been there since the beginning. He and the over 250 investigators BCRF supports are tirelessly working to achieving this mission. We spoke with him to discuss the progress BCRF has made and what advances are on the horizon.

Dr. Norton is Senior Vice President in the Office of the President and Medical Director of the Evelyn H. Lauder Breast Center at Memorial Sloan Kettering Cancer Center. He is also a Professor of Medicine, Weill-Cornell Medical College. Dr. Norton has dedicated his life to the eradication of cancer through his work in medical care, laboratory and clinical research, advocacy, and government. He was a U.S. Presidential appointee to the National Cancer Advisory Board. Dr. Norton is also involved in collaborations with BCRF investigators on several projects––most notably the Mathematical Oncology Initiative. Over his illustrious career, Dr. Norton has received many honors. In 2021, Dr. Norton was elected to the American Academy of Arts & Sciences.

Read more on Dr. Norton here.

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Read the transcript below: 

Chris Riback: Dr. Norton, thanks for joining me. I appreciate your time.

Dr. Larry Norton: My pleasure, my pleasure. Thank you.

Chris Riback: Let’s start with the topic of time. What does “30 Years of Progress” represent?

Dr. Larry Norton: It’s almost unrecognizable. When I think about where we were with breast cancer 30 years ago and where we are now, it’s just been remarkable the advances. And it’s not just in one thing, it’s across the board, which is actually one of the key parts of the philosophy of the BCRF is to work across the board, not on any specific one topic putting all eggs in one basket; better diagnostics, better prognostication, better medical therapy, better surgical therapy, better radiation therapy, and most important, a better understanding of the disease. And not just the biological understanding of the disease, which is obviously key. What are the molecules that make cancers cancerous? What are the changes in the DNA we call the mutations and other DNA changes and RNAs and proteins and other things that we can sort of measure? But the social impact of breast cancer and what we could do to try to ameliorate some of those aspects as well. Survivorship issues. After you’ve gotten treated for breast cancer and the cancer has gone away, what are the issues that are affecting you in terms of your return to normal life, to normal activities? Across the board there have been really major, major advances. And I must say I’m very, very pleased to report that the vast majority, if not all of the significant advances that have happened have in one way or another involved one or more BCRF investigators.

Chris Riback: You and Evelyn Lauder started the Breast Cancer Research Foundation three decades ago. What motivated you to make it a reality?

Dr. Larry Norton: What really happened is that she and her husband, Leonard, were very involved with building our first breast center at Memorial Sloan Kettering Cancer Center, which was also a great innovation. It had not been done before, the idea of a freestanding breast center where the patient could be taken care of comprehensively and not have to go from doctor’s office to doctor’s office and gather opinions and go someplace for a mammogram or someplace else for something, some of the tests and go someplace else for treatment. But the idea of putting it all together for the convenience of the patient, which was really based on her experience in business and basically the department store idea, the concept of you build the store around the customer, you don’t necessarily have the customer searching to find the things that they want. And that was spectacularly successful, so much so that we later on built a much bigger center, a freestanding building. The first center was the first time Memorial Sloan Kettering actually had a center for care that was not in its main campus, was not in its main hospital. And that has been a remarkably successful innovation, copied throughout the world.

But when we did that, we realized that there were other changes that had to be made, and so we met in her kitchen with a beautiful view of Park Avenue over tea. I think it was Darjeeling tea. And said, “We have a little bit of money left over. We can potentially raise some more money. What else is needed?” Having started this great experiment, I said, “There’s another experiment that really should be started.” Thirty years ago was the dawn of the really molecular understanding we call molecular biology. The molecular understanding of cancer in general, in breast cancer in particular. And I was part of a community of great doctors that knew how to take care of patients really well with all the available knowledge that we had at our disposal at that time, but also clinical investigators that we were able to do studies and are a well-oiled operation funded by the federal government largely in those days to do clinical studies.

But there was a disconnect between what was happening in the laboratories and what was happening in the clinic. We were not necessarily testing the really exciting things that we were discovering in the laboratory. So we decided that what would really work well, or as an experiment to try, is to create an organization, a foundation that could bring together the very best scientists who were studying breast cancer, the very best doctors who knew how to take care of breast cancer and clinical investigators and see if they could form a community and work together to understand cancer better and improve cancer therapy.

So, it was an experiment. And she decided that she was going to have a dinner party in her home a few steps away from her kitchen and invite some of her friends. I would invite some really superb colleagues who were doing this kind of cancer research, both in the laboratory and the clinic. We’d get to know each other, we’d raise some money and we’d see what would happen next.

And what’s happened next has really been remarkable. BCRF is the largest non-governmental funder of breast cancer research in the world at the present time. And we really have a global impact all throughout the world in this regard. And it has grown into this extraordinary activity where we find the best investigators. And regardless of their age, we like to have young investigators and older investigators, accomplished investigators, often regardless of the topic they’re studying, as long as we know that it’s an important topic. Because science is always changing. You can’t say, “Well, over the next five years, I’m going to study this” because six months after that or a year after that, this might’ve changed, and you want to be able to move off in different directions.

Part of this was based on the fact that she and I were both very immersed in the arts, supporting the arts. And arts grant-making organizations were different then and still are different than many science-oriented organizations. Many science-oriented organizations have a competitive grant process by which people send in applications, and they’re carefully reviewed and decisions are made. Arts organizations often have a panel that is very knowledgeable about the field, goes to a lot of performances, go to a lot of museums, listen to a lot of music, know what’s going on, and then seek out the best opportunities for funding to be able to make advances. We put together a small, in those days as it has grown to be much larger scientific advisory board of real luminaries in the field with a very broad expertise in all of cancer biology and medicine and social aspects of medicine, diversity and equity issues in the whole spectrum. And we seek out projects, we seek out individuals.

And I would also emphasize that something that makes us different than many other organizations is that we find the best individuals and we fund them. We ask them to give us a proposal of what to do. But the grant is not necessarily for that particular project because that project may change. We fund the artists. You know, you go to Picasso and you say, “You’re a great artist. Do some great art.” We go to great scientists, clinical scientists, laboratory scientists, and we say, “Do great work.”

They report to us. We have a very, very strenuous process of review of the work. Along with freedom comes accountability in that regard. And it’s really worked remarkably well, as I said. So many major advances. So much of what we are now accomplishing in breast cancer can be traced to our investigators but also our style of giving grants and of finding the best science and of moving it forward.

Chris Riback: I have the great honor of having these conversations with BCRF scientists, researchers every month, and the major themes that you just touched on come across in every one of those conversations. The translational aspect of medicine, the connection between the clinic and the labs, so many of your researchers with whom I talk about that, the global nature of what occurs, the collaborative approach. Everyone talks about the collaborative approach. And then I didn’t know that part. And I’ve had the privilege of talking with you before. I didn’t know that part about you and Evelyn Lauder and the arts connection. And it makes total sense because the creativity that scientists with whom you are connected—the creativity that they apply, it’s exactly as you described. They feel like it’s them that BCRF is investing in. And yes, with responsibility comes accountability, with freedom, you had said, comes accountability. They feel it. But the major themes that you just talked about, which I guess were created figuratively on the back of a napkin drinking Darjeeling tea 30 years ago, they are solid today.

Dr. Larry Norton: What you’re saying, Chris, is so important because first of all, number one, that they’’e feeling it. And often when we bring in new grantees, they’re not used to that. It takes them a while to get used to that because they’ve had specific aims. And they have to accomplish their specific aims and whatever too, so they’re not used to that. The other part of it is that when they are grantees for a while and doing this good work, they relax in terms of their collaborations with their colleagues. And this is something very important. Other granting mechanisms create a competition as a gladiatorial combat where if you have a great idea and you share a great idea your colleague may apply for grant and you may be denied that because somebody else already has a grant in that idea.

And it all goes back to something that at that meeting with Evelyn in her kitchen with Leonard walking by and saying, “Gee, it sounds great. I’m in,” with that meeting, she said, “Larry, I’ve worked around creative people all my life. That’s what we do. We create things. And they need two things. They need freedom and they need security.” The freedom to actually follow their most intriguing ideas and the most inventive ideas and the security knowing that if they do good work and it doesn’t work out that they’ree not going to lose their job. And very often, people don’t feel that freedom. They have a job to do and they do it. And very often they feel insecure, is that, “My goodness, I want to study molecule X. And if molecule X doesn’t work out, I’m not going to be able to get my grant renewed.”

And we’re not like that. If they do high quality work and they come up with a different answer, including a negative answer that they weren’t expecting, that we weren’t expecting, it does not mean that they’re not a good investigator. You have to take chances. You have to swing the bat a lot of times to hit a home run. That is really very much an intrinsic part of our community, that feeling. And the very fact that our investigators feel that and they acknowledge it and they speak to you about it is really heartwarming because that’s really what we’re all about.

Chris Riback: They do. And it comes across in every conversation. I’m curious just in listening to you, and we’re thinking about the last 30 years, I want to get into it in a moment a little bit about today and tomorrow. Listening to you describe the impact on the community over the last 30 years, the growth of BCRF over the last 30 years, the way that it’s affected scientists, and then of course the way it’’ affected patients and families and people who think and have to worry about this. You may not appreciate the question, but I feel I must ask it. What about you? What has the journey meant for you?

Dr. Larry Norton: It’s been exhilarating and it’s been wonderful in every aspect of it. I’ve always said that the favorite part of my job is training the next generation. I have an army of fellows and other people that I’ve been in contact with over the years who’ve gone on to do really marvelous, wonderful work—that’s the thing that really is the most exciting thing to me. But that also extends to colleagues, frankly, is that you can be a mentor to your trainees, but also you have relationship with your colleagues and that you can actually help them and influence them in a positive way to do the kinds of things that are important for them to do because their life mission is also to make advances against cancer. That’s been really very profoundly exciting. And colleagues come up to me all the time and speak to me all the time and say, “Listen, I’ve got a major paper that we’re publishing in a major journal, and it’s going to really change the way we practice medicine, and we owe it all to BCRF funding. If you didn’t fund me with this idea, I never could have gotten this funded in any other way. It was just too new an idea. And that led to this advance or to another advance, another advance, and it went on to do wonderful things.” There’s nothing really more heartwarming than that.

Another aspect of it is actually personal. I’ve learned so much from my contact with my colleagues and learned so much in terms of science that’s influenced my own science, my own way of moving forward. I’m going to give you a very concrete example of that is that I’m involved in a lot of areas of science, but one of them is mathematics. My original background was mathematics. Music and math were the things that I thought I was going to do with my life, and then I ended up doing what I’m doing now by the way life works with its long winding road.

And I realized from looking at our program that there were mathematical insights that could be applied to the problem in addition to biochemical insights and other areas of science that we know are very, very relevant. With the support of the Simons Foundation through BCRF, we’ve established something called a Mathematical Oncology Initiative. And that’s been extraordinarily productive in general, but also for myself, for my own personal growth because it’s put me in contact with extraordinary mathematicians who are basic mathematicians often who don’t do applied work, they just do work on theoretical mathematics. But they’re very excited by the opportunities. And we’ve made very significant advances in that regard in terms of understanding biology, picking who’s going to respond to immunotherapy, being able to tell prognosis of a breast cancer patient just from looking at a microscope slide and just analyzing that using machine learning and artificial intelligence and other tools that have been developed to augment mathematics.

The impetus came from my contacts with my colleagues through the BCRF as well as my wonderful colleagues at Memorial Sloan Kettering Cancer Center. We started a program in understanding the molecular biology of breast cancer, called the Founder’s Fund after Evelyn. When we tragically lost her, Leonard stepped up to the plate and auctioned off her high-level jewelry and made other contributions. Many of her friends came in and we established this Founder’s Fund.

The etiology of that is very interesting is that BCRF for many years has been supporting an annual meeting between breast cancer clinical investigators in the United States, North America, and the breast cancer clinical investigators originally in Europe and now internationally, something called the Breast International Group. And we formed together. We used to meet annually one year in Brussels, one year in Chicago at the American Society of Clinical Oncology meeting. And now we’ve been meeting largely in Chicago.

But at one of those meetings, in particular in Brussels, we had presentations of people who were studying the molecular biology of breast cancer. What are the changes in DNA, RNA proteins? What are the molecular changes that are in breast cancer? And Martine Piccart, great European investigator now on our scientific advisory board, and I were in the back of the room. We noticed that all of the studies were breast cancer coming from the breast, tumors coming from the breast. But that’s not the dangerous part of breast cancer. The dangerous part of breast cancer is metastasis, the spread of the breast cancer cells to other parts of the body. And we weren’t studying that. The analogy that popped into my mind at the time is trying to figure out why the cows have left the barn by only studying the cows who are still in the barn. You’ll get the exact wrong answer. The cows who are still in the barn are there for a very good reason. The ones that are left are the ones that you want to know about, the cells that have spread to other parts of the body.

And so the Founder’s Fund was focused on something called the AURORA projects. There’s one AURORA project in Europe and one AURORA project in the United States, both of which have produced extraordinary discoveries about the molecular characteristics of breast cancer, including the discovery, independent discoveries, but coordinated independent discoveries on both sides of the Atlantic that the immune system has a profound effect on cancer metastasis, which has given impetus to studying immunotherapies for breast cancer and a better understanding of that. And in the analysis of all that data, I realized that mathematicians could also get into this in a novel way that had not been done before. And so, we not only have this mathematical oncology initiative and not only have the AURORA projects, but we can marry them together in a productive way.

I can’t think of any other organizational system that could actually do this, that could fund international trials involving most of the stellar leaders in molecular biology of breast cancer together; mathematicians who’ve never had a practical application in all their years of work starting to work on the cancer problem. And then being able to bring them together to be able to work together on this kind of problem. This can only come from a cohesive community. And it really illustrates the wisdom and the insight and the foresight of Evelyn in our kitchen conversation in terms of how to actually make this happen. You find the best people, you give them freedom, you give them security, and magic happens. And that’s what’s happening in BCRF.

Chris Riback: Well, it’s not surprising to me that you raised the mathematical oncology group, the initiative. As I was researching for this conversation and was reading more about that, it absolutely felt to me like the proof was in the pudding…that you were executing in your own activities exactly the vision that you describe.

Additionally, listening to you right now, the importance of the Founder’s Fund and the importance and “challenge “is too light of a word of metastasis. It is written on your page that no topic in cancer medicine is more pressing and no opportunity more significant than understanding and stopping metastasis. Is that at the center of it?

Dr. Larry Norton: No. The dangerous part of cancer is metastasis. It’s not the lump in the breast. Lump in the breast is a big pimple. You could remove it. That’s not the problem. The problem is that cancer cells can spread to other parts of your body. It can go to your bones and your liver and your lungs and your brain. That’s the lethal part of cancer, so that’s actually the essence of it all.

But it starts with the lump in the breast. So yes, we have to study metastasis, which we’re doing, which a large bulk of our research is studying the biology metastasis and ways of interfering with it. And essentially everything we do therapeutically is one way or the other either treating metastasis or preventing metastasis. But there’s a flip side of this as well, which is that if the lump in the breast didn’t happen in the first place, then you wouldn’t have the opportunity for metastasis, so we have to study cancer prevention as well.

We have a cancer prevention initiative that’s going on right now that is also extraordinary with extraordinary individuals because the best way to stop the metastasis is stop the lump in the first place. And so that’s part of it as well.

You see, the whole concept is you got to study the whole thing. Very often when I give lectures, people say, “Well, what’s the most important thing that we should be studying?” And I say, “I will answer your question, but you’ve got to answer your question first. Tell me what’s the most important part of the airplane? Is it the left wing? Is it the right wing? Is it the engine that makes it go forward? Is it the pilot? Is it the navigation system?” The fact is that you need all of those pieces and you need them all to work together. The most important part of cancer research is not let’s put all our eggs in the basket of immunotherapy or all our eggs in the basket of better surgery or better radiation or understanding biology. The important thing is to build the whole airplane and to make all the pieces work together.

So it doesn’t bother me at all that I study metastasis and try to cure cancer once it’s there and once it’s developed into metastasis. It doesn’t bother me at all that I can do that at the same time as I give drugs at the time of the diagnosis of the breast cancer to prevent metastasis, which is what adjuvant therapy is all about. And also that we’re studying how to stop the cancer in the first place. You got to study the whole spectrum.

The other thing that any scientist will tell you, things you learn in one area help you in another area. We use breast cancers that are estrogen receptor-positive or hormone-responsive that have spread to all the parts of the body, we use a whole variety of hormone-based therapies to actually treat such patients to extend their life. And we’re getting better at better at that because we’ve discovered mechanisms of resistance to hormone therapy, and we can give drugs to overcome that resistance. And so we’ve made huge advances in that area. And BCRF investigators have been all over that topic.

But those same drugs could be used early on to prevent the cancer from metastasizing in the first place in the adjuvant setting after the lump is discovered. And those same class of drugs could be used to prevent breast cancer in the first place, which is something we discovered. Studying one category of the disease helps you understand and helps you manage other categories of the disease. And so that is why it’s so very important to really have a comprehensive package of grantees and programs so that we can learn from each other.

Chris Riback: One hundred percent. And that also comes across. I can’t tell you the number of conversations I’ve had with BCRF investigators who have identified lessons or hints or glimmers from colon cancer or some other type of cancer that then get applied. That comes across as well. What a beautiful, powerful metaphor, the airplane. That also comes across not only in the scientific, medical, biological component, but also the emotional, psychological patient care component. And the way that those intertwine also becomes a very, very powerful lesson.

I’m interested in your views on items today. The global data hub, for example that BCRF created. First of its kind to transform how breast cancer researchers access and share data. Talk to me about the global data hub. And maybe if you could talk to me as well, is there anything today current in terms of technologies or evolutions? Of course, something like for lay people like me, we hear a lot about AI. And I had a recent conversation about AI and breast cancer, a BCRF conversation. Tell me, if you would, about some of the things that capture your attention today and the global data hub.

Dr. Larry Norton: It’s the evolution of the BCRF concept. The evolution of the BCRF concept is getting people to work together. But one of the most important things that we’ve learned over the last several decades while we’ve been doing this is the power of big data, the power of having very large data sets that can be scrutinized by a variety of tools, including the emergent modern tools of mathematics, artificial intelligence, machine learning, neural networks, and so on to be able to actually have insights. On the AI area, this is as dramatic a change in the human brain, the ability of human intelligence to interrogate the world and learn from the world as anything that’s happened previous to this. And let me explain what I mean by that.

Chris Riback: Yeah, it’s a powerful statement.

Dr. Larry Norton: The scientific method was a great intellectual breakthrough. The scientific method is largely you formulate a hypothesis, you design an experiment, you do the experiment, you see the results of the experiment. It modifies, confirms, or denies or modifies your hypothesis. You go onto the next experiment. It’s all about testing. I’m frequently asked, “Larry, do you believe in X, Y, Z?” And I say, “I believe in certain things. I believe Mozart is a great composer. I believe in God. I believe in certain things. When it comes to science, I have no belief. It’s all about the data. It’s all about the evidence.” It’s not a belief system. And that’s a dramatically different way of looking at the world when you really think about it is that it’s got to be based on evidence. And the evidence is based on prospective experiments.

We’ve built this incredible world where science has changed our world in so many wonderful ways because of the scientific method. Now we have a different way of actually approaching questions. What I said before is you make observations of nature and you generate a hypothesis and then you generate experiments to test or refute your hypothesis. Now we could actually look at the world, observations, data in a different way, and the data can generate the hypothesis in ways that we could not creatively come up with. It can look at the data and it could say, “It looks that to us like” the machine talking to me. The machine is saying to me that there are certain changes that we see here that are connected to other changes, certain ways that the cells look under the microscope that can tell you whether this patient’s going to be cured or not,” for example. And then we can start to then develop hypotheses that are derived from the actual analysis of the data rather than using our imaginations only to come up with those hypotheses.

This is really a revolution of thought. And where this is going to lead in the big picture, none of us really know. And it’s a very powerful tool, and therefore it has to be applied very, very carefully moving forward. But that means that we have to have the data to interrogate. And now we have these astonishing investigators from all over the world.

And by the way, a lot of people who are not BCRF investigators are interested in getting in on this data hub where all this data can be put in a way that can be interrogated, that could be looked at by qualified individuals. We can be very careful about who can actually look at the data and who can analyze the data. We’re going to have careful controls on that so it can be released to qualified people from all over the world to actually look at the data and, using modern tools of big data science actually derive hypotheses, things that we couldn’t have thought of before.

A lay example of this is look how long it took us to figure out that cigarette smoking caused lung cancer. Decades, centuries where we didn’t have a hypothesis. Cigarette smoking, tobacco smoking was ubiquitous. Everybody did it. It was all over the place. There was no hypothesis. It would take machine learning seconds to figure that out and come up with a hypothesis, “We’ve observed that there’s more lung cancer in people who smoke by looking at big data. Maybe you should look at the impact of cigarette smoke on the lungs,” the machine would say to us. And then we would do a hypothesis and then we would design experiments, and then the usual methods of science would get us to that answer.

There may be a lot of other things that are out there that we just haven’t thought of yet but that the data could speak to us and tell us this about the molecules we’re studying, about social factors, the impact of stress, chronic stress in our environment, the impact of social inequities, which is something else that we’re studying on bodies’ physiology and how that physiology could actually impact the generation of cancer or prognosis once you have cancer. Those are the kinds of things that we can actually study now by actually interrogating the data once we accumulate that data. And so that’s the underlying philosophy of what we’re trying to do with the data hub. And I think it’s going to be a transformative step in understanding not just breast cancer but all cancers, and maybe other diseases.

We’re finding connections now between heart disease, cardiovascular heart disease, clogged coronary arteries and cancer through mutations that occur not in cancer cells but in white blood cells, that normal white blood cells that look normal under the microscope may have mutations in them that predispose us not only to cancer but predispose us to heart disease. And that’s the kind of thing that can come out of these kinds of research. Yes, we’re studying breast cancer, yes, we’re studying all cancer, but yes, we’re studying all diseases.

