Over the last few decades, scientists have discovered that breast cancer is not one disease but many. Understanding the differences between various types of breast cancer can lead to innovation, more effective treatments, and more comprehensive approaches in research overall. One breast cancer that researchers are uncovering new treatments for is invasive lobular carcinoma (ILC), also known as invasive lobular breast cancer. It’s the second most common form of breast cancer in the U.S. and accounts for 10-15 percent of diagnosed breast cancers, but it has long been misunderstood and understudied. As Dr. Adrian Lee’s research demonstrates, the unique biology of ILC requires new treatment and new ways of thinking.

The goal of Dr. Lee’s laboratory is to translate basic cell and molecular research findings to breast cancer treatment. With fellow BCRF investigators Drs. Steffi Oesterreich (Lee’s wife) and Jorge Reis-Filho, he launched a first-of-its-kind ILC biorepository, which was made possible by a legacy gift to BCRF from ILC patient advocate Leigh Pate. A BCRF investigator since 2013, he is the Pittsburgh Foundation chair and director of the Institute for Precision Medicine at the University of Pittsburgh and UPMC. He is a professor of pharmacology and chemical biology and a professor of human genetics at UPMC Hillman Cancer Center and Magee Women’s Research Institute.

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

Dr. Adrian Lee: Thank you for having me.

Chris Riback: I thought we should start with the context and two topics that jumped out to me in regards to you, and I’m certain they’re connected and you’ll help me understand exactly how. One, of course, is precision medicine, which you seem to have dedicated your career to. And the other is invasive lobular cancer, which we may end up calling ILC. So let’s start with the former. What is precision medicine and why did it speak to you?

Dr. Adrian Lee: Yes, so I think we’ve been very fortunate in breast cancer to be leading the charge in precision medicine. The idea of precision medicine, it’s a relatively new concept. It was only coined in 2011 so we’re 10 years into this. But it is the idea that with these great new technologies and our ability to understand the molecular features of disease, rather than calling a disease by the symptoms or the person who found it, that’s traditionally the way, why don’t we call it by the driver, the mutation, or the DNA change or the protein change, that’s causing the disease? So breast cancer has led the charge in that. For example, estrogen receptor–positive breast cancer was because estrogen receptor was identified 40 years ago. So in breast cancer, we’ve had this way to be more precise about describing the disease and a better description allows us to be better about treatment of the disease. And so I’ve been keen to use laboratory research to try and better define the disease.

Chris Riback: And it’s so interesting to hear you frame it that way because as I was researching and thinking about it, I kept coming across almost-interchangeably precision medicine and personalized medicine or personalized care. And that description, it makes sense why the growth, if you can kind of chart it in personalized care and I would imagine as well the transformation in the thinking around prevention care once somebody has cancer, even the progression of the growth of the personalized aspect of that care must be directly aligned with the development and growth of precision medicine. Am I understanding correctly?

Dr. Adrian Lee: Yes. And maybe I could just say one sentence on that because I teach this and it’s quite a confusing area. So healthcare has always been personalized. The way the physician asks you about your personal history relates to your risk and treatment in the future. So that was always personalized. The difference is now it’s precise based upon our ability to measure these features, be those features in the tumor or be those features in blood. It’s precision medicine leading to personalized healthcare, enhancing our personalization of healthcare. And in breast cancer, we have this array now of tests that allows us to really define the disease and try and give the right therapy to the right person at the right time. Tailoring better efficacy and lower toxicity, for example.

Chris Riback: That’s super helpful. I appreciate your increased precision in the explanation. And I promise I would be the student coming to you afterwards and saying, “Well, professor, can’t I get partial credit on this answer? I mean, I didn’t get it completely right, but at least half credit here, please.”

Dr. Adrian Lee: I ask that question. I ask when I teach it, I ask that on my grading exams afterwards. I ask that exact question and see what their answers are and it’s quite interesting. I think over time, people have become more comfortable with the term “precision medicine.” You might remember that President Obama, I think it was 2015, had the Precision Medicine Initiative.

Chris Riback: Oh, no. I don’t.

Dr. Adrian Lee: So in that, the government gave $100 million to start the kind of catapult of what’s happening with precision medicine. And they started something called the Precision Medicine Initiative, which is now called All of Us. And in All of Us, a million individuals are donating blood and biometrics. They already have done this on 750,000 individuals and that led to the great rise in the use of precision medicine and, I think, in the understanding of it as well.

Chris Riback: There may be a book there, professor. So let’s move to invasion lobular cancer and what is unique, if you would help explain for me, in its biology that distinguishes ILC from other ER-positive diseases.

Dr. Adrian Lee: Yes, so that’s a great kind of follow on from precision medicine is that what precision medicine says is that if we can better define the disease, the taxonomy of the disease, what makes the disease, we can then better understand it and better treat it and get better outcomes. That’s the premise. And ILC is like that.

So invasive lobular cancer, or ILC, is a histologic subtype of breast cancer. It accounts for about 10-15 percent and it has a very specific change which the others don’t have. It has a mutation in a gene called E-cadherin, its gene name is CDH1, and this is a protein that causes cells to stick together. And when you mutate that gene and you lose that protein, cells now can’t stick together. Because of that, it has very unique features, which is very different from the other [breast cancers], and those features are important clinically. So because the cells don’t stick together, they grow very differently and they’re very difficult to image the tumors.

