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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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. 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.
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