Chris Riback: What a fascinating way to frame it because it reminded us all earlier that if you want to understand why cows are leaving the barn, you need to look at the cows who have left the barn, not the cows who remained in there. The importance of looking at, quote, “the right thing” or asking the right question. What you’re describing now is the first-ever, perhaps, opportunity to, in milliseconds, not just ask the right question but ask the new question. All of a sudden the ability to think of the new thing. What a fascinating framing.

Secondly, you understand, doctor, that I am not here to argue with you. You’re the last person I want to pick a fight with. However, in terms of Mozart’s excellence being connected to a belief, I think, my hypothesis is we could find empirical evidence of his greatness.

Dr. Larry Norton: Yeah. Well, we could talk about that. That’s a whole other topic. The thing is we can find evidence that he’s popular, we can find evidence that he’s played often, we can find evidence that people appreciate him, but greatness is a term that’s really a little bit harder to define in that regard, too. And so that gets into a little bit of a belief system, and so that’s what I mean. And I think that a lot of wonderful things in life belong to belief; there’s no question about it. When it comes to science, I don’t have any confidence in belief, I’ve got confidence in data.

Chris Riback: I appreciate the distinction. And yes, I look forward to our next podcast series on Mozart and greatness. But what you’re describing right there also aligns with a question that I found myself thinking about vis-à-vis you and your role as I was thinking about what you do in 30 years of BCRF and the things that you have faced, surely, and that you think about. I find myself thinking how you likely sit at the intersection of eternal optimism and frequent frustration. What I mean is, on the one hand, you have this front-row seat that you’ve described in this conversation to some of the most extraordinary, hopeful, and optimistic scientific advancements in the world. It’s nothing short of incredible what breast cancer researchers do and the possibilities that exist; you’ve described it. And at the same time, you know from the translational aspect of what you and others do and that what happens in the lab and what happens in the clinic and the realities of what happens in the clinic, everyday new people are diagnosed with breast cancer. How do you balance that daily hope?

Dr. Larry Norton: And some are dying of breast cancer, too.

Chris Riback: And some are dying. How do you balance the hope and frustration?

Dr. Larry Norton: I was interviewed by a great interviewer many years ago for the New York Times, and she asked me that same question. And I hadn’t really thought of it before then, but I answered her thinking about it. And it’s the same answer. It’s really what motivates me and really what drives me and why I’ve given up other parts of my life like music, for example, to focus in on this particular topic is that as a cancer doctor, I take care of people and I provide the very best care that can be provided for them with my colleagues, my wonderful colleagues at Memorial Sloan Kettering and colleagues throughout the world and collaborators. And sometimes it doesn’t turn out good. And I carry those memories with me through every minute of my life. And I owe it to them that their child will not die of cancer.

That’s really what motivates me every day. Yes, I didn’t save their life, but what I can do is I can work harder, make more discoveries, apply the very best of my abilities and motivate and organize and support, financially support the great investigators in the world so that the people that they love and their offspring never have to worry about this disease. That’s my obligation to those individuals. And I can’t help them anymore, but I can help others that they care about, that I care about.

And that’s really what drives me. If you want to put your finger on exactly the thing that drives me, that’s really what drives me. The successes drive me also, the great glory of those successes that drive me. Many years ago when there was an experimental therapy that’s now a standard therapy that dramatically saved somebody’s life, a new drug where she was really sick and she was clearly not going to make it. And it was an experimental drug. And we gave her experimental drug that’s now a standard drug, and she had a fantastic, remarkable response. And I knew her as a patient.

I was taking my little daughter to a play date. It was my job to take my daughter to a play date. And I knew the name of the child; I didn’t even know anything further. And I took my daughter by the hand and knocked on the door there too. And the door opened and the other child ran out, and they hugged and they went to play. And I looked up and it was that woman, it was her child, the woman whose life I’ve saved. And now my daughter’s playing with her daughter. And we looked at each other, we both broke down in tears, big wet, sloppy tears and both hugged each other at that moment. Because she had that same reaction to me. Here’s a dad bringing a kid from the school play.

The successes really are there as well. I am driven to make it universal and my colleagues are driven to make it universal. And for the ones that we didn’t save the life or we didn’t prevent the cancer, whatever too, is I owe it to them to do better. And that’s really what drives me personally. It’s a very good question.

Chris Riback: Thank you for that. It’s a very, very, very powerful answer. And I can only imagine. I’m playing the film in my mind of your patient who is now in that instant not just a patient, she’s a friend that’s a mother, a human being, a person in your life and in your child’s life. And the eyes locking. There must have been a lot of tears.

It does lead to a wonderful way to close because you’ve taken a conversation that is thinking about 30 years of history and how meaningful it is that what motivates you isn’t the 30 years of history, but it’s tomorrow. And so within the incredible pride and gratitude that so many people have for everything that’s been accomplished, the lives that have been saved and the therapies that have been discovered and the care that has been personalized… We didn’t even really get to talk about the way that the personalization of care, how meaningful that has become. And yet at the same time, everyone shares your well-meaning impatience and want to know what’s next in your mind for BCRF? What’s next for breast cancer?

Dr. Larry Norton: Well, look, we have a lot more work to do, as you said. And that’s what really motivates us and really to move forward. Right now, as I say, we have a very broad, very broad category of research, and we want to provide that. We’d like to give more grants. We’d like to give more individual grants. We’d like to get involved in more projects moving forward. We have an extraordinary collaborative project with the pharmaceutical industry where, with the support of the industry financially and with their medicines, that we could have our investigators design clinical studies to move forward. I’d love to see that expand.

You mentioned the data hub. We’d like that to be bigger. We’d like that to be broader. More connections with other activities that are going on in the cancer space, things that are happening in the U.S. The Moonshot in the U.S. is equivalent activity in Europe, more connections in that regard basically to carry the philosophy forward. To keep our eyes open for the next big things that are happening.

There’s a particularly fascinating evolving view of cancer as not just being a disease of the cancer cell but a disease of the cancer cell and its relationship to what we call its microenvironment. You can have the worst bank robber in the world, but if the bank robber doesn’t have a getaway car and doesn’t have an accomplice in the bank and doesn’t have all these things, they’re not going to be able to do any kind of damage. The cancer cell by itself is an abnormal cell, but there are normal, or so-called normal, cells in the vicinity. We think they’re normal. They’re also helpers and are very important. And that’s why cancer may spread, let’s say, to the liver and not to the brain in individuals because there’s something about the liver that’s supporting the growth of that cancer cell. And so studying the microenvironment is an extremely important topic, and we have every intention of expanding our activities in that regard as well.

And to keep our eyes open and to move forward. The plan is to react to the best science of the moment, of the week, of the month, of the year and move things forward. There’s much more to be discovered. I personally think that, and many my colleagues do also, that manipulating the immune system in a productive way is we’re just beginning. We’re just touching the surface of our ability to use the white blood cells in our own bodies to stop the growth of cancer, prevent cancer from occurring, and help us treat cancer, so the work in that regard is moving forward. We can take white cells out of the body and manipulate them, put them back into the body. That’s another area with cancer-killing capacity. That’s something else that we’re extremely interested in. I can go on and on. I can name many other areas, but that’s really what it’s about. It’’ the philosophy that’s central, and then it branches out into specifics. And that’s what I’d like to see BCRF do.

We could be bigger. I would like to see us have the opportunity to support more investigators. We have many more investigators we want to support than we can support. And that’s also really one of our initiatives moving forward. But the future is bright. That’s the important thing to emphasize. There will be a day that we’ll look back and say that there was such a disease once as cancer. And it was a terrible disease and it caused a lot of devastation and a lot of premature deaths and hurt a lot of people. And now that’s part of history because of what we can accomplish. And that’s what we have to keep our eyes on and keep our minds on.

This can happen, really, in your own life. I gave you the story of that individual patient. Why you’re undergoing therapy or why you’re worried about breast cancer, things are happening right now that could influence you and that could be advantageous to you. It’s not just about the far future, it’s about the immediate future, results of studies coming through.

I didn’t even mention the Translational Breast Cancer Research Consortium, which is a large cooperative group of investigators in the country supported by BCRF and by Susan G. Komen jointly in terms of, again, collaboration. Collaboration is key to that and moving things forward in that regard to be able to do our studies. I said on the steering committee that, and I’m seeing new studies come out all the time with major advances, things that could help individuals. We have to work hard. We have to remember the past, never forget it, but we also have to work hard with an optimistic view of the future because we are going to accomplish breast cancer in all cancers. Our job is to make that happen as fast as possible.

Chris Riback: It is clear from your conversation, it’s clear from the conversations that I get to have with other BCRF scientists. And I very much look forward to having the conversation with you looking back at what was cancer and getting to discuss how that was put behind everyone.

Dr. Larry Norton: Thank you. Thank you.

Chris Riback: Dr. Norton, thank you. Thank you for what you do and for what BCRF and all BCRF researchers around the world do every day.

Dr. Larry Norton: And thank you for this opportunity.

Outro: That was my conversation with Dr. Larry Norton. My thanks to Dr. Norton for joining and you for listening. To learn more about breast cancer research or to subscribe to our podcast, go to BCRF.org/podcasts.

Immunotherapy and chemotherapy are two powerful tools being used in breast cancer treatment now. The former, a newer approach, harnesses the body’s natural ability to fight disease, and the other, a mainstay in cancer care, uses powerful drugs to kill cancerous cells. But meaningful questions remain: Can these two approaches be used in tandem? What are their particular strengths and weaknesses? And though both deal with combating breast cancer in the present, what tools—if any—exist to help prevent cancer in the first place?

That’s where Dr. Nora Disis comes in. Her research is focused on identifying ways to boost the immune response in breast cancer patients to improve chemotherapy outcomes. She is working to discover new molecular immunologic targets in solid tumors to develop vaccine and cellular therapy for treating and preventing breast cancer.

Dr. Disis, a BCRF investigator since 2016, is the Athena Distinguished Professor of Breast Cancer Research and the associate dean for Translational Health Sciences at the University of Washington School of Medicine. She is also the editor-in-chief of the prestigious JAMA Oncology.

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Read the transcript below: 

Chris Riback: Dr. Disis, thank you for joining me. I appreciate your time.

Dr. Nora Disis: Great to be here.

Chris Riback: Why don’t we start with some definitions that I think would help many of us, certainly that I think would help many of us. What are immunotherapy and chemotherapy? How do they work and how might they work together?

Dr. Nora Disis: Immunotherapy is a treatment that really harnesses and uses your body’s immune system to fight cancer. There are many, many types of immune therapy. Chemotherapy is a drug or a series of drugs that directly act on rapidly dividing cells, kind of poisoning them. Now, the biggest difference between immune therapy and chemotherapy, you can imagine when you get chemotherapy infused it only stays in your body for a short period of time and then it’s cleared out of your body and it’s not doing any killing. Immune therapy, if the immune system is appropriately stimulated so that it is primed to recognize the tumor, it will keep killing and killing and killing and killing long after you’ve received immunotherapy.

Chris Riback: How might they work together? If you have one in your system, might you also want the other in your system?

Dr. Nora Disis: Well, I kind of liken it to this. If you had an overwhelming pneumonia and you went to the emergency room, you wouldn’t ask the doctor to give you a vaccine. You’d ask the doctor to give you antibiotics, and I kind of look at chemotherapy as antibiotics. Once cancer has gotten out of control or is rapidly growing, you need to cut it back because the immune system doesn’t tackle lots of disease. Well, at one time. In fact, almost everyone who dies of an infection dies with a pretty good immune response against that infection, but the infection was progressing too quickly for the immune response to be able to control it. I look at chemotherapy as a way to kind of stop the cancer in its tracks or slow it down while immune therapy begins to build and build, and then you get that continuous killing. Studies have shown they kind of work hand in hand. I think most of the treatments that you see nowadays use a combination of chemotherapy and immune therapy.

Chris Riback: It’s such a terrific analogy and really does help make it clear in such an everyday way. What is the STEMVAC vaccine? Perhaps as part of that discussion, you might also be able to bring to light the role and importance of type one T-cells.

 Dr. Nora Disis:  Sure. I think vaccines, which are a form of immunotherapy, are really at a tipping point. The reason why they are is for three major reasons. The first reason is we know the type of immune response you need to kill cancer. Now, if you think about the Covid vaccine, the vaccines that are out there generate antibodies predominantly, and those can bind to the Covid virus and inactivate it. For cancer, you need T lymphocytes and in particular you need type one lymphocytes, type one or a specific type of type one lymphocyte is called the TH-1 lymphocyte. These are highly inflammatory lymphocytes. They cause tissue destruction, which is what we want for cancer. Type two T-cells generally dampen an immune response, and when you have cancer, you don’t want that immune response dampened.

The second tipping point is that we now understand what parts of cancer can be recognized by the immune system. We know a lot of immunogenic proteins, hundreds of immunogenic proteins as a matter of fact. You can almost tailor-make a vaccine for any situation in cancer. Then, the final thing that’s really tipped cancer vaccines over is we now have really effective and safe vaccine technologies, nucleic acid based vaccines, either DNA or RNA are very effective at stimulating and using the patient’s own immune system to get that right type of immune response to attack cancer.

Chris Riback: And in terms of those type one T-cells, and what I’m wondering is do patients who need the vaccine or who use the vaccine have an insufficient amount of those cells? Is the body not making enough? Or is the situation that given they are dealing with breast cancer or something else, they need an extra boost or the ability to manufacture more beyond what the body could create?

Dr. Nora Disis: I think it’s a combination of what you just said. We used to think in the past, the problem with cancer patients is that of course they had cancer, their immune system isn’t functional, but that’s absolutely wrong. Patients with cancer have very functional immune systems. That’s part of the issue. It isn’t until you’re in the last stages of cancer and you’re very, very sick, do you have problems mounting an immune response. The key is in what the immune system is seeing. For some tumors like melanoma or kidney cancer, those tumors have a lot of mutations. They’re very aggressive cancers, but those mutations that occur in the cancer appear foreign to the immune system. The immune system has never seen these mutations before. They only occur in cancer. For those patients, they have quite a few type one T-cells because the immune system calls a danger signal. That says these are foreign, we need the tissue destructive immune response.

That’s why some immune therapies, the most common that we use, which are called immune checkpoint inhibitor therapies, they work best in those diseases because you already have a lot of those type one T-cells in the tumor. For most common solid tumors, most colon cancers, most breast cancers, ovarian cancer, prostate cancer, those cancers are not highly mutated. What is the immune system seeing in those cancers? The immune system is seeing abnormally expressed normal proteins. When you have a cancer that’s growing, just think of all the proteins that are involved in driving growth of a cell. Those proteins in cancer become very abnormally upregulated. Now the immune system is very good at telling when something is wrong. It gives the body a signal. Something is not quite right here, but the proteins are not foreign. The signal that the body gets is we have a wound that needs healing and that’s a totally different immune response. It’s an immune response that quenches inflammation, doesn’t start inflammation.

Most cancer patients, the ones with the most common cancers like breast, colon, ovarian cancer, they don’t have a lot of mutations in their tumor. The antigens or immunogenic proteins that are recognized by the tumor are abnormally expressed self proteins. The immune system responds to this because the immune system recognizes they’re abnormal, but the type of immune response that’s generated is an anti-inflammatory immune response. The immune system will not attack itself because we’re built not to develop autoimmunity. What happens is the patients mount an immune response. In most cancer patients, you can find T-cells in the tumor, but the T-cells are the type two T-cells and those suppress inflammation. In fact, they actively work against type one T-cells.

Chris Riback: What a series of challenges that must be overcome. In circling back to part of what we talked about earlier and that you explained so wonderfully about the relationship between immunotherapy and chemotherapy and the ways and timing and efforts that one might want around those, what is the status of using the STEMVAC vaccine alone versus combining it with chemotherapy? I believe, and please correct me if I have this wrong, are you still in preclinical trials on that?

Dr. Nora Disis: We have advanced to phase two clinical trials with STEMVAC.

Chris Riback: Congratulations. I’m very happy to hear it. I’m glad to be behind.

Dr. Nora Disis: STEMVAC is a vaccine that was developed to target cancer stem cells. Cancer stem cells are a very early cell that have the capabilities of being immortal. Cancer stem cells don’t respond well to chemotherapy. They don’t respond well to radiation. After you’re treated, those cells, which have been kind of immortalized, are the ones that have a tendency to come back and start growing again. They’re the ones that have the capability of causing metastases. Our concept was if we could create a vaccine that targeted immunogenic proteins that are found in cancer stem cells, that vaccine might be an excellent vaccine to prevent disease recurrence but it also might be an excellent vaccine to prevent breast cancer, especially in patients who have a genetic predisposition to breast cancer because their tumors tend to have a lot of stem cells. We developed the vaccine, engineering the vaccine specifically to elicit those TH one cells against five different immunogenic proteins that are expressed in cancer stem cells.

Much like getting the flu vaccine, you’re not immunized against one type of flu. That’s important to think about in cancer because cancer isn’t really caused by one individual protein. We focus really on creating multi-antigen vaccines. In preclinical models, in triple-negative breast cancer, which is a very STEM-y type of breast cancer, we were able to show that we could change the T-cell repertoire in the tumor from a type two T-cell to a type one T-cell with lots of killer T-cells that were activated. We performed a phase one clinical trial really looking at doses of STEMVAC in 30 patients with hormone receptor–positive and triple-negative advanced-stage breast cancer. The patients had been treated to a complete response and or had bone-only disease. We chose this patient population because we wanted to look at immunization over a long period of time.

Like I said, it’s not like chemotherapy. If you think about the COVID-19 vaccine, we had to get vaccinated to be able to achieve the level of neutralizing antibodies that would protect us. We did something very similar. We immunized patients once a month for three months, and then we gave booster shots three months after the last vaccine. Then again, nine months after that vaccine, the antigens or immunogenic proteins we were immunizing against were not mutated. They were some of those non-mutated proteins. There was a lot of concern that maybe we would precipitate autoimmune disease, but the vaccine was safe. It was very similar to the Covid vaccine. People got redness and swelling in their arm. They felt sick for a few days, but we didn’t see any evidence of autoimmunity. We found the most immunogenic dose.

What was important was the boosters. More people converted to a positive response when we gave the boosters. You might say at the end of the initial series of vaccines, those three vaccines, we had 60 percent of the patients having a high level of immunity. But after the two boosters, 90 percent of patients had very high levels of immunity, and they responded to almost all of the STEMVAC antigens. Now we have two clinical trials ongoing. One of them is a phase two study in triple-negative breast cancer—we’re almost done enrolling it—where we looked at patients who had finished their adjuvant chemotherapy and we added STEMVAC as a continuation of therapy once they were done with their chemotherapy and immune therapy after surgery. Our goal is to get more data on the safety and the immunogenicity of the vaccine, but we are going to look to see whether the vaccine can prevent disease recurrence, which is a major problem for triple-negative breast cancer.

The second study that we have is a randomized phase two study in non-small cell lung cancer, which is also a very STEM-y tumor. In this case, we’re enrolling patients who have received immunotherapy and chemotherapy. They have not achieved a complete response, but they have disease stabilization, which is about 40 percent of patients. At that time, when they go off one of the chemotherapies, a platinum drug, and they’re on maintenance immunotherapy and a chemotherapy called pemetrexed alone, we’re adding the vaccine. We hope that what the vaccine will do is to stimulate those type one T-cells while they’re still getting an immune checkpoint inhibitor, which kind of takes the breaks off the immune system. It would really let those type one T-cells flourish and hopefully push more patients into a better remission and hopefully extend their lives.

Chris Riback: Wow. Well, two studies going on, I guess it sounds like going on simultaneously addressing different types of cancers, but also at the stage that you’re at enrolling patients, it sounds like you maybe are just a little bit closer to having a fulfilled roster on the first one than on the second one, but that is a lot of juggling. Is the difference between the phase two and the phase one that you already discussed with the 30 patients, is it that the N is greater, it’s a greater number of patients, or did you do something else to increase the degree of difficulty?

Dr. Nora Disis: Yes, that’s an excellent question. We generally talk about clinical trials in terms of three phases, phase one, phase two, and phase three. Phase one is the earliest study. For us, it’s the first in-human study. The way the study is designed is really to emphasize safety, safety, safety, safety. Most phase one studies also are looking at finding the best dose to move forward into a phase two study. The phase two study is a larger study, and it’s generally designed to try to get some data on whether the drug, or in our case the vaccine, is doing what we think it should be doing. In this case, we think it should prevent disease recurrence. It will not be a definitive answer, but if the answer is encouraging, then we would move on to the final study, which would be the phase three study.

Now, those studies are big, they’re expensive, they enroll hundreds of patients, and they’re powered to give a definitive answer. In that case, a phase three study compares the new approach, in our case vaccines, with the standard of care. In the case of triple-negative breast cancer, people would get their neoadjuvant chemoimmunotherapy, their surgery, their adjuvant chemoimmunotherapy, or the exact same treatment with STEMVAC added. The question would be, do we truly prevent more recurrences in the [clinical trial] arm that got the vaccine?

Chris Riback: It sounds like I need to get on your calendar for another conversation around phase three.

Dr. Nora Disis: Hopefully in a couple of years. That’s how long it’s going to take to get, once we enroll the patients, then we have to watch them and see how they do.

Chris Riback: Okay, well, I want to reserve my spot on your schedule. I should ask you as well, if I could quickly, about another vaccine you have developed, ADVac.

Dr. Nora Disis: Yes.

Chris Riback: What is it and what does it do?

Dr. Nora Disis: Well, ADVac is a different approach. I told you that we create vaccines that engineer a type one immune response, but to create those vaccines, to engineer that type one immune response, we have to identify within a protein, all those type two fragments or epitopes that stimulate a type two response. Because what we do is we remove those epitopes from the vaccine, so we get an unfettered type one immune response. As we did this for dozens and dozens of antigens, we also validated that these type two T-cells for some of these proteins were anti-inflammatory. We started thinking about how could we use these epitopes to create a vaccine to fight chronic inflammation, because chronic inflammation is one of the things that can lead to cancer. We started thinking about a cancer prevention vaccine.

Chris Riback: Wow.

Dr. Nora Disis: One of the biggest things that we’ve come to know is that obesity causes cancer, and it’s responsible for some breast cancers, some prostate cancer, some colon cancers. What happens when people become obese is not that they develop more fat cells, it’s that the fat cells or adipocytes expand. They balloon up and they stress the system. These expanded adipocytes cause the blood vessels to be pinched and the tissue becomes hypoxic. They utilize a lot of the nutrients in the fat. Metabolic dysfunction occurs and the tissue in obese fat, these adipocytes, begin to upregulate proteins that stimulate the immune system. But in the face of all this inflammation going on, what happens is that the immune response that’s stimulated is a type one immune response. CD8 T-cells are drawn to the fat and CD4 T-cells as well. They begin to compete with these ballooned adipocytes for the nutrients, and they become extremely dysfunctional. It’s thought that over time, as this stress and inflammatory immune response continues, it causes changes in the cells that can lead to the development of cancer.

Unfortunately, the T-cells that are already there are dysfunctional due to the fact that they’ve been living in this environment without the appropriate nutrients. We asked the question whether we could develop an adipocyte-directed vaccine, and that’s called ADVac. We identified proteins that were highly upregulated in inflammatory fat, and we created a five antigen vaccine this time using the type two inducing epitopes from those proteins so that the vaccine generates high levels of cytokines, which are substances that help feed the immune response like IL-10 and those cytokines dampen immunity, like I told you before.

We hope to continue working on ADVac and bringing it to the clinic as the first vaccine approach to reduce your risk of breast cancer when you have a very high BMI so that we can buy people time to be able to correct that metabolic disorder without continuing to increase their risk of progressing to an invasive breast cancer.

Chris Riback: How extraordinary that would be.

Dr. Nora Disis:   It would be. Wouldn’t it?

Chris Riback: Yes. Yes. Given what we all read about, you certainly have the data on, but the role, just as one example, the negative role that obesity plays in so many health aspects, not just cancer, but including cancer, to be able to, if I’m understanding you correctly, help create the environment where the obesity can be disaggregated a little bit from the effect, that would certainly, that would be a big deal for sure. Along with all of the other big deals that you are working on and have accomplished throughout your career, which makes me want to ask you briefly as we close the conversation, how did you get into this all of it? Going back, where did you grow up? Was it always science for you? Did we all ever almost lose you to a career in poetry or creative writing or anything else?

Dr. Nora Disis: Yes, that’s funny. I was drawn to an English major. My mom was heavily into English literature, but I was a geek. Science was always it for me, kind of wonky. I went to college and medical school, and I loved being in the laboratory. I always found opportunities where I could work in a lab. When I was in medical school, I had a very excellent mentor who was an immunologist and really turned me on to immunology. I thought cancer was a fascinating and scary disease. I ended up marrying the two, my love for trying to figure out how to harness the immune system to combat cancer. When I went on to my fellowship in oncology, I was lucky enough to be able to go to one of the places that was the top place for immunology and cancer, which at the time I started was a long time ago. People didn’t even understand whether the immune system had anything to do with cancer. I had another wonderful mentor who really influenced my path to attack solid tumors like breast cancer. It’s been a wild ride, and I’ve loved every minute of it.

Chris Riback: It sounds like you have, it’s totally evident in the way that you talk about your work and with the very, very, very accessible comparisons as well as the wonderful detail you give around the process and shout out to mentors. They are so powerful in so many of our lives. Lastly, I would be remiss if I didn’t ask you, I know mentors have played a big role, it sounds like. What role has BCRF played in your research?

Dr. Nora Disis: BCRF has played a tremendous role. I’ve been able to launch really crazy ideas with funding from BCRF. Oftentimes, when you’re applying to the government, they practically want you to be done with the project. People are not risk averse, but BCRF, if they see an idea or something that is a spark, they encourage you to generate that data so you’re able to go on and get the bigger awards. I can tell you, our work in ADVac would not be advancing without BCRF, and it’s a crazy idea and it’s a wonderful thing to think about. It’s a project that’s going to keep us busy for a long time to come, and BCRF will be instrumental in us being able to get that vaccine to the clinic.

Chris Riback: Dr. Disis, thank you. Thank you for this conversation. Thank you for the work that you do every day.

Dr. Nora Disis: Thanks for talking with me.

Despite their tremendous potential, advancements in medicine don’t reach all communities equally. This reality is complicated by social, personal, and informational barriers. Why are Black women 40 percent more likely to die from breast cancer than white women? And why is it such a challenge to make clinical trials reflect everyone who faces breast cancer?

That’s where Dr. Sonya Reid comes in. Dr. Reid and her team are working to address these disparities in breast cancer diagnosis and treatment through research.

Dr. Reid is an assistant professor of hematology/oncology at Vanderbilt University Medical Center. Her three-year Conquer Cancer–BCRF grant was made possible by The Estée Lauder Companies’ Charitable Foundation Awards. Dr. Reid is also focused on improving healthcare delivery to underserved communities and increasing the representation of minority patients in clinical trials. She is actively involved in breast cancer research in Jamaica.

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Chris Riback: Dr. Reid, thank you for joining. I appreciate your time.

Dr. Sonya Reid: Thank you for having me.

Chris Riback: I read a powerful quote where you said, “I’ve always been intrigued and appalled by the significant racial disparities among patients with breast cancer. Black women are more likely to be diagnosed at a younger age with breast cancer. Black women also have more aggressive disease and have worse mortality.” To understand the importance of your Conquer Cancer study, which I really look forward to getting to talk with you about, I think it’s important to first establish the context and the fact that Black women are 40 percent more likely—you correct me if I have that stat wrong—to die from breast cancer, compared to white women. It’s a remarkable starting point. How do you reconcile that statistic?

Dr. Sonya Reid: Yes, it’s disheartening when you think that overall the mortality rate from breast cancer is actually reducing. But then when you look at a certain population of patients, that is Black patients, we see that there is a significantly higher burden of death among that population. And I think that’s just appalling. We know, however, it’s not one thing that’s causing that statistic. It’s definitely complex. We know it ranges from differences in social determinants of health, for example, where people live, how people live, the access to healthcare that patients are able to receive. Where they get their healthcare, we know matter, right, and whether or not they have insurance. We know all that plays into it as well. We also know that tumor biology as well as genomics could potentially have an impact or play a part in what we see as this overall disparate outcomes when it comes to survival among females with breast cancer.

Chris Riback: It’s such a potential mix. I mean, you’re talking about nature versus nurture, genetics versus social inputs. How does that end up getting unwound?

Dr. Sonya Reid: I don’t think we can say it’s one or another, right? I don’t think it’s only nature or it’s only nurture, as you said, right? But what I will say, race is a social construct. Most of the racial disparities that we are seeing in breast cancer and in other types of cancer and in health overall is really based on a lot of societal discrimination that we see when it comes to access to care as well as comorbidities that start from prevention, screening, and all the continuum of care that we see. So that’s the first thing. I always like to frame that: Race is a social construct. And it’s something that I have to even remind myself as a researcher when we start thinking about questions and how we approach a research question from the beginning.

However, we do know that there are certain aspects of breast cancer, for example, even incidence. We know that Black females are more likely to be diagnosed at younger ages. They’re more likely to get triple-negative breast cancer. So we know that there’s some differences inherent in the type of breast cancer that certain patients get versus others. Does that mean that they will have a worse outcome because they’re more likely to have triple-negative breast cancer? I don’t know if we know that answer at this point.

There’s a lot more research that needs to be looked at to say to ourselves, for example, “Triple-negative patient that’s Black, triple-negative patient that’s white, if they receive the same level of care, the same quality care, will these patients have the same outcome?” And I think that’s a lot of what fuels me and a lot of the questions that I’m interested in—really trying to make sure that we don’t blame one or another, but really then drill down to say, yes, there may be differences in biology, but once we appreciate those differences and once we know and understand what’s driving some of those differences, if we understand how to address those differences, can we then level the playing ground to allow those patients to have the same level of care?

Chris Riback: It’s such a fascinating approach for someone like me to hear about from someone like you. You’re a researcher, you’re a scientist. I would think about the genetics. I would think about hearing, how can we get at the heart of the genetic makeup and how could potentially CRISPR be a tool so that we could start to affect the genetic approach going forward? But it’s both, is what I’m hearing from you. It’s, yes, let’s get at that genetic answer, but you’re a scientist, you’re a researcher, you’re not about to ignore the potential social inputs as well.

Dr. Sonya Reid: Absolutely. And I think, as I mentioned the fact that we know race is a social construct and a lot of the data that we have today always does Black versus white, and look at it across Black, white, Asian, other, Hispanic, non-Hispanic, white, et cetera. But what I think we have missed is the opportunity to look at ancestry in a lot of our studies. And I think it has been done now more recently, where we’re really trying to understand, being Black, looking at it from a race standpoint, we know it’s different if you’re from West African ancestry versus East African ancestry, for example. We know that there are differences in incidence and even mortality rates depending on where your ancestry originates. I actually think that’s something that we maybe need to layer on, not just looking at race, but also trying to understand, are there underpinning from an ancestry standpoint that could be contributing to some of these differences we see in incidence as well as mortality rates?

Chris Riback: So you need to be an oncologist, a sociologist, a genealogist, and with some of the locations perhaps that you get to go, a bit of an outdoor explorer as well. I don’t know how –

Dr. Sonya Reid: Yes, a little bit. A little bit.

Chris Riback: Terrific.

Dr. Sonya Reid: It’s complicated, right?

Chris Riback: It’s complicated. But I would assume also that that really keeps it even more interesting and must fuel the curiosity that must drive somebody like you.

Dr. Sonya Reid: Absolutely.

Chris Riback: That’s what I expect. So let’s get, if we can, to the main event. What is your Conquer Cancer study? What questions does it seek to answer? What is your hypothesis? How is the study structured?

Dr. Sonya Reid: Great question. So my Conquer Cancer study, which is funded by BCRF, is essentially trying to understand differences among patients with hereditary breast cancer. So essentially, we’re recruiting patients that have breast cancer and a germline mutation in either BRCA2, BRCA2, PALB2, CHEK2, or ATM. And we are creating this very diverse cohort, which essentially we’re leveraging our partner groups that have more diverse representation of patients to make sure that we have approximately a 20 percent or higher minority enrollment rate was one of our targets that we set out to achieve.

But we’re trying not to only understand the differences across these different mutation carriers, but really trying to understand how that may differ across different race and ethnic groups. So once these patients are enrolled, we will then do tumor profiling. So patients will have DNA and RNA sequencing done on their tumors for us to truly understand even tumor development and how we can perhaps refine treatment in the future for patients with hereditary breast cancer.

Chris Riback: Where are you in the study?

Dr. Sonya Reid: I think we’re more than halfway with enrollment. And I will say we have met our accrual goal when it comes to diversity. So that’s something that we’re super proud about, but of course, still more work to be done. So we continue to partner with our different research collaborators and patient advocacy groups, because we truly want to ensure that we don’t only understand how these differences may be accounting to maybe some of the disparities that we’re seeing in outcome, but truly do a deeper dive as it relates to how does this differ across different ancestry, because that’s another future goal of this endeavor, for us to then look at not just race, but how does that intersect as it relates to ancestry of these patients that are diagnosed with hereditary breast cancer?

Chris Riback: So Dr. Reid, the obvious question that anyone would want to know, what’s next?

Dr. Sonya Reid: So that’s a big question. And I think I alluded to some of that as it relates to the ancestry studies that we will be performing. But another passion of mine is really increasing the diversity in clinical trials. And for example, I’m a part of a pilot study that we’re doing here at Vanderbilt in breast center, where we’re truly trying to engage the community to increase the patients, the diversity of patients that actually come through our doors at Vanderbilt, right? Because we do know that in order to increase diversity in clinical trials, it really matters when we think about the patients that you’re seeing. We know that most patients that get treated for breast cancer actually get treated in the community. About 80 percent are treated in the community, yet most of our clinical trials are in academic centers.

So I think that’s one lens that we need to make sure that more clinical trials are actually in the community where patients are being treated. But as an academic center, which is where I practice, one of my endeavors that I’m working alongside some of my colleagues here to focus on is how can we be patient-facing, have those inputs in the community to increase minority patients that come through our door, and then increase minority patients that get onto clinical trials? Hopefully then this concept would be something that we could roll out across different disease types here.

Chris Riback: Why is it such a challenge to increase the representation of minority patients in clinical trials? Is this a challenge of supply or demand? It would seem to me, sadly, that there’s no shortage of supply.

Dr. Sonya Reid: Right. No, great question. And even with my Conquer Cancer award, it’s embedded in the fact that we’re leveraging different organizations, different patient advocate organizations, as well as different research organizations that we know have more diverse representation, because again, my intentional focus with this study is to make sure we actually over-represent Black patients in this study. And so far, I would say that we’re meeting that target where we have more than the 13 percent Black patients in this study, which is something that we’re super proud of. But again, that takes intentionality. From the get-go, we decided to align ourselves with different groups that we know we could leverage because we truly want to understand, how do these different clinical pathological differences that we’re trying to unravel, how does that look across different racial ethnic groups? Unless we are intentional when we’re starting out different projects, I think we will continue along that cycle where we exclude these groups, if we’re not intentional about included them in our research projects.

Chris Riback: Earlier in the conversation you were discussing that the ways to get at the heart of the role or not role, or the amount of factor or not amount of factor, of race in breast cancer instances and outcomes was you described wanting to understand the genetics and the biology, but then off of that establishment or some level of establishment, then also move into the social components. Does this study help advance you in that first part in terms of the biology of the understanding? And then the other part, how do you connect what we’re talking about right now to the first part of the conversation? Did I interpret that correctly?

Dr. Sonya Reid: Absolutely. So because now we will have this cohort essentially that we expect by the end to be over 200 patients with breast cancer and a germline mutation, we will then be able to sequence their tumors to try to understand from an actual tumor standpoint, looking at the somatic mutation, again, now we’re looking at even tumor development. Does that differ across different racial ethnic groups? And of course, we’re able to understand these things better when we have a representative sample. So we will be able to look at patients’ tumors, of course, we’ll have treatment information, we’ll have clinical information from beginning to survivorship essentially. But one of our future goals is also to be able to look at ancestry, because we would then be able to look at RNA  sequencing data and then leverage that to then look even within this cohort to understand how ancestry impacts some of the differences or similarities that we may see across patients with hereditary breast cancer.

Chris Riback: And I know that maybe it’s a related priority of yours, is improving healthcare delivery to underserved communities. Is that where this leads? Is this a baseline for affecting-

Dr. Sonya Reid: Yes, yes.

Chris Riback: Tell me about that, please.

Dr. Sonya Reid: Yes, because a lot of times we think about hereditary breast cancer, how does one know that they have hereditary breast cancer? If you are not tested, if you are not offered genetic testing, you would not even be a part of this study. And we know that minority patients are not offered genetic testing as they should, for whatever reason. I think that’s a whole other conversation. And we know that once they’re offered and it’s explained that they’re just as willing to want to understand whether or not they have a gene that could change their treatment course.

The bottom line is not only for this study, but to answer your question as to access to care, et cetera, I think we need to really try to make sure that we’re making information available to the community, so community awareness and patient education as it relates to: What is genetic testing? What is hereditary breast cancer? What does that mean? Can that help me? Can that improve my outcome? Answer is yes. But why didn’t I receive testing? And how can I now get it?

So part of our study, and a lot of the groups that I partner with, that’s actually a part of our initiative, to make sure that we are not just educating patients, but once a patient is interested, they actually offer testing for free. We know that we have a group of patients that not only have they not been offered genomic testing from germline to even tumor sequencing, that really changes one’s treatment path, but they’re also not offered clinical trial as equal as their white counterparts.

So I think we need to make sure when we’re tackling that whole thing, when we think about access to quality care, we need to make sure that we understand the reason why this is so critical. Because we now have over the years, have kind of, I would say, maybe even keep widening these disparities. We now have PARP inhibitors, where PARP inhibitors are a treatment for patients that have a germline mutation in BRCA1 or BRCA2 as it relates to breast cancer. So we know that treatment with a PARP inhibitor will improve outcomes, improve survival. These patients will live longer, is what this means, if they know that they have that mutation.

But if a patient doesn’t know that that treatment even exists, because guess what, they were not tested, that patient then don’t get offered it. Now we have an advancement, and the disparity continues to widen. So I always say whenever there’s a treatment advancement and we don’t ensure that all patients, whether rural, urban, Black, white, can get access to that advancement, in this example, a PARP inhibitor, when you have a BRCA1 or 2 mutation, if we’re not able to make sure that that advancement reaches all our patients, we will continue to see widening disparities in breast cancer, unfortunately.

Chris Riback: Well, and that’s just a terrible gap, because now you’re talking about something where there actually is something that could be done where the positive impact on the patient is not being made, not because the cure or the help hasn’t been found. It’s because they don’t know about it, the communication isn’t there, the testing. It also makes me think, you mentioned it very, very quickly, but I know from other conversations how important and deep of a role these partnerships play, because getting to those communities … I assume that you’re in Nashville right now as we’re talking.

Dr. Sonya Reid: Yes.

Chris Riback: But obviously you work at Vanderbilt. You’re not on the ground. You might be on the ground at certain periods, but you’re not on the ground at these locations 24/7. Those partnership relationships are everything, aren’t they?

Dr. Sonya Reid: They are. And these patient advocate groups are our champions. They are the true heroes, because the groups not only allow us to partner, but they also inform how we carry out our research. They’re the ones that a lot of time allow us to say, “Maybe we didn’t think of this right. Maybe this is the true question.” And a lot of times, I think what we have realized as a research group these days is that engaging them earlier in the conversation to actually help us as we develop a lot of our research questions and strategy, it’s critical for us to really move the field forward.

Chris Riback: Well, that is spoken like a true researcher who knows that great questions can come from anywhere.

Dr. Sonya Reid: Absolutely.

Chris Riback: I’m sure you’re keeping your ears open for them all the time. So let me ask you then another question, which is about you. Let’s talk about you. How did you get into this? And I mean, going back. I know that you grew up in Jamaica, but maybe you can talk about that. And was it always science and math for you, or did you have other interests that were going to take you in a different direction until the science community grabbed you and didn’t let go?

Dr. Sonya Reid: Wow, that’s an interesting one. It has always been science. I think that I knew. I actually always knew I wanted to be a doctor from very early. I don’t think I had honed in on what type of doctor. But yes, so science was always there, and going into medicine was always there. What I will tell you, I never thought I would fall into this passion, I always call it, because I never really thought about it initially, that there was a career maybe looking at disparities and breast cancer and all that. That’s really, I guess, something that more evolved over time. But I really think it started with my upbringing in Jamaica, if I’m being honest. Because growing up in an island where a lot of times opportunities for quality care is not afforded to our patients because of lack of resources, to put it very plainly, a lot of times patients just cannot afford different treatment, maybe it’s not even available in the country, then they just can’t afford it.

So I was faced with that growing up, and understood it very clearly. I went to medical school in Jamaica, so I saw that firsthand, spoke to patients in hospice settings, where sometimes patients in hospice, in my mind, I’m like, “Did they need to not get treatment?” In my mind, when you read the textbook, you would think, “Oh, but there is a treatment for this.” But they couldn’t get in to get treatment, or they got diagnosed at late stages because they didn’t get access.

So just different issues that really weighed on me, I believe as early as medical school, where I saw that just lack of resources essentially caused patients to die. And then I came to the United States for my residency training, and I saw a lot of the same issues.

Chris Riback: Interesting.

Dr. Sonya Reid: And I think that’s when a bell went off in my head, to be honest, because I thought to myself, “In this country where it’s a developing country you see some of these disparities.” But when I came to the US and you think, “Oh my gosh, there’s so many resources here,” but then I saw patients that had no insurance or under insurance, or Black patients in the county hospital here in Tennessee, that it’s almost as if I was right back in Jamaica. And I think it was appalling. I think at that point I was like, “How could this be, in this day and age, patients are not able to access a healthcare system because of just who you are?” So I guess that is full circle, really finding something that fueled me. And I really thought if I could be one person to try to be a part of the change, and that’s how I decided to go into breast cancer and breast cancer disparities.

Chris Riback: You’re taking your ideas, which are at the center of your work, but you have a team. You have partnerships in various countries, in various communities. You’re reaching out to various groups. So you are a person in the ecosystem, let’s say. But what I’ve learned among the things that I’ve learned from these conversations is I know you all feel the same way, that you’re one person, but you have such a powerful network. And that just grows everything exponentially.

Dr. Sonya Reid: Absolutely.

Chris Riback: Speaking of networks, how would you characterize, what role has BCRF played in your research and this Conquer Cancer grant supported by The Estée Lauder Companies’ Charitable Foundation Awards?

Dr. Sonya Reid: The Breast Cancer Research Foundation has been amazing. So this project would not have been funded without the Breast Cancer Research Foundation. So that’s for starters, that it has funded this idea that really started out as a junior faculty, just someone supporting your idea and funding that idea to allow me to have protected time to do this research is huge. I am very honored to be able to partner with such an organization. In addition, being able to collaborate with other BCRF awardees had been great because you can hear everybody else’s idea that practices across the different states and really pull from that energy and those collaborations. And I think that has been truly impactful as well.

Chris Riback: Yes, it’s a very, very powerful, fascinating, and energized network for sure. To close, and it’s funny because nearly all the comments I read about you and from you in preparing for this conversation mentioned this, and then you just used the word a moment ago, and that’s passion. It totally came across how passionate you are about your research. It came across in what I was reading. And it now has come across, of course, in this conversation. Why does passion matter? I mean, Dr. Reid, this is science. Many of us are led to believe that science is meant to be a dispassionate study of reality. Why does passion matter?

Dr. Sonya Reid: I think science is fun. I truly think that. I think it’s something that fuels discovery. It fuels the reason why I keep doing what I keep doing, keep fueling when I’m in that clinic with that patient and we’re running out of options. It actually fuels me to do more research to try to figure out how could we better treat these patients? That way I’m not here 10 years from now trying to tell someone that I don’t have any better option for you. So I think that passion truly keeps science alive. It keeps hope alive, because when you’re dealing with a disease like breast cancer that we have seen it, right? Mortality rates have continued to decline, albeit because of better screening, better treatment.

But I think when we’re not able to give those treatment advances or those better strategies to all of our patients, I think that’s something that without passion and with us just keep allowing it to just pass us by and we hear it, it’s almost like it reels off your tongue nowadays. I told someone recently, if I hear that 40 percent higher mortality rate one more time, I may scream, because you hear it over and over again. And I think we have been hearing it for a while now. And it feels like it’s not going anywhere. Unless we have enough people that are passionate enough about that to make a difference, then we’ll be here in years to come as well.

Chris Riback: Well, I hope that we are here in years to come, but talking about new topics and new advancements, many of which will have been constructed and advanced by you and your team. Dr. Reid, thank you. Thank you for your work. Thank you for your time. Thank you for your passion.

Dr. Sonya Reid: Thank you for having me.

While our culture and media often reduce scientific brilliance to individual minds, great advances are accomplished through collaboration.

Over recent decades, innumerable scientific accomplishments illustrate the impressive capacity of researchers, clinical scientists, and of course, their patients. But to operate well, these networks can’t just be pointed in the same direction; they need to be speaking the same language and working together.

This is where translational investigators like Dr. Ian Krop come in. His efforts, insights, and understanding not only connect labs to clinics—balancing resources, research, and opportunity—but they also underscore the importance of centering patients in research.

A BCRF investigator since 2017, Dr. Krop is the chief clinical research officer and associate cancer center director for clinical research at the Yale Cancer Center. Dr. Krop also currently serves as chief scientific officer for the BCRF-supported Translational Breast Cancer Research Consortium. He is a member of the National Cancer Institute’s Breast Cancer Steering Committee and co-chairs its Immuno-Oncology Working Group. He is also the co-vice chair for correlative science for the Alliance for Clinical Trials in Oncology.

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Chris Riback: Dr. Krop, thanks for joining me. I appreciate your time.

Dr. Ian Krop: I‘m happy to be here. Thanks for asking me to talk about this.

Chris Riback: Before we start with your area of focus, I‘d like to better understand how you think and how you see the world. What is a translational investigator?

Dr. Ian Krop: So that‘s a really good question, and this idea of a translational investigator is certainly not a one-size-fits-all kind of moniker. But essentially, we have a large number of very smart scientists in laboratories trying to understand the basic mechanism of cancer, what drives a cancer, what are cancer’s vulnerabilities? And we have equally smart people in the clinic who are doing clinical trials to test new drugs and take care of patients with cancer. But for the scientific discoveries to become useful drugs, there needs to be somebody to bridge the gap between these two groups of investigators. And that’s essentially what a translational investigator does, is it basically translates the basic laboratory scientific discoveries about cancer into useful information, useful drugs, so that we can actually help patients. And so what that means is helping develop drugs from the, taking advantage of insights from the laboratory and figuring out how to best use those drugs.

And it goes the other way, too. It means looking at the results of a clinical trial, looking at the tumor tissue that was obtained as part of that trial and trying to understand why a particular drug works well in one patient but doesn’t work so well in another patient. And so looking at, are there molecular features of a cancer that allow us to figure out why a drug worked in one person and not another? And then take that back to the laboratory people and say, “Okay, here’s what we think is going on. Can you help us figure out a way to overcome this particular obstacle for this particular type of tumor so that the drug works in more people than it did originally?” And so that we don’t treat patients with drugs that don’t work, identify which patients are going to benefit upfront and which ones aren’t. So that again, we can personalize our therapies for the people for whom they’re going to have the most benefit.

So that’s really the role of a translational investigator, to help the laboratory discoveries get into the clinic and help the clinical discoveries get back to the laboratory so they can be further improved for the next generation of drugs.

Chris Riback: So, among your chief scientific skills is the fact that you’re multilingual, you speak laboratory and you speak clinic fluently?

Dr. Ian Krop: Yes. Unfortunately, I don’t speak other languages. So, when I travel it’s not very useful. But I do speak both the lingo of basic science and the lingo of clinical research of clinical trials. And I think that’s, and that’s really a prerequisite for doing this kind of job because you really are the conduit between these two groups.

Chris Riback: I was going to joke and say, well, that’s why Google Translate exists to help you with your travels. But then I started to think, well, in a way you, people like you, are kind of the Google Translate between the labs and the clinics. I’ve had the privilege, the benefit of getting to speak with other researcher scientists who are involved in translational medicine. And the conversations really are fascinating because each time and each scientist, in their own way, what they learn from the clinics and then bring to the labs, but then what they do in the labs and then bring to the clinics. And I understand the unique role that you have, but there is those two, bringing those two parts together is just central to making progress holistically. But also, as you were just saying individually and making sure that you’re helping folks one patient at a time.

Dr. Ian Krop: Not all translational investigators are actually taking care of patients, but it certainly makes my life much more satisfying and enjoyable to be able to meet with patients on a regular basis and see the impact of all of our work, all of us who are doing involved in cancer medicine and cancer research, to see how much impact there’s been. Because there really has been a tremendous amount, I’ve been doing this for about 24 years or so, and just in my professional lifetime, what’s happened is really extraordinary in terms of where we were when I started and where we are now. And obviously, we still have plenty of room to go and everything always is slower than we would like it to be. But objectively, if you look at where things were 20 years ago compared to now, it’s really night and day.

And in fact, 20 years ago, there probably wasn’t a real need for translational investigators, or at least we didn’t really appreciate that because the state of science was such that there wasn’t so much to translate. It’s only been more recently where the way we developed drugs is so much more rational. It’s not just, “Here’s a thousand different chemicals, let’s try each one on a Petri dish cancer cell and see what kills it.” Which is in some extent the way drugs, cancer chemotherapies were developed back in the day. And so, there wasn’t really a need to translate that. It was just, “Okay, this drug seems to work, let’s go try it in patients.” Now that virtually never is the way we develop drugs. Now, almost everything is, “Okay, someone identified, someone in a laboratory identified a particular pathway into cancer that seems like it’s a potential vulnerability. Let’s design a drug that hits and inhibits that pathway and then we’re going to take it into the clinic.”

And so, there’s a much more rational, science-driven approach to drug development. And because it’s so much more sophisticated there, it’s basically necessitated the need for us translational investigators, to do the translation that you just alluded to because it’s just so much more complicated. In a good way. But again, it requires this type of person, whereas before there wasn’t so much of a need. And unfortunately, I mean because this is a relatively new profession, there has needed to be a lot of work in medical schools and in cancer centers to develop this role because these people didn’t exist before.

Chris Riback: With the added complexity that you are describing though, I assume that the partner of that complexity is greater precision, greater customization. Perhaps, you correct me if I’m wrong, maybe less, I’m hesitant on the word guesswork, so I would absolutely put it in quotes, but more precision with individual patients with, there’s more complexity involved, but that is resulting in better opportunities. Again, you correct me if I’m misinterpreting this.

Dr. Ian Krop: No, I think they’re exactly right. When I started, the number we tossed around in terms of the percentage of early-stage clinical trials of a drug that actually worked was less than 5 percent. So, in other words, 95 percent of drugs flamed out early on because there was a lot more guesswork involved back then. Now we’re surprised when drugs don’t work because they’re just designed, as you were pointing out, they’re just designed in such a more targeted way for the particular patient’s tumor that they tend to work now. And we still need to tweak things and there may be unexpected findings, but we’re starting in such a better place now because of all the work that was done to get the foundation that was built to that, were now just doing everything in a more sophisticated way because under our scientific understanding, our scientific tools are just so much more effective than they used to be.

Chris Riback: So I want to get into one of maybe your particular area focus, HER2-positive breast cancer area. But before I do, just in listening to you and your use of the word, a couple of times—impact—and it’s feeling evident to me that that’s an important result for you, feeling both factual and tangible, but also on some level emotional or a feeling, a positive feeling that you get. And I mean you lead clinical research initiatives at Yale, and on the one hand, what an incredibly inspiring opportunity to have such potential impact on such important work. And yet at the same time it must be very intimidating because any organization has a limit at some point on its resources and you have to help make very hard decisions. How do you think about that balance?

Dr. Ian Krop: Fortunately, we’re in an era where there are resources available to do good science and that’s resources from biotech companies, from NIH, and the Natural Cancer Institute, which funds a lot of research. And then we have foundations and I’d certainly be happy to talk about how BCRF has impacted my research and allowed me to ask questions that I wouldn’t have been able to ask otherwise. But I think the question of just what is the scientific strength of a particular question now is really the strong driver of what goes forward. I mean, there’s always going to be some guesswork because none of us have crystal balls. But now because science is driving things so much rather than more random kind of, as I said, choice of chemical one versus chemical two as a drug candidate, because science is driving things, you can really be objective.

Actually I just spent the last two days reviewing grants for trials, proposals, and you can sit around, and you can objectively say, “Hey, this science is really strong, and I think this is going to therefore have a very good chance of helping patients. So, I’m going to fund that. This one really needs more work and I’m going to send this back for revision.” Now we’re at a point where we can adjudicate things based on the strength of the science and allocate our resources that way. Again, because everything is just being done in such a more rational way than it had been before. And of course we also can are influenced by the need. There are cancers where the unmet, unfortunately, there’s a huge still unmet need and we need to devote more resources there. And so that factors in as well when we review things, is this going to be the seventh drug for a particular cancer context or is this the first? And obviously that should factor in as well.

Chris Riback: What is HER2-positive breast cancer?

Dr. Ian Krop: Well, I’ll start from the beginning. So HER2 is a protein that sits on a vast, a large number of our normal cells. And its job is to tell that cell under situations of stress, “Hey, we need to toughen up and we need to grow faster, and we need to be resistant to toxins and we can’t afford to die.” So, it’s kind of a stress response protein is what we call it. And again, it’s a normal protein. Usually a cell has a thousand or a few thousand of these guys sitting on surface sensing situations of stress. But in about 15 or 20 percent of breast cancers, as they’re forming, there’s an alteration in their DNA that leads to duplication of the gene, the of the DNA that codes for this HER2 protein.

Normally every protein has two copies of a gene in these subsets of cancers because of this. What this mutation essentially that happens in the DNA, they end up with 20, 30, 40 copies of the HER2 gene and the genes are the blueprints for the protein. So now instead of the cell working off two copies of the blueprint, they have 20 and each blueprint is making protein. So what happens is you get way too much of this HER2 protein. So, in these 20 percent of cancers of breast cancers, they have instead of a few thousand copies of HER2, they have a million or 2 million copies on each individual cancer cell.

Now if the job of that HER2 protein is to tell the cell to get more aggressive and grow more quickly and not to die, and you’ve got now millions of these guys each telling the cell to do that, it’s not a surprise that these cells start growing more aggressively and become resistant to death and can become very problematic.

So, when I first started as an oncologist around 1999 or so, having a patient be identified as having HER2-positive breast cancer was a scary thing because we knew those cancers were going to grow more quickly and they were at a much higher risk of recurrence, and they were tended to be resistant to standard things like chemotherapy. So we all dreaded finding out that a patient was HER2-positive.

But right around that same time, it was recognized by several individuals, laboratory scientists, and probably one of the first, one of these early translational scientists, a guy named Dennis Slamon, that the reason these cancers were behaving this way was because of this over expression of this HER2 protein. And once that realization was made, it led to the development of drugs that blocked that HER2 protein. And the first one of those was a drug called trastuzumab or known as Herceptin®.

And that was one of the first demonstrations because when they took the AT protein and they injected it into patients with HER2-positive breast cancer, along with chemotherapy, it dramatically improved the effectiveness of the chemotherapy, and the survival increased dramatically. And it was one of the first demonstrations if you can identify what’s driving a cancer, you can make drugs to block that driver and that can have really dramatic effects on your ability to kill those cancer cells. So, it’s one of the first examples of targeted therapy that really kind of changed our mindset of what understanding the driver of a cancer can do in terms of leading us to effective therapies.

And in HER2-positive disease, this Herceptin really changed the outcomes of patients for the better. Not only did it treat people with advanced HER2-positive breast cancer and extended their survival, but it markedly, by half, cut the number of patients who had early disease after they had their lumpectomies or their mastectomies for their cancer cut down the number of patients who had recurrences down the road by about half. So it really revolutionized the treatment for HER2-positive breast cancer and led to many other HER2 directed therapies. But it also kind of really opened the door to this idea of targeted therapy, not only in breast cancer but in other cancers. So that’s kind of the very quick high-level summary of HER2-positive breast cancer.

Chris Riback: It’s a terrific summary and the visual of those HER2 proteins—millions of them communicating and over-communicating and over-communicating to negative cells, cells doing bad things. Yes, that’s a very powerful and upsetting visual, obviously. However, as you just described, there’s been the work with the Herceptin and chemotherapy. And now as I understand it, and you’ll correct me please if what I have wrong, your clinical trials are testing the benefit of immunotherapy in combination with Herceptin and chemotherapy in advanced HER2-positive breast cancer.

What is your hypothesis? What is the status of the trial? I understand you may be seeking or were seeking a total of a hundred patients for the trial. Have you gotten there yet?

Dr. Ian Krop: Yes, so you’re spot on in terms of what we’re doing in this particular trial. So, you know, you could say, well if we’ve got this great drug Herceptin and we’ve got other drugs, second and third-generation drugs like it, are we done with HER2-positive breast cancer? And in fact, it’s now in many ways better to have HER2-positive breast cancer than almost any other kind of breast cancer because now with the advent of HER2-directed therapy, people do extraordinarily well, and recurrence rates are way down and people with advanced disease are living much longer.

But in patients with metastatic disease, which is when cancer spreads beyond the breast, even in HER2-positive disease in most patients, unfortunately, eventually the cancers become resistant to all of our therapies. We have eight or nine of these HER2 therapies now. But in most patients, eventually the cancer learns to be resistant to all of them. So, there’s still a need to do better even in HER2-positive disease. And there’s a lot of different approaches being tried.

But the one that we had been working on recently, and the one that BCRF is most correctly helping us with, is asking this immunotherapy question. And many people have started to hear about immunotherapy, but just so we’re all on the same page, what immunotherapy from a cancer context anyway is, is trying to teach our own immune systems how to fight a person’s cancer. It turns out actually that while we think of the immune system as fighting off strep throat and the flu and COVID, bacteria and viruses, it’s also designed to fight off cancers and there’s the idea that people develop cancers, little microscopic cancers all the time, but most of the time our immune system recognizes that they shouldn’t be there and the immune system just goes in and wipes them out before they ever amount to anything.

So, our immune system is designed to kill cancer cells, but for some reason, and we don’t completely understand this in some patients, at some time, the immune system doesn’t recognize a budding, nascent cancer as being foreign and for whatever reason doesn’t attack that and allows the cancer to grow. So essentially when a person has a cancer that’s diagnosed, it means that for whatever reason, that person’s immune system wasn’t able to effectively kill off that cancer cell. So, the idea is of an immune therapy is to help that person’s immune system recognize and effectively kill off the cancer. Like it was essentially originally designed to do.

And we’ve made enormous strides in that area. We’ve identified some of the ways that the cancers suppress the immune system, and the field has developed drugs that prevent the cancer from suppressing the immune systems. It’s kind of like a double negative there. But by using these drugs, it allows the cancer basically, I’m sorry, it allows the person’s immune system to wake up and start attacking the cancer because the cancer can’t suppress the immune system anymore. And that’s really when we talk about immune therapy right now, that’s what we’re talking about. We’re talking about drugs that allow, that prevent the cancer from suppressing the immune system so the immune system can reactivate and attack the cancer. And those have been extraordinarily effective. Extraordinary effective in a number of cancers where there really were very few options in the past, like certain kinds of lung cancer and melanoma and kidney cancer, those have just been revolutionized by the development of immune therapies.

In breast cancer, immune therapies have been a little bit harder to develop, but there are now several that are approved in a kind of cancer called triple-negative breast cancer, but so far not so in HER2-positive breast cancer. Which is in some ways a little surprising because in fact we’ve known now for years that one of the ways that Herceptin, the first drug to target HER2, not only does it block HER2’s function to some extent, but it also kind of alerts the immune system that this cancer is there and kind of attracts the immune system to attack the cancer.

But very, it turns out it’s a pretty weak stimulant of the immune system, but we know that there is some ability there for the immune system to work against HER2-positive cancer cells, but it’s quite weak compared to other immune effects. And so, our hypothesis was, “Okay, there is some ability of the immune system to attack a HER2-positive cancer, but what can we do to build that up so it becomes more effective and have a bigger impact. Especially in these patients whom for whom our regular HER2 directed therapies have stopped working.” So that’s kind of the general idea of this.

Our first hypothesis was what can we do to stimulate the immune system beyond where we already are? And the way we tried to address that hypothesis was to say that there already, as I mentioned, there are approved immunotherapies that stimulate the immune system. Those had been shown to have a pretty modest effect if maybe even less than modest effect, in HER2-positive disease. But what we wanted to do was combine Herceptin with these immune therapies because we said Herceptin already has a little bit of an immune effect. Let’s add these approved immune therapies or at least approved for other cancers. Let’s add that to Herceptin and chemotherapy.

And as a further way to push the needle, take completely a very novel immune therapy, a drug that hasn’t been approved, only just recently developed, which is targets a slightly different part of the immune system; let’s test that too, because there’s a number of laboratory studies saying that that could be particularly valuable in HER2-positive disease.

Chris Riback: Is that AVIATOR?

Dr. Ian Krop: So the trial is called AVIATOR. The central question in AVIATOR was can we take patients who had HER2-positive metastatic disease that had already developed resistance to pretty much all of our usual therapies and compare what was available at the, what was standardly available, which was a different chemotherapy with Herceptin, to that same chemotherapy and Herceptin, but add the more standard immunotherapy or add all four drugs. So chemotherapy, Herceptin, and both the older immunotherapy and the newer immunotherapy. So fortunately, these immunotherapies are pretty targeted. So, you can use four different drugs together without making it have too many side effects. If you tried to do that with chemotherapy, that wouldn’t work. But we’re adding, we’re testing basically three targeted therapies and one chemotherapy, and so you can combine those safely.

So that was idea of the AVIATOR trial was to randomly compare a standard regimen with one plus against standard therapy plus one immunotherapy or both immunotherapy. So it was a pretty ambitious approach, but we felt that it was, this was the right time to try that, given all of the science behind it, saying that in the laboratory, this kind of four-drug combination could work really well in patients with this HER2-positive kind of breast cancer.

Chris Riback: And where are you in the trial now?

Dr. Ian Krop: So funny you should ask that. So you were correct that we needed to enroll a hundred patients, 40 patients got one immunotherapy, 40 patients got two immunotherapy and 20 patients just got the chemotherapy and the Herceptin. But if in those patients, if that didn’t work, they could then get immune therapy. So, it was a hundred patients, and literally yesterday I got the notice that the final hundredth patient was enrolled.

Chris Riback: Wow.

Dr. Ian Krop: So your timing is impeccable. We are now finished enrollment, and so we now are waiting to allow patients to see how they’re doing on these three different kinds of treatment.

Chris Riback: Wow. Well you want to break any news here?

Dr. Ian Krop: We need to wait to see how these drugs work. We haven’t analyzed the results, but we’re very excited to finish enrollment. And now we’re hoping that patients stay on these therapies for a very long time. And it’s going to take, we hope that it takes us 10 years to analyze it because that means that patients stayed on these therapies for a very long time. But anyway, it’s excited to have finished enrollment and we will hopefully have the results in the not-too-distant future.

But I would say that not only one of the nice things about a trial like this, and with BCRF support we’re allowed, we’re able to do this, which we wouldn’t have been able to do if this was just us [and a] company, a study that would be supported by a pharmaceutical company. What we’re able to do is do biopsies of the patient’s tumor before and during the treatment.

Chris Riback: Wow.

Dr. Ian Krop: And by doing that, and we’re very appreciative that patients are willing to undergo these biopsies because they know it’s going to help the science and help us make progress, but what we are able to do with those biopsies is really understand at the molecular level what these different drugs are doing, how the immune system is being stimulated, how is it being stimulated in one patient and not in another patient? And does that help us understand how all these different drugs are working together and hopefully give us clues on if they’re not working in each patient, what we can do to supplement that so that they do work.

It also allows us to understand how the cancers could become resistant, either to the particular therapy that we’re giving or by looking at the biopsy before they even start, why did the patients be developed resistance to the last two or three drugs that they were on? So, there’s a lot we can learn. And this is that translational aspect of, yes, we’re testing a drug, but we also want to learn as much as we can about how the tumor’s behaving so that we can then develop the next drug.

Chris Riback: You just touched on yet another point that runs true through these conversations that I’m so fortunate to get to have, and that just is the courage and selflessness of patients who enter trials, literally give of themselves. And it is to help folks like you be able to help them and help unfortunately the people to come. And yes, you just phrased it so well about what the patients in your trial are doing and their courage is always very, very inspiring to me.

Dr. Ian Krop: Yes, and to me too. I mean, it’s one of the most satisfying aspects of this job and why I feel so very fortunate to be able to work in the clinic as well as in the office, is to see the heroism of women who are—[and it’s] mostly women—who are dealing with very difficult circumstances. And yet almost always ask, “Well, what can I do to help figure out how we can beat this thing, not just for me, but for all the patients who are going through this.”

Chris Riback: What role has BCRF been able to play in your research?

Dr. Ian Krop: Biopharmaceutical companies spend an enormous amount of money developing drugs. They’ve helped us make great progress, but their job is to develop drugs as quickly as possible. And when they design their trials, they’re usually fairly straightforward. What do we need to do to get to the next step of drug development? And we partner with them all the time. We do trials with pharmaceutical companies support all the time because it really has led to a lot of breakthroughs, but it’s harder to ask the kind of questions that we’re asking in this trial. Again, not only does drug A help versus drug B and whether one immunotherapy or two immunotherapies, but as we’ve kind of talked about, by looking at these biopsies, can we understand more fundamentally why one drug is working and another is not working in a particular patient but may work in another patient.

Why does the cancer respond initially, but then six months or a year later, stop responding? Those are questions that if we’re really going to make progress in the big picture and long term, we need to get at that. And that takes both contributions from the patients allowing us to obtain these biopsies. And it costs money to do the biopsies, it costs, the sequencing the DNA of these cancers is expensive. All those things cost a lot of money, but it’s the way to really understand fundamentally what’s going on. And that’s something that BCRF was incredibly generous in supporting, not only this pretty large trial that took several years to carry out, but add on these additional fundamental tests that we are doing to both to help figure out how to use these particular immunotherapies, but also hopefully learn more about how breast cancer’s behaving in general.

So that’s something that BCRF has allowed us. I mean, they allowed us to do the trial at all, but really went beyond that to say, “Okay, you can also to learn as much as possible from this trial from our patients. Do these extra biopsies, do the extra molecular testing that’s going to yield hopefully the really key information that we can use to make progress.”

Chris Riback: Dr. Krop, thank you. Thank you for your time. Thank you for the work that you do.

Dr. Ian Krop: Sure, my pleasure. Thanks for giving me the opportunity to spread the word.

Of breast cancer’s many realities, one of the most confounding is the possibility that the cells can travel, hide, be gone, and then reappear as cancer in a new location. It’s called recurrence and metastasis. Researchers like Dr. Angela DeMichele are exploring paths to find out why that occurs, and how it can be stopped.

Dr. DeMichele is a professor of medicine and epidemiology at the University of Pennsylvania, where she leads a multidisciplinary team conducting novel clinical trials including a BCRF-supported phase 2 trial called PALAVY that is focused on answering: How might dormant cancer cells lead to a clearer understanding of the cancer in remission? And what leads some cancerous cells to behave differently than others?

Dr. DeMichele is a member of the NCI Breast Cancer Steering Committee, has authored over 130 publications in high-impact journals, and has been a BCRF Investigator since 2017.

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Read the transcript below: 

Chris Riback: Dr. DeMichele, thanks for joining. I appreciate your time.

Dr. Angela DeMichele: It’s great to be here, Chris. If we could, tell me about you. How did you get into all of this? Was it always science for you growing up? Did you ever believe that, no, instead you might say, be a soccer star or a rock musician?

Dr. Angela DeMichele: Well, as much as I love sports, I’m not very coordinated and I love to sing, but I have a terrible voice. So, it did sort of rule out certain careers.

Chris Riback: So, defaulted into medicine. Yes, I understand.

Dr. Angela DeMichele: But, no, I actually wanted to be a doctor starting in second grade. I always loved medical shows. For some reason, I just was really drawn to medicine and to being a doctor and being someone’s doctor. That just was kind of a job that I always thought would be amazing. And I started volunteering as a candy striper when I was 12, and I just loved being in the hospital. So, I came at it mostly in that people part of interacting with people who had medical issues. And when I was a medical resident, I rotated through the oncology ward my second month. And to this day I can recall the patients in each of the rooms, because it had such a big impact on me. And this was 30 years ago.

But, to me, cancer patients are just really special. And there’s nothing like cancer that really helps you get your priorities in order. And I just found working with cancer patients to be incredibly rewarding. And then I happen to be training when targeted therapies were just coming into their own. And Herceptin was the first drug that I ever studied in a clinical trial. So, it was an amazing time scientifically to be coming into the field.

So, to me it just is the perfect combination of taking care of people, but also just incredibly interesting [and] creative. I’m always learning. I love to teach. And so, I feel really, really lucky to have this job. And I love it as much, if not more than I ever have. So not many people can say that, I think.

Chris Riback: No, for sure.

Dr. Angela DeMichele: And I will just say, I am also incredibly grateful to BCRF who takes chances on research like this, that’s really early and potentially transformative, but not the way people usually do things. And I think that that is what’s going to help us really move the needle. And so, the creativity that I love bringing to my work is something that I think BCRF recognizes. And there’s not a lot of other groups that will really fund that type of research that I think can be transformative. So, we’re really grateful to them for the support.

Chris Riback: Understood. And, yes, the ability to fund creativity and exploration, as you’re describing, really matters. I’m left, I just about to say thank you very much, but you realize there’s the pertinent question that you just raised that I have to ask you. Which medical show?

Dr. Angela DeMichele: All of them.

Chris Riback: All of them.

Dr. Angela DeMichele: But Medical Center was the first one and then St. Elsewhere, of course. And then ER.

Chris Riback: Of course.

Dr. Angela DeMichele: And now, of course, it’s Grey’s Anatomy. I mean it goes on and on. I can’t help myself. I still watch them. Now with a little more critical eye, but—

Chris Riback: I’m sure. And so, a little more critical eye on their product. And I hope maybe just slightly less drama in your own medical environment.

Dr. Angela DeMichele: That’s right. We try to keep it a little cleaner.

Chris Riback: What drew you to focus on recurrence and metastasis? And I know it’s the billion-dollar question, why does [breast cancer] occur?

Dr. Angela DeMichele: Well, I really got into this work after, gosh, 10 years of taking care of patients. And we would do a lot of testing to understand their initial diagnosis. We do very extensive therapy with surgery and radiation, chemotherapy sometimes, to really get to a point where I can say to a patient, “Okay, we’ve gotten rid of all of the cancer that we can see.” And they would say, “Okay, well, and now what do we do? How do I know it worked? And how do I make sure that it’s not still there?” And I would have to say, “Well, you know what? We don’t really have a way to know whether or not it worked. And we don’t really have a way to tell you whether or not it’s still there.” And you can only sit in front of these people for so long and feel that helplessness of, “Gosh, why don’t we have these tools to figure out, we better do something about this.”

Because really this is the thing, I think for most patients that I encounter is the most stressful part of this whole thing is I can tell a patient that you have a great prognosis, but unless I can say, “I know you’re cancer-free, and here’s how I know,” every single patient’s going to worry about this. And particularly for some kinds of breast cancer, like estrogen receptor–positive breast cancers, that risk of the cancer coming back extends for your whole lifetime. So it’s just weight on people’s shoulders of just waiting for, is this going to come back? And how do I know that it’s not still there? That made me want to get involved in this kind of work.

And I’ll say that when I was training 30 years ago, we just didn’t have the tools to even start to figure this out. That was really after sort of the heyday where we learned that you could give additional chemotherapy and antiestrogen treatments after you removed the tumor, and it would prevent the cancer from coming back. But we didn’t really know why. And so only in the last five to 10 years do we now understand the biology and have some tools to help us be able to actually start to think about how to monitor people, how to do more active surveillance, and then ultimately how to intervene if we find any evidence that the cancer is still there.

Chris Riback: And I want to ask you about that biology. But quickly, the first part of what you were discussing and that stress and stress obviously for the patient, and it’s got to be somewhat disconcerting for the doctors, scientists, researchers in your position, you’ve done the medical work, but there’s still that gap of you can’t promise the future, and you surely want to do more. And you surely want to remove all aspects of that stress.

I watched a YouTube video of you from 2011, it’s exactly what you’re saying now. You spoke of the importance of providing not just excellent medical care, but also to provide the emotional support and the practical support needed. And even with all of the advancements over the last decade plus since then, that component of what you do, I imagine remains the same.

Dr. Angela DeMichele: It really does. I think this is a life-changing diagnosis, not just while women are and men are going through that initial treatment, but afterwards. And it’s been well documented through research that fear of recurrence is the major stressor for breast cancer survivors. And partly that’s because we only have watchful waiting to offer people. And so a patient will say, “Well, how do I know if the cancer’s come back?” And I’ll say, “Well, we watch for symptoms.” “Well, what symptoms? Everybody gets a backache, everybody gets headaches. How do I know whether or not it’s something I should worry about?”

And some breast cancers can be there and not have symptoms. And yet doing a lot of scans is not the solution. And we do have data that tells us that simply doing scans in patients who don’t have any symptoms actually adds to distress, because there’s a lot of false positives. We pick up things that turn out not to be cancer. Sometimes we can’t even prove that, and that is just going to add to the distress. So, what we needed really are ways to find microscopic tumor cells that are still there, detect them, figure out who’s got them and who doesn’t. And if a patient has them, figure out how to get rid of them. That really is the goal.

Chris Riback: Let me ask a little bit of the biology as context that I think will help listeners really understand the power of the work that you’re doing. Take me through the process of metastasis. How does it evolve? And what is dormancy? And why is it so hard to learn why cells exit dormancy?

Dr. Angela DeMichele: These are great questions, and we don’t have all the answers, but we’ve learned a lot in the last 10 to 15 years about this process. So, it turns out that there are only some cells that have the ability to become dormant, which essentially means sleeping. And so, these cells are able to escape from the tumor in the breast, travel through the bloodstream, and then ultimately find their way to what we would call a niche or a place that’s a welcoming environment. Often that’s the bone marrow, but it can be in other places. When the cells arrive in this location, they go to sleep. And I think of it about it like a bear hibernating for the winter where it’s kind of going in and it’s going to sleep, and it doesn’t need any external energy sources. And it’s not interacting with anyone in its environment, it’s just sitting there, and then it’ll wake up when the spring comes.

And a lot of what we see with these cells, they go into the dormant state, they sort of power down, the cell’s not dividing anymore, all of its electrical systems are turned off. It can sit in this suspended animation for a period of time, and then something triggers it to wake up, power back up, turn all the systems back on, start dividing again, leave that location, go back into the bloodstream and travel to another location.

So, when the cells are in their dormant state, not dividing, we call those disseminated tumor cells or DTCs. When the cells are circulating in the bloodstream, they circulate as circulating tumor cells or CTCs. But we also now have the ability to actually just detect the DNA from those cells. So, you’ll hear about a term called circulating tumor DNA or ctDNA, that’s the DNA from circulating cells that are dividing, moving their way to another location.

So, if you think about this black box between when there’s a tumor in the breast, you remove that with surgery and a tumor that pops up somewhere else. Now you can envision that that black box consists of these cells that have left the breast, traveled to another location, gone to sleep, wake up, travel to that distant location, set up shop, become a metastasis.

Chris Riback: And is it the going to sleep or the waking up that piques your curiosity the most?

Dr. Angela DeMichele: Actually neither, to be honest. I mean, of course it’s all important, but one of the key things is what allows them to stay asleep, because that’s the part that we believe can go on for years. So certainly, we’ve seen patients who are diagnosed with their cancer, and then it doesn’t come back someplace else for years to decades later. Well, those cells were there, but they were sleeping. So, if we understood what allows them to stay alive and asleep, we could kill them in their sleep. That gives us a really big window of time in which we can find them and target them, because we think that, as I said, that can be months, years, even decades.

It looks like once they power back up and start dividing again, that window may be much shorter. It could only be a year or two or even less between the time that the cell powers back up and the time that it finds its way to the lungs or the liver and starts to form a tumor. So just playing the odds, you’d kind of like to be targeting the cell at a point where it’s spending most of its time in that sleeping state. And so, we’re really focused a lot on the processes that enable the cell to do that.

Chris Riback: So, this mark’s a good time to segue to your PALAVY trial. It opened only last year, I understand. So, we know that there’s only so much that has occurred since then. But if you would, what is the status? What is the process? What do you hope to learn?

Dr. Angela DeMichele: So, we are targeting several different features of these disseminated tumor cells. So, I should back up a moment and say that for, gosh, the last 20 years, we’ve known that if you identify these disseminated tumor cells in the bone marrow, patients who have those cells are more likely to have a metastatic recurrence than patients who don’t have the cells. So that tells us that if you find the cells, it impacts a patient’s prognosis.

What had never really been done was to then try to intervene and see if we could actually do something at the point where we found those cells to prevent a recurrence. And ultimately what you’d like to be able to do is use the cells as what we call a surrogate marker to say, “Okay, I know that the presence of these cells is associated with a patient having a metastatic recurrence. So ultimately, what if I can get rid of them all, kill them all off? Will that mean the person doesn’t relapse?” Well, that’s really the question.

So, we are utilizing actually a fairly simple test to find the cells in the bone marrow. We do this using a small hollow needle that is inserted into the hip bone under just some numbing medicine. So, it’s done in the outpatient clinic. We take out some of that liquid part of the bone marrow through a series of different techniques where we filter that fluid and enrich for these cells. We then have our pathologists take a look and see if they see any of the cells. If a patient has the cells, then they’re eligible to come onto the trial.

The trial is testing several different drugs. We don’t know which drugs are going to work, but I work closely with a basic scientist, Dr. Lewis Chodosh, who’s also a BCRF-funded researcher, who has developed really elegant models in the laboratory. And in these models, he actually can embed tumors, primary tumors, but these tumor cells are labeled so he can actually follow what happens if you treat or turn off the signals, what happens to these cells? You can see the cells become dormant. You can remove them when they’re dormant and figure out what’s keeping them dormant or allowing them to stay asleep.

So, utilizing that information, we’ve worked closely together to study different drugs that would target those things that allow the cells to stay asleep or the things that allow them to wake up. He did testing of these different drugs in the laboratory, and it showed that you could kill these cells. So, we’ve now been working to bring those treatments to the clinic.

So, in the clinical trial, the patients who we find have these disseminated tumor cells, may receive one of several different treatments. They target some kind of unusual processes. One is called autophagy, it’s how a cell uses its own internal energy sources, just like that bear in the cave that doesn’t need any external energy. The cell can use its own internal energy. The drug that blocks that, crazy enough, is hydroxychloroquine.

Chris Riback: I read that.

Dr. Angela DeMichele: So, it turns out that hydroxychloroquine was used as a treatment for different infections. It used as treatment for inflammatory disease, but really we all heard about it because it was touted as this treatment for COVID, which of course didn’t pan out. But it’s a really safe drug. It’s been around for a long, long time. It’s oral and so it’s fairly easy for patients to take it. So that’s one of the drugs we’re using.

Another drug we’re using is actually trying to make these cells visible to the immune system, because, of course, you think, “Well, this cancer cell is there. Why is the immune system not recognizing it? Why isn’t the immune system attacking it as foreign?” Well, these cells are really smart, and they’ve developed what I would call an invisibility cloak. They can stay shielded from the immune system.

So, we’re using a drug called avelumab that can basically take off that shield and make the cell visible. And try to turn the immune system on to attack the cell. And then lastly, we’re using a drug called palbociclib, which actually stop cells from dividing. So, if the cells are trying to escape, they’ve got to start dividing. We want to keep them from dividing. We want to keep them in this suspended animation, so that they’re sensitive to these other drugs.

So that’s the trial and it’s open at six different locations around the country. So that’s been exciting for us to be able to get this out to other places and to patients outside of the Philadelphia area. Our initial studies were all done here at University of Pennsylvania, and really provided the proof of principle that we could do this. And the patients then subsequently have additional bone marrow aspirates, so that we can see if the cells are going away. And then we will follow to see if the patients relapse. So, it takes time, but the hope is by using this surrogate marker—the bone marrow DTCs—we can figure out if the drugs are working without having to wait for the rest of the person’s life.

Chris Riback: And am I understanding correctly the three different drugs, are they attacking or addressing kind of three different stages or parts? And then, two, if they are, is part of what you’re then wondering is: Are there combinations of the drugs that might work A and C, B and C, A and B? Or are you looking at each drug individually and then going to, in a sense, pick a winner, or say, “Okay, for people who have these symptoms, or these circumstances use this drug for”? Am I understanding the approach in the initial case? And then how are you thinking about the three drugs going forward?

Dr. Angela DeMichele: Yes, you’re absolutely right that this is really considered to be the groundwork that we need to do to understand which drugs are going to work the best and if there are combinations that are better than the single drugs alone. So, we are testing the drugs alone, we’re testing them in combinations. We also are trying to figure out how long we need to give the drugs, so we do another bone marrow after three months and then we do another bone marrow after six months. Because we don’t want to have to treat people any longer than they need it, but we want to give it long enough for it to work. And we don’t really have a sense in people how long this will take.

So, this is pretty common when you’re really working in a space that’s brand new that we kind of have to figure out, what’s going to be the best approach? Because the definitive trials that we’ll need to do that would really show us whether this could actually become a standard of care, will need to be pretty big. They’re going to be a big investment. And so, a lot of this groundwork is what we do to make sure we’ve picked the right drugs, the right doses, the right duration, and we have the right biomarker for the trials.

Chris Riback: And how far into testing these drugs with patients are you?

Dr. Angela DeMichele: So, we just finished our pilot trial that included hydroxychloroquine and a second drug called Afinitor® (everolimus) in a little over 50 patients. And we’ll be reporting those results out later this year. So, we’re in the process of analyzing those results. And then this trial is now, as I said, open in several different locations. I will say about a third of the patients who have the bone marrows have the cells. So, remember that we have to screen three times as many people as we need for the trials to find patients for them. So, we’ve been screening, and it’s fairly early on in the trial at this point.

Chris Riback: Yes.

Dr. Angela DeMichele:  There’s opportunity for people to get involved. But this is the process. It takes time. But we’re learning so much. And I have to say that the patients are amazing who are participating in our trials. They are so willing to do this. When I started, I was talking to an advisory board at one point and someone says, “Patients will never have bone marrow aspirates.” And it turns out that the patients get it. What they were telling me all those years was right. They want to know, and they’re willing to do this procedure in order to find out.

And more than half our patients came from outside of 50-mile radius of our center to get screened. So, I think that this is something where patients are real partners with us in this research. They talk about our trials on their Facebook groups, because this is something patients really want and need in their lives.

Chris Riback: Can I say, among the many, many, many things I have learned in having these conversations with people like you, and I’ve been privileged to have quite a number of them at this point, is do not underestimate for a moment, it’s more than a willingness that patients, I hear it from so many scientists and researchers like yourself, they want to be part of and it’s bigger than themselves.

I mean, sure, you just said they want to know, they learn about themselves, but I’m sure you’re finding the same thing. They’re not doing these trials necessarily for themselves. They want to help find a cure. They want to help the next people. And I hear it time and again, the selflessness of patients who join these trials and how much they’re willing to, I don’t know if endure is the right word, but endure.

Dr. Angela DeMichele: No, I think it’s true. There’s just incredible altruism to really help find the solution to this. And we really engage our patients and patient advocates for that matter in the research. We also are studying the psychological impact of going through this testing on the patients in the trial. I would never want to do something that’s going to cause harm. And to the extent that I knew that many patients wanted to know these things, sometimes you want to know. But then once you know, can’t unknow. And we have to always be mindful that we can induce other kinds of stress. That what we do is not without a cost. And so, for all that altruism, we also have to make sure that we don’t do anything that could make things harder for patients who’ve already been through so much. So, it is really a partnership and something that we really treat as a very sacred relationship.

Chris Riback: And your sensitivity and appreciation for that sacredness comes across in what you’re saying. So, what’s next doctor on this trial? I mean, everyone’s happy for whatever you’ve done to date, but it’s what’s next that matters. So, what do you have on that front?

Dr. Angela DeMichele: Well, I think that several things. Number one, as I mentioned earlier, there are kind of two parts to this story. There’s the sleeping part, while the cells are dormant and there’s the awake part, when the cells are now back to circulating and dividing and finding their way to a new place. So, we can’t ignore either compartment or either part of that equation. So, we’re also, we collect a lot of blood from patients who are participating in the trials. We’re actually looking at the circulating tumor DNA in these blood samples to see if in the patients who have the sleeper cells, at what point do they also start to show signs that they’re cells in the bloodstream. And so just trying to really get the whole picture and make sure we’re measuring everything that matters is very important.

The second thing is that I’m working really closely with Dr. Chodosh on a new test. A test that’s much better than the test we have now for the cells, because the test we have right now, while it’s been so strongly associated with relapse, it doesn’t allow us to interrogate the cells. So, we can’t do anything to figure out what the targets are on the cells. What flavor, if you will, of cell the person has. We’d really like to know that because then if we find multiple treatments that can work, well, then we could actually tailor the person’s treatment to the kind of disease that they have, the cells that they have, and be that much better at finding something that will work for them. And also, to find new targets. So, if we can interrogate the cells, then we can figure out what else are we missing that we could be targeting with our treatments.

We’re also doing a lot of immune profiling. So, when we try to interact with the immune system to target these cells, what happens? And do people who have the cells differ from people who don’t have these cells in terms of how their immune system functions? Because maybe part of the problem is some patient’s immune system does find these cells and they’re never going to relapse because their immune system gets rid of the cells. And maybe other patients have the cells because there’s something wrong with how their immune system is functioning, and maybe we could fix that.

So, I think those are the main things that we’re focused on. And also, just really honing in on different subtypes of breast cancer and not just right after diagnosis, but even five or 10 years later trying to find those patients who are still at risk. So, a lot of work to do. I’ll be busy for a while.

Chris Riback: Yes, you’ll be busy for a while. There are always deeper additional questions. And I’m certain there’ll be items that you discover in this research that surely will advance other questions.

Dr. DeMichele, thank you. Thank you for your time. Thank you for the work that you do.

Dr. Angela DeMichele: Well, thanks for having me. It was fun, and I really enjoyed talking to you, Chris

Each October, BCRF holds its annual New York Symposium and Awards Luncheon. The event recognizes BCRF-supported investigators for their devotion to ending breast cancer and announces the Foundation’s research investment for the coming year.

This year’s program began with a symposium, “Targeting Cancer Where It’s Most Vulnerable,” featuring an expert panel of BCRF investigators who discussed novel breast cancer therapies, disparities, and what’s on the horizon in research.

The panel was co-moderated by BCRF Founding Scientific Director Dr. Larry Norton and BCRF Scientific Director Dr. Judy Garber. Joining Drs. Norton and Garber were panelists Drs. Lisa Newman, Andrew Tutt, and Maria Jasin, who received the 2022 Jill Rose Award for Scientific Excellence.

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Read the transcript below: 

Dr. Larry Norton: It’s been an exciting year of science and an incredible time for BCRF. The pandemic is not quite over yet as we all know, but we got through the worst of it and the organization stayed intact through the extraordinary team that is working.

This year, we brought in 12 new investigators under the leadership of Dr. Judy Garber, who I’m introducing here, BCRF’s scientific director. It’s really been an extraordinary time. I learned an astonishing fact, which is 90 percent of what we know about cancer we discovered in the last five years, if you are people who track these things in publications, it’s an incredible time of discovery. We have with us true world’s experts to discuss. We’re focusing on the topic of hitting cancer where it’s most vulnerable and all the large aspects of that topic. I’m going to ask each of them to introduce themselves and to talk about what they’re interested in, what they really think is exciting, and then we’ll have some discussion among ourselves, and as soon as possible, we’ll open it up to your questions. All right. The Rose Award winner who will receive special accolades is sitting to my immediate left, and I’d like her to introduce herself and say what she does.

Dr. Maria Jasin: Thank you, Larry. My name is Maria Jasin. I am a researcher at Memorial Sloan Kettering Cancer Center. I do relatively basic research and came into I would say the breast cancer field through the original identification of the genes and some relationships with a key protein that is involved in a DNA repair process that we had been studying. It’s termed homologous recombination. This DNA repair process is particularly notable because when there’s DNA damage, so for example, when the DNA is broken, then this process is a way to perfectly restore the sequence prior to the DNA damage. It’s a really critical repair pathway, and so it’s perhaps not surprising that disruptions of this lead to tumor predisposition. We’ve been working on these proteins, especially BRCA2, since our initial discoveries. There’s an amazing amount of things we know and also still an amazing number of things we don’t know, so we continue to study it.

Dr. Larry Norton: Okay. We’ll talk more about the importance of DNA and why DNA going awry is a problem as we move forward. Andrew?

Dr. Andrew Tutt: Good morning. It’s a real pleasure to be here. My name’s Andrew Tutt. I’m a clinician scientist, which means I am a practicing clinical oncologist, but I also had the opportunity to train in laboratory science during my development. My opportunity there was actually working with my mentor, Alan Ashworth, now a BCRF investigator. Long-term with Alan, now I’m joining the family as it were. We were trying to work on what the function of BRCA2 was after Alan cloned it. You’ve heard the amazing work of Maria to my right in that area, and then as a clinician trying to see how that might be usable in the clinical context, how that might change how we treated women who had breast cancer associated with the inheritance of those gene faults. A large group of people, labs, wet laboratory, scientists like Alan and Maria, geneticists, and clinicians running clinical trials came together over recent years in trying to develop a way of targeting the Achilles’ heel that these particular forms of breast cancer had.

I’ve been able to be part of that as that’s developed the concept of PARP inhibition using this synthetic lethality principle in order to develop a very individualized treatment approach using the weakness that these cancers have despite the fault in the gene leading to the cancer developing. This has been a really big year for that concept because the Olympia trial that I’ve had the pleasure of leading has been a huge cooperative effort. An organization led by another senior BCRF investigator, Dr. Martine Piccart, has worked with colleagues around the states, many BCRF investigators, Judy Garber to my left, Susan Domchek, many to ask the question, “Could a PARP inhibitor treatment improve outcome for women with early breast cancer caused by these gene faults?” The answer that’s come this year is yes, and this can reduce the rate of recurrence, life changing recurrence by over a third more women alive as a result of having access to this treatment, a new drug.

This is a big year. This is, I think, the result of collaboration that BCRF is so much part of bringing laboratory science and clinicians together, but we move on always to try and solve the new problem. It doesn’t always work. What myself and others working within BCRF are now trying to do is understand when this doesn’t work, why doesn’t it work, and develop the new treatments in that setting. One of those causes of why it doesn’t work is when the BRCA gene fixes itself. It caused the cancer, but then the cancer can learn how to fix that gene change. It’s called a reversion. When that happens, the cancer can escape PARP inhibitor, but in the process of fixing its Achilles’ heel, patching its Achilles’ heel, it potentially creates a new sign, a new flag that the immune system could recognize and be taught to act upon a new form of treatment approach. We’re trying to investigate could this be a new way of improving the outcome in this genetically defined form of breast cancer, and BCRF is enabling us to do that in a collaborative way.

Dr. Larry Norton: Thank you. Yes, I love your New Jersey accent by the way. It gives me a lot of confidence, I must say. Lisa? Lisa, you’re on.

Dr. Lisa Newman: Good morning, everybody. My name is Lisa Newman. I’m a surgical breast oncologist and chief of breast surgery for Weill Cornell Medicine, and I am also the founder and medical director for an international breast cancer team, the International Center for the Study of Breast Cancer Subtypes. My career focus has pretty much always been in studying breast cancer disparities, and in particular, studying the breast cancer impact on African ancestry communities. Today, it’s obviously wonderful that we can celebrate all the advances that we’ve made in breast cancer treatment and outcomes, but of course, we still are heartbroken over all the pain and suffering that this disease still causes. We are all also appalled by the alarming statistic that breast cancer mortality is 40 percent higher in African Americans compared to white American community.

Now, a lot of this breast cancer survival disparity is of course explained by socioeconomic disadvantages that are more prevalent in the Black American compared to white American community. It’s been a definite honor for me over the past 20 plus years in my career to work with wonderful community-based organizations such as The Sisters Network Incorporated, Tigerlily, Touch for the Black Breast Cancer Alliance. All of these organizations are doing wonderful, wonderful work in addressing breast health inequities, both at the patient awareness and patient education level and at the provider level because there are unfortunately persistent implicit biases and systemic racism that affects how we deliver breast cancer care. This results in the more advanced stage distribution that we see for breast cancer in African American women, and ultimately, this translates into some of these survival disadvantages that we see. There is also a huge gap that we have in research to understand the genetics specifically of African ancestry and how the genetics of African ancestry can also impact on breast cancer biology and breast cancer outcome.

This is why I’m so grateful to the Breast Cancer Research Foundation for agreeing to support some of the work of my team, the International Center for Breast Cancer Subtypes, where we’ve been partnering with researchers not only across different areas of the United States, but across different regions of Africa. We are specifically studying the genetics of African ancestry and its impact on breast tumor biology. About 10 years ago, we characterized the breast cancer burden of women from West Africa compared to East Africa and documented the fact that triple-negative breast cancer, which we see much more commonly in African American women, it’s also extremely prevalent in women of West Africa, in particular of Ghana where we see it accounting for about half of the breast cancers compared to East Africa where we see triple-negative breast cancer accounting for only about 15 percent of the cancers.

Now, all of us remember from our history classes, the transatlantic slave trade many centuries ago brought the ancestors of contemporary West Africans across the ocean, and so we, as African Americans today, have quite a bit of shared ancestry with contemporary West Africans, including Ghanaians, but we don’t have quite as much shared ancestry with East Africans including Ethiopians because the East African slave trade largely went further eastward to the Mideast and Africa. Our group is specifically honing in on the genetics of Western sub-Saharan African ancestry in understanding tumor biology of the breast. We did actually identify several years ago that a particular gene called the Duffy gene has a specific variant associated with Western sub-Saharan African ancestry called Duffy null, and we were able to document the fact that the presence of this Duffy null variant is specifically linked with the risk of having a triple-negative breast cancer compared to having a non-triple-negative breast cancer.

Our scientific director, the card-carrying and brilliant geneticist, Dr. Melissa Davis, who I recruited to be the scientific director for our international team, she’s been studying this Duffy gene for most of her career, and it’s been extremely exciting to learn that this Duffy null variant, which is linked to Western Sub-Saharan African ancestry, is associated with that ancestry because of its development due to evolutionary selection pressure in conferring some resistance to malaria. Malaria, of course, became endemic in that part of Western Africa because the tropical climate supports the mosquito life cycle, which is the perpetrator of malaria. The populations in that area were under tremendous evolutionary selection pressure to acquire any variance that would allow them to survive this deadly disease, but East Africa, actually, has a lot of higher altitude climates that don’t support the mosquito, and so the history of malaria is different in East Africa, and you don’t see this Duffy null variant to the same extent in populations with East African ancestry. Now, we are connecting the dots between this Duffy null variant, West African ancestry, and triple-negative breast cancer, and the effect of this Duffy null variant on the inflammatory landscape of the mammary tissue microenvironment. Very, very exciting work and we are really optimistic that it’s not only going to teach us more about the biology of breast cancer disparities here in the United States, but it’s also going to develop novel insights regarding the pathogenesis of this biologically aggressive tumor, triple-negative breast cancer. Coming all the way back around to social determinants of health and health inequities, we also see that there is a lack of diversity in our medical, our cancer research workforce.

By improving the diversity of that workforce, we’re also optimistic that we will have better and more robust disparities research. That’s why I’m also very proud and happy and grateful that BCRF has agreed to support a very novel breast cancer consortium where my international team will be partnering specifically with the black members of the American Society of Breast Surgeons to develop a more robust biorepository to better understand the genetics of triple-negative breast cancer and African ancestry. Thank you for your time and attention, and thank you to BCRF.

Dr. Larry Norton: Judy, you’re co-moderating, but also, you’re working in this area as well. Do you want to just tell them a little bit about what your work is before we have some more internal discussion?

Dr. Judy Garber: I’m Judy Garber. I’m also a breast oncologist and a clinical cancer geneticist at Dana-Farber. I have worked with Andrew on the Olympia trial. We also are interested in how we can help make cancer genetics more accessible for many communities and how it can help the medical community in general to help their patients understand when they might want to be tested, how they might use the information. Then our work has focused a lot on the prevention side, trying to understand not only the surgical approaches to risk reduction, which we all understand are effective, but not necessarily what everyone most wants to do, and looking for alternative medical therapies that we might use.

I would say that within BCRF that our job in part, Larry’s and mine, and our scientific advisory board is to find the most talented, most effective, most passionate researchers across the spectrum of work that will bring progress across all the areas in breast cancer where we need that progress. The addition of new investigators is a huge step forward in that regard. We’ve always been able to do it before. A few years into the pandemic, it’s been harder, but we’re thrilled to be able to be back on that track again.

Dr. Larry Norton: Wow. We’ve covered a whole lot of things here, and if you hear specific things like what is triple-negative breast cancer, write down the question so we’ll get back to that, but I think many of us in the audience know that these are breast cancers that don’t have the estrin receptor or progesterone receptor or HER2, and they tend to grow more rapidly and we don’t have specific targeted therapy yet for them although, I guess, Olaparib would have to be considered a targeted therapy. It means that’s a PARP inhibitor going forward. I’m going to ask to define exactly what we mean by PARP inhibitors in a second, but I just can’t help but do this, is that I was very unconvinced when I was a younger doctor that there was such a thing as familial breast cancer, and I thought that probably the environment was the dominant feature.

Obviously, we’re learning the genes that you inherit and the environment you interact called gene environment interactions and lead to all sorts of diseases, and not just breast cancer but other cancers and heart disease and many other things, and understanding what we’re carrying in our genes and its relationship to the environment is important. We heard this fascinating story where a certain mutation that can give you an advantage in a place where there’s a lot of malaria can actually cause problems when you’re in a place that doesn’t have malaria. Those things are important, but I was unconvinced. I thought the environment was really more important just as the thing is, and I had to be convinced that there was such a thing as abnormal genes that you can carry that could predispose to breast cancer. The breakthrough occurred because of Mary-Claire King, who’s sitting right here, who really nailed it that there was a place in our genome, in our genes that was abnormal that people could carry and that could lead to cancers.

That started not only everything that we’re doing in terms of susceptibility to breast cancer and to other cancers, but this whole relationship between the genes that you can inherit and your sensitivity to drugs and the instant disease. It was really a major turning point in my life professionally and I think all of our lives because it’s just uncovered so much of what we now discover, so thank you, Mary. I just want to get back to this thing about PARP because we threw the term out without a specific meaning. Maybe, Andrew, explain exactly what PARP is and why it’s important in this context.

Dr. Andrew Tutt: PARP is what we call an enzyme. It’s a protein and it’s a really important part of how cells do many things, but one of the things that it does is it creates a polymer network of proteins around our genetic code DNA when it’s damaged. That gets used as a scaffold to bringing other business building blocks needed to repair our genetic code if it gets damaged. The drugs, the PARP inhibitors, stop that scaffold being formed, but also gum it up and stick it on the DNA in a way that our cells normally handle if they’ve got their BRCA genes working, but the tumor cells in someone with a gene fault in BRCA1 or 2 don’t have that working. That’s how the cancer developed, but it means that’s the Achilles’ heel. If you stop that scaffold forming properly, you gum it up on the DNA and you don’t have your PARP working the cell dice. That’s the cancer cell that’s dying. The normal cells of the person, quite happy. That’s how the concept of synthetic lethality works. Gum up the pop, stop it working, and selectively kill the tumor cell.

Dr. Larry Norton: Maria?

Dr. Maria Jasin: Well, it’s interesting. We focus on DNA repair and the specific roles of BRCA1 and 2 in this process of homologous recombination that’s very precise, but then there are ways of getting around this deficiency to some extent to allow tumor cells to survive, but even the idea of hitting a second DNA repair pathway so elegantly with PARP inhibitors turned out to be more complicated. It’s really this instead of necessarily losing another DNA repair pathway, it’s gumming things up, as Andy said.

We learn more and more about these things as we go along, and then PARP inhibition having perhaps other effects like affecting the immune response and things. We need to keep going forward and not just be satisfied with the simple original papers that are out there, but really to delve into things more deeply to understand why there are issues with treatment being unsuccessful or how reversions develop-

Dr. Larry Norton: Talk about reversions for a second because I think that’s a more difficult concept. What does that mean?

Dr. Maria Jasin: Okay, a simple way of thinking about it is you have, for example, a BRCA2 mutation that disrupts this process of homologous recombination, but then that can be a mutation that truncates the protein so you only have half of the protein, but then a mutation can occur in the DNA that allows the rest of the protein to be made, and so then as if you have a functional protein again. That’s one way of getting reversion, and that’s a real problem that is often seen in BRCA1 and 2 tumors that are treated with PARP inhibitors or platinum drugs, but then there are other ways that are often not understood of how initially susceptible tumor to a PARP inhibitor then becomes refractory to treatment. That can be through completely different pathways, and some of these we know, and then some of them we don’t, and so that’s also a very active investigation because, obviously, it’s so sad when a woman is successfully treated with a PARP inhibitor and then becomes resistant to it, so it’s a major clinical problem.

Dr. Judy Garber: I think Lisa wanted to say something.

Dr. Lisa Newman: This is such an incredibly important conversation regarding PARP inhibitors and BRCA status and BRCA testing, and so I have to just make a plea in favor of our addressing the fact that African American women historically have been under genetic tested, and so we don’t have as robust an understanding of the BRCA patterns in the African American community as we need to have. Historically, we’ve seen that African American women are more likely to have these patterns that we call variants of uncertain significance in the BRCA genes, which are genetic patterns that we just don’t understand how they fit into cancer risk, and in particular, triple-negative breast cancer risk.

Women with these VUS, which includes a lot of African American women, will not derive the benefits of PARP inhibitors because we don’t understand if they are just as beneficial or not and women with variants of uncertain significance. I’m glad is here. She’s also been funded by BCRF and Funmi [Olopade] has done some wonderful work to try to better understand BRCA status in black women, so just a plea for all of us to work harder at more genetic testing in diverse communities.

Dr. Judy Garber: Thank you. Andrew, maybe you could tell us a little bit. You’ve heard that PARP inhibitors have become an essential element of treatment that we didn’t have before, and I think in a reasonably short time, and now we know that they don’t work completely all the time. Where are the most important places, we’re going now with PARP inhibitors? Can they replace chemotherapy sometimes? Their pills? They’re easier to take? What do we do when resistance emerges as often happens in our targeted therapies?

Dr. Andrew Tutt: Thank you, Judy. I think we have several opportunities. I think one is, as exactly as you say, to not congratulate ourselves collectively too much for what we’ve achieved, but also say, “Right, how do we make it better?” Because so many women now will be receiving these drugs in the early breast cancer setting as well as sadly in advanced disease, we can work with them to try and understand the differences between those that they work well and longer for and those who they’re not working for, and study that in the laboratory to bring together what we call forward translation, understanding from the Petri dish what can cause resistance to PARP inhibitors, and reverse translation which is coming back from the clinic and saying, “When we take blood and we look at tumor DNA in the blood or we analyze biopsies deeply, what is really happening in the clinic with women having PARP inhibitors?” Bring those two things together and study what are the most important things we need the science to focus on solving when it doesn’t work?

What that is beginning to tell us is that one of the causes of these fix-up mutations, these reversions may be the use of another form of DNA repair. Dr. [Alan] D’Andrea, one of the BCRF investigators, others in our research center, Alan Ashworth’s group that’s still interested in this area, is using a different repair process that actually causes the cancer to create these fix-up mutations, but if you drug that, you might have a different Achilles’ heel, kill the cancer in a different way, and stop the resistance happening. Studying this reveals the new Achilles’ heels. I think the other opportunity is in the other direction. It’s saying when this works really well for women, maybe we can back off. Maybe we can back off that chemotherapy. Maybe we can avoid the chemotherapy at all or replace some component of it that is particularly challenging or causes most side effects with the PARP inhibitor instead. We must look for both of those needs and opportunities, and that’s what’s happening.

I think the thing that’s so exciting, and the thing I think BCRF enables better than any is the bringing together, it’s what gets me out of bed in the morning, is bringing together the power of fundamental science and fundamental scientists with clinicians and trialists and our patients, women with breast cancer, to crack this. It doesn’t always have to be in a clinical trial. It can sometimes just be in practice. When people are being looked after, they sign up to the idea that you would study their blood, you’d study any biopsies after the pathologist has finished the diagnosis to really try and understand this. This is now going to apply to thousands of women around the world of all sorts of different ethnicities, geographical locations, and it must involve all of that diversity, otherwise we’ll be studying something very particular. That is our opportunity. That is what I think BCRF enables to happen through these scientific meetings, and I think it’s amazing as an opportunity.

Dr. Larry Norton: That actually was the core idea that underlined the founding of BCRF. We were seeing an explosion of laboratory science that looked like it could be relevant, superb doctors and clinical investigators who had the capability of testing things, but the two communities weren’t really communicating very well, and to bring those communities together is what really what BCRF was about from the beginning, and really, it’s worked, obviously. The extraordinary collection of investigators you see that is spread around the room, the periphery of the room, really attests to that and the advances that have actually occurred. This is a question that I’m asked a lot in this regard. You’re studying BRCA1, BRCA2, you’re studying this PARP, and things like that, but I don’t carry an abnormal BRCA1, I don’t carry an abnormal BRCA2, or other genes that I think we’ll get to that may predispose. How does this research relate to me and the kind of situation that I’m in? How do we answer that question?

This is studying special populations, all right? By the way, European Americans are a special population. It just happens to be a majority population, but it’s a special population. It’s a minority of the world that can trace their ancestry to Europe. It just so happens that we have a concentration of them right here in the United States, and so in that kind of thing too, but if you look at the world population, it’s actually a minority. All this work that we’ve done on people of European descent, how does that relate to people who, their ancestry goes back thousand years in Asia and so on and that forth? How are we going to take this knowledge that we’re gaining out of special populations and extend it to the entire world? Judy, look like you’re going to respond to that.

Dr. Judy Garber: I’ll give a small beginning. Maybe Lisa will add. I think at the most basic levels, you could say that it’s very difficult always to know where the next breakthroughs will come from, and that the more we understand the fundamental workings of the genes that predisposed to breast cancer, the genes that determine   breast cancers, the genes that are involved in fighting breast cancer, the immunology of all of this, that the more we understand in some groups, the smarter we hope we’ll be about understanding other groups. Then still there are surprises. I would say this year, a big surprise was that one of the drugs developed for the treatment of HER2 positive breast cancer.

There are many people here today, Ian Krop and others, who’ve led the way on these drugs, but one of these drugs targeting HER2 was shown to be extremely effective in triple-negative breast cancer, and to suggest that maybe some of the tumors that were HER2, which required they be high HER2, that ones that were low HER2 might also benefit, and even the triple-negatives where there’s no HER2. That’s a surprise. That’s an opportunity you have to sort out. For the study of genetics, there have been genes that we didn’t expect to be involved in breast cancer. NF1, that’s not a gene we link to breast cancer, but it is, and now we have to understand why and then can expand from that what are the populations where this might be more important? That’s not a defensive discussion of genetics, but it is true overall. That is as smart as we think we are, we always have more to learn, and that’s really why the most basic science is still important to contribute to breast cancer. We just don’t always know where the next breakthrough will come from.

Dr. Larry Norton: Yes, that’s my favorite Mark Twain quote. It’s not what you don’t know that gets you into trouble. It’s what you know for sure that turns out to be wrong. It’s always an evolving pattern of knowledge. I got to say my own view on this is, and just to interject since we’re having an informal conversation among our friends here, is that what I’m very impressed with is that the genes that survive evolution are the genes that affect more than one process because the multiplicity of things is really what’s gets rewarded by the evolutionary process. The more and more we learn about genetics, we learn that we think we understand this gene does this thing and then does this consequence and this approach, but it does many other things. The relationship between the immune system, the relationship to the other cells that are in the cancer, these are all things that we’re discovering.

My own view is that the simple way that humans think, A goes to B goes to C, is probably not going to get us really the same kind of comprehensive answer to these puzzles that we suspect that we’re going to have to use more sophisticated ways of using data, so I’m doing a lot of stuff with mathematics now to try to actually look at complex systems and predict complex systems that are not necessarily intuitive, that things that are not intuitive or often true, and things that are intuitive or sometimes wrong. We have to look at more novel ways of looking at complex processes and it all relates together to our understanding of genes, understanding of fundamental biology, understanding of how they could be perturbed and what happens actually in the clinic, and how this relates to the genes that you may inherit, and how that relates to the environment and the social situation you’re in.

Chronic stress, chronic unemployment, food insecurity, all those things are going to affect your biology and are going to have those things, so understanding this complexity is something that I’m really very much immersed in now and trying to derive tools that we’ve used for studying it, but also be able to predict in the individual what could help them and why they’re not getting helped. I’m starting to think that eradicating the last cancer cell in somebody who has metastatic disease may not be the right goal. Well, the right goal may be to get down to a very small number of cancer cells and ever prevent them growing to a large enough number that causes trouble and achieving what I call low level plateau of cells. That may be more achievable thing that Silvia Formenti and I were talking about immunological approaches this morning to use the immune system to try to accomplish this as well. All of this is really related, and all fundamentally connected.

Dr. Lisa Newman: Our research team coined the term “oncopologic anthropology” to try to understand this interplay between population migration and genetics of ancestry and subsequent cancer risk. Earlier, I commented on the connection between the Duffy null variant and malaria being endemic in West Africa and so resulting in this variant that confers some resistance to malaria that’s seen in any individual that has Western sub-Saharan African ancestry, but I do also want to comment that this type of evolutionary selection pressure is something that has occurred across the globe, and populations, our ancestors everywhere had develop different variants allowing them to survive different climates, different altitudes, different food sources.

The general public has actually been way ahead of the cancer research community in showing their hunger, their appetite for understanding these ancestral genetics because when people purchase those commercially available kits to spit into a little container and send it off and get a report back regarding where their ancestors came from, those reports are very oftentimes reflecting some of these genetic variants that were acquired by our ancestors as a function of evolutionary selection pressure in different parts of the world, but we see those variants today expressed in current generations regardless of where they live. We have to start harnessing that technology to understand how these variants can also impact on the inflammatory landscape of different organs and subsequent cancer risk.

Dr. Andrew Tutt: To come back to your question about the relevance of some of the perhaps very discreet group of women who have inherited gene faults in the BRCA genes that cause this defect in homologous combination.

Dr. Larry Norton: Homologous combination? What is that?

Dr. Andrew Tutt: I’m nervous even trying to describe this with the amazing scientist to my right, Maria Jasin, next to me, but it is as Maria described, a very accurate way in which a cell can repair its genetic code when it’s damaged. Damage happens to our genetic code all the time. We are housekeeping our genetic code all the time. Breaks in the DNA code are dangerous to the cell so it’s developed ways of housekeeping it really well. Some are kind of, “Let’s do a quick clean up and just put it back together. Someone’s coming around to the house and have a look.” It’s not very good cleaning. Others are really pernickety accurate ways of cleaning up DNA. Homologous recombination is the most accurate way of getting the house back in order. When it doesn’t work, you’ve got a messy house and your genes don’t work properly and bad stuff starts to happen. You need it working.

Dr. Larry Norton: Maria?

Dr. Maria Jasin: I think one thing that is hard to appreciate perhaps is that we learn about DNA in school. It is the basis of life providing all the codes we need to develop during pregnancy, growing up, et cetera, to form all these tissue types in the body yet, so we focus perhaps in school a lot on how important DNA is in this mode of transmission, but forgetting that actually every cell DNA and every cell in our body is constantly being damaged from a number of different processes. There’s this race to there’s damage and then the cell is repairing the damage as a matter of course, and so there are some times when we’re clearly exposed with radiation to agents that are going to damage the DNA, but just the normal cellular processes lead to a lot of DNA damage, and that’s why these processes are just so important to work normally.

Dr. Andrew Tutt: The recombination group is bigger than just the defective cancers that have a defect in that process. It seems to be a much bigger group than just those who’ve inherited mutations in the gene. We can now understand that that could be as much as a third of people with triple-negative breast cancer even if they haven’t inherited a mutation. Try to study how the BRCA1 gene, for instance, is turned off rather than damaged, mutated, makes that relevant to a much higher proportion of women with breast cancer and potentially a significant proportion of those with triple-negative breast cancer even if they don’t have the familial form of it.

Dr. Larry Norton: One of the things that BCRF supports is a cooperative group of hospitals that work together on cancer problems, particularly the focus on breast cancer, called the Translational Breast Cancer Research Consortium (TBCRC), and it’s led by Antonio Wolff. That group did a clinical trial that made an interesting discovery that, I think, is very relevant to this question. Stand up, Antonio, because I see you.

Dr. Antonio Wolff: Thank you, Larry. The Translational Breast Cancer Research Consortium, which receives a significant amount of funding from BCRF, had a study called TBCRC 048, and Dr. Judy Garber and Nadine Tung led the study, and it showed that in many patients who did not have a germline mutation in BRCA1 or BRCA2 but went on to develop a tumor that developed a specific mutation in those genes could then potentially receive treatment with a PARP inhibitor. This was a major discovery showing that you don’t have to be born with a germline mutation to potentially benefit from these tumors. These mutations can quite commonly happen, and if they do, all of a sudden it becomes a new targeted treatment. We are beginning to understand that breast cancers not just traditional phenotypes, ER-positive, HER2 positive, and triple-negative, but understanding the molecular profile of individual cancers can really tell us a lot about new treatments that could potentially be used, some of which derive from the wonderful work that we are hearing today about.

Dr. Larry Norton: Right. Thank you. Thank you very much. Actually, that gives me a segue into something else. So much of what we’re learning about the genes and the relationship between the DNA in the cells and the cellular function is dependent on a technique that’s been developed for actually changing genes and looking at what those changes do. How does the gene function? Well, you can change that gene and see how it functions differently, and then you can understand those gene function. This got a lot of something called CRISPR-Cas9. It’s a technique for actually editing genes in the laboratory. There’s actually some clinical applications of it now really as well. None of that would’ve developed without the work of Maria Jasin. Maria, talk to us about that discovery of yours.

Dr. Maria Jasin: Well, this is CRISPR-Cas. You’ve probably heard of The New York Times talk about it a lot. This sounds counterintuitive from what I said earlier, but it’s a way of introducing DNA damage at specific sites in the genome. We didn’t develop CRISPR-Cas ourselves, but years ago, in this ’94 paper showed that if we put DNA damage to a double-strand break in the genome-

Dr. Larry Norton: That DNA is two strands, one from mom, one from dad, basically sort of simply. This is a clean break across both those strands of DNA, double-strand break.

Dr. Maria Jasin: This double-strand break, so the DNA is broken that the cellular repair processes then can repair it and it can repair it imprecisely or precisely by homologous recombination. Having then many years later this tool being developed, CRISPR-Cas, that can put DNA damage anywhere in the genome to change the genome the way you want, has really been a powerful technique to address all sorts of questions and is being used in therapeutic processes, CAR T cells, for example, for immunotherapies. This is why the Nobel Prize went to CRISPR two years ago. It really changed how people could do experiments. It really accelerated the ability to do a whole slew of experiments, as well as not just experiments, but actually going to the clinic and treat patients with it.

Dr. Larry Norton: Maria should have shared that Nobel Prize, but instead, she won the Shaw Prize, which is the equivalent of the Nobel Prize given out in Hong Kong, so thank you for that discovery.

Dr. Judy Garber: The Nobel Prize did go to two women, so we’ll take that. I think one of the other things just to remember for all of us is that the BRCA1 and 2 genes, and the PALB2 genes, and these other genes we’re learning about are not only for triple-negative breast cancer but also for some hormone receptor-positive breast cancers. I just wouldn’t want our conversation to feel like it’s really only about the benefits to triple-negative disease. That’s not the case. One of the things that we have to learn about is which of the hormone receptor-positive breast cancers might these drugs work for? The ones related to these genes that are from inherited mutations as we’ve heard, but what else? It is more broad than just triple-negative.

Dr. Larry Norton: Right. Thank you. We’re going to go to Q&A now. Do you want to do the first question, Judy?

Dr. Judy Garber: I will. The first question for Dr. Newman is certainly there’s more work to be done in African American communities related to breast cancer. What can African American triple-negative survivors do to help? I would broaden that to ask what can breast cancer supporters and survivors do to help science?

Dr. Lisa Newman: Thank you for that wonderful and very important question that we definitely need to address because our patients, our survivors do have an incredible energy and desire to contribute to all of the work that’s being done and to helping design better work because our survivors understand firsthand what the needs are, where the gaps are, so we definitely need to listen to our survivors in the design of research. To breast cancer patients in general, and especially patients from diverse communities, it is incredibly important for us to make sure that we spend the time educating the public regarding the power of research and clinical trials. Being in a clinical trial for a breast cancer patient doesn’t necessarily mean being in a study where your treatment is going to be randomized. It can be as basic but yet equally powerful as contributing tumor tissue or your clinical medical information to a biorepository, a biobank, a registry study. All of this information is important and necessary.

Dr. Judy Garber: Thank you. Larry, do you want to talk about AURORA?

Dr. Larry Norton: Well, yes. Martine Piccart is here somewhere in the room, our longstanding colleague from Brussels and a great doctor, but a great organizer of clinical research. She and I were standing in the back of the room at a BCRF-funded meeting, and I think it was in Brussels. We were hearing presentations about the molecular biology of breast cancer. We’re talking about DNA mostly, and RNA, and what are the really important molecules that make cancer cancerous. Everything we’re talking about genes. It was just the dawn of the basic understanding of that. We were both impressed with the fact that all the studies were in DNA taken from tumors from the breast, that a tremendous amount of information was starting to be gathered about the nature of the cancer in the breast. It occurred to us in conversation that that probably was not the right question because it’s trying to figure out why the cows are in the field by only studying the cows that are still in the barn.

It’s the cancer cells that spread to other parts of the body that’s where the lethal cancer cell is. If it stays in the breast, it would be a lump, but it would never bother you. It would be a large pimple and would never really bother you. What do we know about the DNA abnormalities and other molecules, RNA proteins in cancers that have spread to other parts of the body? It was a very important question, but it would require an enormous amount of organization and international cooperation to achieve that, which means it would require will and intelligence but also funding. A great tragedy in all of our lives was the passing away of Evelyn Lauder, co-founder of this activity that we’re in right now. Her husband did a remarkable thing to start this off in discussion, which is basically he took her high-end jewelry and auctioned it and gave all the money into a project called the Founder’s Fund for exactly that study.

That generated the AURORA studies because the complexity of exchanging data and information across the Atlantic. We have an AURORA in the EU and AURORA in the U.S. for actually studying the molecular biology of metastatic breast cancer. It took an enormous amount of organization, and many of you around the room, many of the colleagues have been involved in this activity, the TBCRC that Antonio just mentioned, and Nancy Davidson in terms of her enormous organ organizational ability, and Chuck Perou in terms of his enormous skill in analyzing DNA and DNA modifications. We launched this international activity that has just been absolutely remarkable in terms of what is actually discovered. Major publication on the European side, a major publication on the US side just happening now, and learning about the genes that go awry in metastatic disease.

An important finding on both sides of the Atlantic is the importance of the immune system in the progress of cancer that spreads from the breast to other parts of the body. It relates to everything else that you’ve heard about here. It’s all connected and that’s really what BCRF is really all about is connecting the dots. We have still more work to do to complete our project and that’s really underway, and the funding of that is committed and further funding being arranged. That’s really where that particular project is going. It really shows you the power of organizations like this and the power of your support of these kinds of activities to really make a difference and really make progress.

Dr. Judy Garber: And the willingness of patients to participate by giving their samples.

Dr. Larry Norton: Right. Yes. Again, that’s another one of this is that everybody on earth is either an actual or a potential cancer patient. We’re all together and everybody on earth is either an actual or potential healer, and that we can control so that we all have to go onto the healer side of the equation in terms of our activities. That’s what you’re all doing today. Everybody in this room is a healer and contributing everything they can in terms of their skills, in terms of their support, and working together toward the process. We’re just a large community, and the arc of that activity is moving rapidly towards progress. We have a lot more work to do. We have to work on the equity situation, and we have to work on advancing science. We have to make accessibility greater, but we’re moving in the right direction. If I sound a little emotional, it’s because I am on this particular topic. We’re moving in the right direction, and I just basically thank you all for working together towards this really commendable goal. Thank you.

Okay. Amy wrote a question as we’re talking about triple-negative breast cancer, which we defined as not having estrin receptor, progesterone receptor, or HER2. Are there other different types of breast cancer? What’s happening in the space of breast cancer subcategorization and how does it relate to our understanding of genetics? It’s a huge topic and many of us are really working on this topic as well. Actually, Chuck, are you here? Yes, let me get your answer to that.

Dr. Charles Perou: Certainly, within triple-negative breast cancers, we can subset them a number of different ways. One is using gene expression profiling, which I’ve been doing for many years and certainly many others in the audience. There, we can see there’s at least a couple kinds. One, we call basal-like breast cancer, which actually has significant similarities to serous ovarian cancer and lung squamous cancer, so we can see common themes between what you might think are different cancer types, but actually, they have many similar gene expression features, and they have many DNA somatic mutation features as well. We can also subset the patients according to the types of DNA mutations they have. Particularly, those that are therapeutically actionable are the most important classification tools. There, we had wonderful discussions about a subset of triple-negatives being BRCA1 or 2, faulty or not. I think yet other means that Larry alluded to is the immune system.

We’re going to now classify patients and tumors according to the activity of their immune system. If they have certain immune characteristics today, they’re going to get a certain class of drugs. If they have other characteristics, they seem poised to potentially interact with the immune system and we’re going to give them additional activators. I think you can see we’re now beginning to classify all tumors, not just triple-negatives, but all breast cancers according to the phenotype of the tumor, according to the DNA of the tumor, and according to the immune system, and in some cases, according to the genetics of yourself. We’re just getting better and better at this personalized medicine. Actually, you can see there’s going to be interactions between these as well. It’s very exciting times and I think we’re just going to get finer and finer clinical bins and better outcomes.

Dr. Larry Norton: Chuck, thank you. The first time we did this, breast cancer was really very simple. I remember the time, as Marc Lippman, who’s also in the audience, and I were talking earlier before we knew about the importance of the estrin receptor, but by the time BCRF was formed, we always knew that there was some tumors sensitive to hormone therapy that had estrin receptor and some not. The classifications were really very simple. We’ve just had this explosion of our ability to subclassify cancers and to understand their DNA abnormalities, understand links to hereditary susceptibility, and so on.

This has created a huge mountain of data with answers in it. The answer is somewhere in that data, but how are you going to get the answers out of that data? We’ve had a lot of discussions in BCRF about how we can approach the accumulation of the information from AURORA, the accumulation of further information that you’ve heard about, and really not only be able to analyze it ourselves, but release it to the world in a way that properly vetted scientists can look at the data. I’d like to ask Dorraya El-Ashry, who’s our chief scientific officer, who’s right here, to stand up and just explain in a very few minutes what the data hub that we’re organizing is all about.

Dr. Dorraya El-Ashry: Thank you, Larry. Yes, we’re at a very exciting time. You’ve heard about all of this tremendous data that has been accumulated over the last decades and the progress that is just at a tremendous pace right now. You heard from Chuck and from Mary-Claire about just tremendous amounts of data, big data that has been accumulated from all of these studies and on the stage from these clinical trials. We, at BCRF, where a part of our foundation is also collaboration, have just launched the BCRF Global Data Hub. What this will be, will be a cloud-based, computer-based system that will have in it at as its first phase all of the BCRF-funded breast cancer data sets, whether that’s laboratory-based data, whether that’s clinical data.

Whether that’s DNA analysis data, all of the BCRF-funded data sets that will then be available for BCRF-funded investigators to go into this portal and analyze the data, analyze their data with these other investigators’ data, and in this way, take this mountain of data that while each investigator is using for their own research, but vastly underutilized in terms of, as Larry mentioned, the answers being somewhere in there, and move it forward to greater impact. In the second phase, we will open it up to data from the breast cancer research community of other investigators so that this will be then the largest data hub and collection of breast cancer data sets available for breast cancer researchers to analyze.

Dr. Larry Norton: Thank you.

Dr. Judy Garber: Here’s a question that we haven’t touched on before which is where are we with liquid biopsies to detect metastasis or to detect breast cancer? Can you explain what’s a liquid biopsy and then how can they be used?

Dr. Andrew Tutt: An excellent question. I think there’s a huge excitement in the field around this concept of liquid biopsies, so what is that? This is taking a relatively simple blood sample, and in general, spinning it and having what we call plasma, the clear fraction of that, and looking in that for DNA that has come from tumor, and then analyzing to see, one, is their tumor DNA? Because that might tell you something about whether someone has still got some cancer on board as it were. Also, more deeply, what does it say? What is the fingerprint of the cancer that you could read from that DNA in the blood? Liquid biopsy could give you both of those things. Where is the status of that at the moment? I think in my own view, and it’s not my special area of research, we’re probably more advanced in using the information in people with advanced breast cancer as a way of perhaps sometimes avoiding an actual needle biopsy, and yet having very useful information about the tumor that could guide treatment.

There are approved liquid biopsy tests that could give the fingerprint of the cancer and inform the oncologist as to an option for targeted drug treatment. That might be a PARP inhibitor if a BRCA mutation was found in the tumor. It might be a PI 3-kinase inhibitor in ER-positive breast cancer. It might reveal something about the HER2 gene. This is useful. I think this is probably ready for primetime. The other part of the question is for detecting the recurrence of cancer. There is the potential that this liquid biopsy could be so sensitive that it could work out when someone has maybe finished their surgery and maybe their chemotherapy treatments. Do they need more? Do they need more treatments? Would it be better to catch that presence of cancer in the system early rather than wait for inevitable recurrence?

There’s a lot of work in this at the moment, and the assays are getting better and better, and it looks promising that one may be able to pick up recurrence earlier than someone becoming ill and it becoming detected on a scan, but it’s not yet completely clear whether that is sufficiently accurate to give someone that diagnosis of metastasis early and whether you are going to change their outcome by knowing it early and doing something about it. It’s still a matter for research. I think many people believe hugely important research much going on. I think if people can ask about this when they see their oncologist could they be involved in research, what is the relevance to them, I think it’s really good.

The final comment I’d just like to make is Dr. Norton was describing the AURORA program and the importance of understanding biopsy. Liquid biopsy is great. It tells you a lot. At the moment, it mainly tells you about DNA. DNA is really important, but how cancer behaves, a lot of that is to do with more complicated things to do with RNA, the messages in cancer, and the proteins that actually do the business, and in fact, what cells are talking to each other, and how the immune system is perhaps orchestrating immune response. You don’t get that at the moment through DNA in the blood. We think you can get much more of that now from biopsies in the complex study of biopsy. Real biopsy is still important. The two complement each other.

Dr. Judy Garber: Thank you.

Dr. Andrew Tutt: Thank you.

Dr. Judy Garber: I would just add that Andrew raised the question, can you use this as an early detection tool? Can we find cancer so early in patients that it’s not yet a lump detectable by imaging or in any other organ? Can you look for all cancers at the same time? That would be so efficient. We could stop those annoying colonoscopies. I don’t think we can stop the colonoscopies because not only are they early detection, but they’re also prevention. If you take out those polyps, then you don’t get colon cancer, so it’d be nice to have a few more of those.

I would say this has been a very exciting time. There are a lot of mostly companies trying to develop these tests and they have great potential. I certainly hope that in my lifetime, that I’ll be able to avoid some uncomfortable imaging in favor of a blood test, but we have ways to go. Like many things, you can see that the future of this is likely to be wonderful, but for the moment, especially for breast cancer, 30 percent sensitivity’s not good enough. We do much better with those uncomfortable mammograms and annoying MRIs than we can do with blood tests, but stay tuned because I’m sure that just as there will be progress in using these tests in treatment, there will be progress in using them for detection.

Dr. Larry Norton: Well, we always get practical questions also in terms of sophisticated theoretical ones, as you’ve heard. Lisa, you’re a breast surgeon. What do you think about breast self-examinations? People in the audience are getting confusing messages of breast self-examination. What is your feeling about that?

Dr. Lisa Newman: Yes, what a great question. The American Cancer Society really did move away from the recommendation that we used to all be very, very passionate about educating women about the monthly breast self-examination. They moved away from it many years ago because it did become apparent that the breast self-examination is tricky. All women will have some degree of lumpy bumpiness in the breast because that’s just the way the breast tissue is made up, fatty tissue, glandular tissue, ductal tissue. With all of the hormonal cycles from our ovaries, those tissues cause differences in ridges of the breast. Once a woman thinks that there might be a change in her breast exam with that monthly evaluation and she sees her physician, it’s really hard to unring that bell. If a possible abnormality has arisen, it can unfortunately lead to a biopsy that might have been unnecessary if the woman was actually detecting a normal variant in her own breast.

The exam is tricky and that’s the history behind why the American Cancer Society moved away from monthly breast self-examination. It does tend to result in more biopsies. However, I don’t think that we can abandon it completely. Women are going to be more in tune to significant changes in their breast compared to any clinician that’s seeing them once, twice a year. We do need for women to be aware of changes in their breast. I continue to talk to women about the “danger signs of breast cancer,” new lump in the breast, lump in the underarm, bloody nipple discharge, changes in the skin appearance of the breast. When those changes develop, you do need to seek medical attention promptly to get it worked up. Don’t panic because those symptoms can also be caused by benign problems, but we do need for women to be aware of changes and to seek medical attention promptly when a change develops.

Dr. Larry Norton: Good comprehensive answer. We’re getting down to the time limit. Last question from Judy.

Dr. Judy Garber: We’re actually going to have to ask Bob Vonderheide to stand up because the visionary question is what’s happening with breast cancer vaccines?

Dr. Robert Vonderheide: Thanks, Judy, and thanks for the question. The big picture is that immunotherapy is now available for some women who have different types of breast cancer, and it’s opened our eyes to having more opportunities as we do across all cancers to use the immune system. You asked specifically about a cancer vaccine. We think that one of the problems, one of the challenges has been that the immune system for most women with breast cancer is not reliable to fight breast cancer and we need to actually activate an immune response, and so there’s a lot of work. We had a discussion yesterday at the symposium about all sorts of great new ideas, that are in clinical trials. They’re not available. They’re not prescribable. The great visionary possibility as we learn more is can we use a vaccine for women who are at risk for breast cancer? Healthy individuals?

When we take this concept to our infectious disease colleagues, they don’t think it’s visionary at all because this is how we use vaccines, to prevent, and it’s what you alluded to before, Judy. Can we use something other than surgery to prevent breast cancer in the first place, or if a woman is at risk for breast cancer and has very early lesions but is not yet invasive breast cancer, can we intercept those lesions and reset the clock and send things back? This has attracted a lot of attention. There were articles recently in The New York Times and Time Magazine, which we can refer people to. I think it’s like the car, the mirror. Things are a lot closer than they appear. The knowledge of immunology, the ability to deploy that knowledge for patients at risk for breast cancer is here, and there’s a great amount of work. BCRF is leading that in terms of supporting any number of us who are thinking about these ideas. To me, it’s a super exciting possibility that we would have a vaccine to prevent cancer in addition to treating it as well.

Dr. Larry Norton: Thank you. It’s a great way to end the symposium, which we have to end on the future note of the fact that the future actually does look bright even in the area of prevention as well as everything else we’ve talked about. I just want to thank all the panelists, thank my co-moderator, Judy, and thank all of you for being here.

About 30 percent of people diagnosed with early-stage breast cancer will experience a recurrence and develop metastatic disease. To end deaths from breast cancer, we need to better understand both processes: recurrence (when breast cancer comes back) and metastasis (when it spreads to other areas of the body beyond the breast and lymph nodes).

Why recurrence and metastasis happen and how we might then personalize breast cancer care and prediction is what Dr. Christina Curtis and her colleagues are working to uncover. With BCRF support, Dr. Curtis and her team are specifically looking to develop more effective treatments for patients with metastatic estrogen receptor-positive breast cancer—and to develop novel ways to prevent recurrence in people with this form who are at a high risk of recurrence. 

A BCRF investigator since 2011, Dr. Curtis is an endowed professor of medicine and genetics at Stanford University, where she leads the Cancer Computational and Systems Biology group and serves as the director of Breast Cancer Translational Research and co-director of the Molecular Tumor Board at the Stanford Cancer Institute. 

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Read the transcript below: 

Chris Riback: Dr. Curtis, thanks for joining. I appreciate your time.

Dr. Christina Curtis: Absolutely. It’s a pleasure to be here.

Chris Riback: I want to get into your science and approach to care, for you first to explain. I think I understand what molecular biology is, but what is computational biology and why is it so central to your work? And I think the real question that I want to understand here is, do you self-identify more as a science nerd or math geek? Where are you?

Dr. Christina Curtis: Ooh, that’s tough. I’ll say I’m a science nerd because I’m really motivated by the biology that we can unpack and understand using computational and mathematical techniques, but it’s really the biology that drives me and the tools which can be computational and experimental in nature, often both are a means to an end.

Chris Riback: Computational biology is the science or the practice of applying math or math skills or computational skills, specifically to biology, for biological outcomes. Is that kind of the mashup of the terms?

Dr. Christina Curtis: That’s right. It sort of emerged and actually there’s been recent celebrations of sort of the 40-year anniversary of computational biology, it was just a couple weeks ago. And this has really been motivated by the vast amounts of data we can now generate using high-throughput technologies. And so where this comes to play is, what are the methods, the algorithms that we need to dissect this data and then how do we interpret it, really? How do you interpret and distill hundreds of thousands, millions of data points, to uncover biological patterns?

Chris Riback: Yes. With very, very big computers, I would think, or maybe increasingly small, but still very, very powerful. Maybe let’s dig into the two big questions that I believe, in reading about you, drive your life’s work, which is, why does cancer return and why does cancer spread or metastasize?

Dr. Christina Curtis: Yes, so we’re really interested in the origins of cancer and what allows some cancers to be particularly aggressive, and in breast cancer, we know that there’s subgroups that we’ve helped define, subgroups of women who can recur at different points in their trajectory. And we’re interested in understanding why there might be lapses in time, why some patients might recur early versus late. And these late recurrences, we can talk more about, but have a characteristic of being dormant. And by dormant, I mean, they could lie silently and they’re undetected for many years, and we really want to intercept those tumors before they recur and present at different organ sites in the body because it’s of course much harder to treat them at that point.

Chris Riback: That is the part that I would like to get into now and some of that data that you’ve collected in your studies in these subgroups. But just listening to what you just said. Historically, and maybe it’s literally before your discoveries and other colleagues, but a dormant tumor. For example, I know that some of your discovery, which you’ll talk about, shows how to identify areas that might have high relapse in as late as 20 years. Before we get kind of specifically to that, historically, a tumor that was to use your word dormant, for some extended period, 5, 10, 20 years, did folks believe historically like, “Oh, I’m cured.” And then all of a sudden, 10, 15, 20 years later, whammo, they got hit with something out of the blue. Is that kind of what you were up against?

Dr. Christina Curtis: That’s right. So I think our understanding of metastasis is probably still, it’s been limited and that’s in part because it takes new tools to study that. But yes, I think the challenge is these are patients who think, “Okay, I’m five years out, I might be disease free. I’ve made it.” And then five, as you say, past five, often 10, 15, 20, and beyond, the tumors are emerging again. And of course this is alarming, and we’re seeing this at an increased rate to the point that this actually has been recognized as one of the great clinical challenges of our time.

And part of that’s of course, because the primary tumors are being treated more effectively. These patients are living much longer, so we see them. So this is also sort of fueled by the many advances that we have achieved in breast cancer, and I want to make that clear. But of course we want to treat patients through the duration of their journey. And I think first knowing that this happens, recognizing it, and then being able to identify those patients, is the next critical step that we’re, I think, making a dent in.

Chris Riback: Why is it so important and why is it so revolutionary to be able to identify patients whose tumors express the estrogen receptor, but not the HER2 receptor?

Dr. Christina Curtis: These are the sort of markers that we use routinely in clinical practice. They in fact, guide therapy, of course, for estrogen receptor positive patients, that’s been indicative of the use of anti-estrogen therapies that have really, in a way, one of the first targeted therapeutic approaches. And on the other hand, we have HER2-positive disease, we can of course have ER-positive and HER2- positive tumors and those HER2-positive tumors again, also represent an archetype type of precision medicine, where we’ve just seen tremendous advances in being able to target HER2, starting with the development of Herceptin and now many, many other FDA approved agents.

But the patients that are ER-positive, HER2-negative and have active hormone receptor signaling, the standard of care has been endocrine therapy. And that works very well for many, many patients. And I want to acknowledge, the vast majority of patients are indeed hormone receptor–positive, some 75 to 80 percent. Typically, we actually think of those tumors as being somewhat less aggressive because we can treat many of them well with anti-estrogen therapies. But there is this appreciation that there’s a subset of that population, roughly a quarter.

Chris Riback: I was going to say, if 75 percent are in one direction, does that necessarily mean that a quarter are in this other segment, and it sounds like, yes.

Dr. Christina Curtis: Right. To zoom out, about 75 percent, 80 percent are ER-positive, the total breast cancer population. And then within that 75 percent, I would say that there’s a 75 percent that tend to respond quite well to therapy, but don’t recur so late. And yet, there’s been observations that there’s about a quarter of the ER-positive subset, that can recur well beyond five years and work from many groups, has shown that these populations exist and that they may not have the completely typical characteristics. These patients might actually have no lymph node involvement, so they look like they’re very low risk tumors. And yet, despite having no lymph nodes at the time of diagnosis implicated that are malignant, some of these patients are recurring very late. And so that tells us that our standard approach of just looking at clinical covariates such as tumor size and grade lymph node status, may not tell us everything we need to know about the patients that are recurring and that we really need to understand the biology, the makeup, the genetics of those tumors.

Chris Riback: Were these initial results in 2019?

Dr. Christina Curtis: That’s right. So our study came out in 2019 describing the sort of late recurrence, but there had been a meta-analysis of a large number of studies by multiple groups in 2017, showing that we have patients who are recurring late, it’s about a quarter of ER-positive, HER2-negatives. But in that study, which was incredibly powerful, there wasn’t detailed molecular information. So we couldn’t further refine who those patients were, what their biological makeup was and what the 2019 study, where we followed on from our analysis of the METABRIC Cohort, is molecular taxonomy of breast cancer, international consortium. It was a study of 2000 women with very detailed molecular profiling. So the genome and the transcriptome and beyond. So really looking inside the cells at the genetic makeup of the tumor, we were able to follow those patients for many years.

In fact, such that we would have, up to 20 years of clinical follow-up, which linked to the molecular data, then allowed us to go back and ask, “Okay, there’s a subset of patients that are recurring late, who are these patients?” And it turned out that really, they mapped entirely onto the subgroups that we had defined years in the past, back in 2012, using an unsupervised approach. And by unsupervised, I just mean that we really let the biology speak to us. We weren’t trying to prescribe how we define subgroups. We asked how many subgroups there were based on the molecular features. And so that was a big kind of insight into what the molecular features of these high-risk patients might be.

Chris Riback: And am I understanding correctly, the data that you’re examining and the patients, 20 years looking at this, this is the centralized data that the consortium was able to pull together, and then groups like yours, is able to access that?

Dr. Christina Curtis: Right. So I was the first author of the first study that led that analysis back in 2012 that combined these data sets, it was a consortium effort, a major effort across five hospitals, led, at the University of Cambridge and British Columbia, Vancouver. And there were hospitals from multiple sites. So it was this collective effort that really allowed us to amass enough samples, enough data points. And at the time when we did the deep molecular characterization, it remains really the largest study of its kind, with this kind of molecular information and outcome. And we’ve made it available to the public. It’s been used broadly by breast cancer researchers around the world. And so I’m really pleased that we were able to allow others to build on that. And then we went back and built on it when we were able to get additional follow-up information for these patients. We’ve been following them and following them. But of course, then there’s a collation effort to say, “Aha, we’ve got the follow-up time we need to go back and do these statistical analyses.”

Chris Riback: Yes. I’ve spoken, had the privilege to speak with other researchers who dig into some of that shared data, it may be other consortia, but the power that comes from people like you identifying, collecting that data, but then pooling it and finding ways to make it shareable, it’s become clear to me as a layperson, how important that is. I wonder, is now the time when I should ask you what you think about scientists who studied at the University of Cambridge?

Dr. Christina Curtis: Whenever, I have warm, warm memories and had a brilliant time there. It’s such an intellectually stimulating environment, so yes, always happy to talk about different environments.

Chris Riback: Yes. It must be fantastic there. What other subgroups did you identify and why was identifying those so significant?

Dr. Christina Curtis: Sure. We had originally described, there’s 11 integrative subtypes, is how we refer to them and they’re integrative because what we did in this first study that was quite novel, was to combine not only transcriptome information, which is how the genes are expressed in our cells, but also they’re copy number state. And by copy number, is a particular gene amplified, are there are multiple copies in a cell. And typically, genes that drive cancer, might be represented in more copies, than in a normal cell. And it fuels this kind of overdrive of a particular signal in cascade.

By bringing in the copy of HER2 information, which hadn’t been done before, we found that there’s a number of subgroups that actually look a lot like HER2-positive breast cancer, with different genomic drivers, and HER2 is really an archetype of, that gene can be amplified and over expressed many, many times, and we target that ONCA gene. But as a field, kind of as a whole, we haven’t really followed up on targeting copy number drivers. We go after mutations. And so that’s a bit nuanced, but what we really defined here was new subgroups that we think might be targetable in a similar fashion to HER2.

And that, knowing how transformative that has been for the field, I think that gives us a lot of optimism. And it happens to be that there are four subgroups amongst these ER-positive, HER2 negative patients, that account for this 25 percent that are at high risk. There’s four different groups. They have different molecular aberrations or mutations. And so really the interest comes in, how do we go about targeting those specific subgroups in a way that we can ultimately, circumvent relapse. And when a relapse has occurred, perhaps treat it more effectively. And so, the notion is that perhaps, endocrine therapy alone isn’t enough for these patients. And there’s of course, other agents in development as well, and a lot of exciting work in the past few years to bring forward new therapies, but that’s really the premise.

Chris Riback: Which leads, I think, to an area that I’m certain, that you spend a lot of time thinking about: personalized breast cancer treatment and risk prediction. From your point of view, why is personalization of care and prediction, both so important and so hard, and where do you see personalization going?

Dr. Christina Curtis: Yes, that’s a great question. I think this is really where we need to move to and where there’s already been a lot of developments, but we can certainly do more. I think personalization’s so critical because we want to make sure that we’re delivering the right therapy to the right patient at the right time, also in the right dose. And that we’re sparing them any unnecessary toxicity, and that’s a whole other area of focus within my group is, when can we deescalate or reduce the therapy that we’re giving, perhaps chemotherapy in favor of a targeted agent and when do we need to escalate? And this is an example of escalation where we think we need more than just endocrine therapy to prevent these recurrences. And part of that may be because such patients are intrinsically resistant to those endocrine therapy. When we think about personalization, we really want to take as much information into account as possible, about the likelihood that this tumor is going to be an aggressive one and the likelihood that it would respond to particular agents.

We want to be predictive with respect to the treatment response as well. And we know that molecular features can influence the vulnerabilities of those tumor cells, so we want to go after them and target the tumor cells and hopefully not the rest of the cells, want to really mitigate that. There’s a lot that can be done with this information. It does require a lot of data and it requires these kinds of computational modeling approaches to say, “How do we categorize patients? How do we group them together? And when do we need more refinement in that grouping?” And there’s multiple layers to that.

Chris Riback: You started to segue then into my next question, which is, what’s next regarding your study, or were the areas that you were just talking about, not the areas that you plan to attack next?

Dr. Christina Curtis: No, they absolutely are. We think that this framework that we’ve described, really provides a lot of potential for how we can tailor these therapies because it turns out, I think, what’s really exciting about this discovery is that, it’s not just that we can define which patients are at risk, we can do that. But the very fact that we can group them actually the way that we’ve grouped them, uncovers novel vulnerabilities, that we can then target potentially therapeutically. And so of course, bringing new therapies forward is always a long road. There’s a lot of testing to make sure that these are safe and efficacious for the population. And we’ve been doing a lot of experimental work in the laboratory to sort of evaluate these therapeutic strategies and then to design new clinical trials.

And we’re really, I think, excited about the fact that these new biomarkers that we’ve developed predict risk, potentially predict benefit from particular therapies. And so we’re looking to essentially deliver trials to early stage patients, where we can really understand the unique biology and doing trials in the early stage setting, can be more challenging in some set. We often start in the more advanced setting and move drugs back up the pipeline, and sometimes that works and sometimes it doesn’t work. And our rationale around this is that we really need to understand that unique biology. And if we can start by looking how these therapeutic interventions work in these high risk populations, we can learn a lot about how to do better for these patients. And so we’re embarking on clinical trials to do just that, to do biomarker stratification.

And these are ambitious in many respects, because we’re doing very comprehensive molecular profiling up front. But I think that this also sets the stage for the wave of the future and how we can personalize therapy at the very beginning. And the reason I think that ultimately is so important and of course there’s great standard of care options, so that’s where the challenge is, we’ve come so far in our therapies for breast cancer patients. So to do better, the bar is very high. And I want to make that clear. The bar is very, very high. But I think that if we can do more sooner and set patients on the right course for the beginning, with therapies that are tailored to their risk and we can monitor them, because we also need to follow them. It’s not, as I said, some of these patients may recur later and we want to continuously track that risk, then I think we will be achieving better outcomes. And we don’t want to wait to just the end to do it when it’s later than we would like, and the efficacy may be lower.

Chris Riback: Tell me about you. How did you get into this? Going back, where did you grow up? Was it always science and math for you? Did you ever think perhaps, fiction novelist, world class skier. How’d you get into this?

Dr. Christina Curtis: Yes, well, I still have ambitions to be a world class skier. I don’t know. I think my kids have surpassed me by now.

Chris Riback: Probably, yes.

Dr. Christina Curtis: Yes. It was always science. It was always this from the time I was really a high school student, I determined I would do a PhD in genetics and to focus on cancer, but I wanted to understand the genetic basis of cancer. And of course, I didn’t know what tools I would need to do that. That was predated, the sort of genomic revolution that we have now lived through. But, a family history of cancer and I thought, “This is encoded in our cells. I need to get to the bottom of this.” And it’s really been the driving force for everything I’ve done. And I feel so fortunate that that passion was sparked really early, because in some sense, it made my path really clear. And as these technologies emerge to allow us to probe hundreds, millions of molecules simultaneously, it suddenly was also obvious that we needed computational tools to interpret this.

So in many ways I feel like I was in the right place at the right time, where these programs to train people in this new field that was kind of largely unrecognized, a merger of folks from computer science and math and biology, to really get to train in that space, I think has been just a huge privilege. And now I think it’s hard to even think about some of the questions we address in biology without some of those tools, so it’s certainly changed, but I do feel really fortunate. And I think, this is just such an amazing time to be doing this kind of work as well. The pace at which discoveries are happening and clinical translation is happening, that I think we can really move the needle so much faster, and I tell that to my trainees, that this is the golden era to be doing this.

Chris Riback: And incredible to me that you were able to develop such a passion in high school. That was pre-CRISPR. There were aspects from the human genome project, obviously that had come to light. And so they were in society to a certain extent. But pre a lot of the exciting, more popular innovations that many of the rest of us have heard about, and yet even back in high school, you were finding it inspiring. That’s pretty terrific. What about BCRF? What role has BCRF played in your research?

Dr. Christina Curtis: BCRF has been instrumental. They funded me early on when I was just getting going as an assistant professor and taking my first ideas to the lab, some of which were bold and probably would not have been funded by conventional means. And the funding allowed us to get some of our first federal funding, federal awards, but I absolutely would not be doing the work that I’m doing today, and I think that I wouldn’t be as close to translating it to the clinic, which is what I find to be of immense reward. I always hoped when I started doing this back, even early on that this would, some of the discoveries we would make would eventually reach patients. You never know if that will happen, how long that will take and some of it’s serendipity and some of it is, we’re starting with very basic fundamental questions that may not have an immediate path.

But I would say some of the most rewarding things that I’m pursuing right now is how do we deliver on this new knowledge and how do we deliver that to patients? And though I’m not a clinician, I really enjoy being able to see how this can move that needle. And yes, I’m kind of hooked on it. I think now, passions emerge along the way and it’s like, “How do we do better? And how do we do better, faster? How do we accelerate this?”

Chris Riback: That seems to be a theme of yours. Just in listening to your answer, how do you balance bold versus practical, whatever the opposite of bold is? How do you balance that both in how you run your lab, how you think about the problems that you want to attack? What’s your philosophy on that?

Dr. Christina Curtis: Yes. I guess part of this is I think that couple fold, one is we need to be multidisciplinary in our approach and my lab certainly is that. We are using computational techniques. We’re using experimental techniques. I don’t think we can fully move this needle without doing that. And we work very closely with clinicians to make sure that we’re really thinking about this from where is the biggest bang for buck for the patient? How do we move that? But I also feel like, I don’t know, some sense because I also trained in these other fields, I was a bit of an outsider, and so sometimes my perspective that come in with is different.

And I just am sort of asking these questions, “Well, why do we think this works this way? Why is that? Do we know that it works that way?” And maybe I’m a bit of a skeptic, but as a result, you don’t always know when you start asking these questions, that what you’re doing might challenge dogma. You don’t know, you get going and then you realize, “Oh, this was the status quo,” and we are seeing this, and this is what we see, and I’m a big believer that we have to let the data speak to us. And sometimes that leads you in bold places and new places.

But I think I’m not really afraid to take risks because I think that if we want to get there faster, we have to do some risky things. And there’s great value in continuing to build on what our knowledge is. But sometimes I think we have to look at it through a different lens and see what’s there and accept that occasionally, that maybe more often than not, that will be a dead end. But sometimes we’ll find things that allow us to really understand the biology differently and maybe treat patients differently as a result.

Chris Riback: And I’m certain that the team members in your lab are thrilled to get the question from Dr. Curtis, how do we know that? I’m sure they don’t panic at all when they get that question, do they?

Dr. Christina Curtis: We have a lot of fun in lab and I’m always learning from them. I think that’s the amazing thing is the great thing about this job, the best job in the world is that, you never stop learning. And it does mean that it can be all consuming at times, but it is a great privilege.

Chris Riback: You’re all fighting this and trying to get these answers for patients and for people together, and we thank you for that. Dr. Curtis, thank you. Thank you for your time. Thank you for the work that you and your team do every day.

Dr. Christina Curtis: Thank you so much. It’s a privilege and yes, I really enjoyed our discussion.