So a fundamental understanding of the molecular basis of the disease, the E-cadherin mutation, leads to the phenotype, the different growth, which leads to a problem with imaging. So that’s the premise of precision medicine that we should probably pay attention to that. That leads to other features. Because it’s difficult to image, it tends to be detected later, which is bad. It has different types of recurrence, it tends to recur later. And then it has different sites of metastasis, very different sites of metastasis. So all of that is related to the original definition of disease, the precision medicine, if we can measure the mutation.

Now, funnily enough, we’ve known this for years. For 40 or 50 years, pathologists have looked and said, “Oh, this is a different type, 10 to 15 percent. So 40,000 cases a year of this unique type.” But there was really no research to try and understand why or what’s the importance of that. It was simply lumped together with the more common form. So I run the laboratory with my wife, Steffi, and she was really one of the pioneers in forcing this field forward and in the last 10 years have made fundamental understandings and increased awareness. You would say 20 years ago, if you look in the records, people just won’t consider it. Now I think it’s kind of come to the forefront that people should be trying to understand this.

Chris Riback: And as I understand it, you are focusing on inhibiting tumor growth. And what I found myself wondering was does that mean tumor growth from zero to the first stage, which as a lay person I would characterize as prevention or early spotting? And I’m hearkening now to what you just said a moment ago that one of the characteristics of the cells not sticking together is that they become very difficult to image, and so one sees them later. So I’m wondering is that what you are kind of focused on? Or we’ve identified the tumor finally, or I’m sure part of what you’re working on is trying to identify it obviously as early as possible, but we’ve identified it finally and now we want to prevent it from growing further. So we’re in the spectrum, or is the answer to that, “Yes, everywhere in the spectrum”?

Dr. Adrian Lee: That’s a great question. I haven’t been asked that before, but I think it’s very thoughtful, the question. It’s very hard to study the early parts of the disease. To do prevention research, it’s incredibly difficult. We don’t have many good models of it. And in humans, the disease when we detect it is already there so it’s just hard to do that. Our current goal is really a focus on, as you said, the established disease and how do we treat it? So nearly everyone dies of metastatic breast cancer. They don’t die of that early disease. If we can catch it early enough and do surgery, we can cure most of those patients with surgery, radiation therapy, and standard therapy. But it’s the patients, 40,000 dying a year from advanced or metastatic breast cancer. We really, in our lab, are focused on that.

I think it is true that most approaches to treatment in that setting might relate to preventional treatment of the early disease. So, if you take, for example, hormone therapy, tamoxifen [this is true for HER2 therapy as well] most of them act very well in the advanced setting, they work well as adjuvant once the disease has been cut out, and then they also work as tamoxifen for prevention, for example. So I do think that many of these ideas we learned from helping reduce the rate of death from metastatic breast cancer might be moved into earlier settings, but we don’t study that in our lab per se.

Chris Riback: And so let’s talk about the part that you do study and inhibiting the tumor growth. Talk to me about your studies there please.

Dr. Adrian Lee: Yes. So to try and put this in simple lay terms, when you lose this E-cadherin gene, something has to compensate for that because the cells have to adapt, because now they’re not stuck to each other. They’ve lost their natural environment and so they’ve adapted. And if we can identify those adaptions, those are probably requirements for them to grow, that maybe that’s a dependency that we can then block and then kill them off. The E-cadherin isn’t there so we can’t target that, but we can target the thing they’re now dependent upon, or this requirement. So we have ways in the laboratory where we can identify those dependencies and then target them. And the most exciting thing is what we study in the BCRF grant is that one of the things that happens is that when the cells don’t bind to each other with this E-cadherin, now it’s not sticking the cells together.

What happens is this frees up growth factor receptors that drive growth and they become hyperactive. And this has been shown by us, been shown by a number of groups now, and that gives you a potential therapeutic target because we target these pathways all the time in breast cancer. So we first showed that the loss of E-cadherin upregulates a classic growth factor pathway called IGF1 receptor, and there are drugs targeting that in clinical trials. And most recently, we showed that it also upregulates HER2, which is one of the major drivers of breast cancer and there are lots of drugs available for that. So this is this kind of translational relevance. We’re trying to identify these therapeutic vulnerabilities. Hopefully, we have drugs already available or FDA approved, and we can then use those in our models and hopefully move those into clinical trials.

Chris Riback: And so the part that folks always become interested in, which is rubber actually hitting the road, where are you in the stages of those studies? Are you re-finding patients or people to join? And what’s your hypothesis?

Dr. Adrian Lee: Yes, so I think the pre-clinical laboratory and pre-clinical data is very solid. I mean, you have different levels of confidence. I’d say probably it’s the highest level that this, we’ve done as much as we can relatively do. And so now, as you said, the rubber has to hit the road. Does it work in the clinic? And sometimes it does and sometimes it doesn’t. Maybe our models are wrong, for example. So we have been discussing the idea of testing these growth factor receptor inhibitors, specifically in lobular cancer. And I think there’s a number of clinical trials in development that are floating around to do that. I think there’s quite a lot of interest from pharmaceutical companies to do that.

So, there’s a number of concepts at the moment where we will do trials, specifically in lobular cancer, to try and understand better imaging, for example. Such that we can better understand response and then tailor the therapy, make sure that maybe we will increase, put in this growth factor receptor inhibitor, or maybe we’ll decrease some form of chemotherapy. So we have quite a few of those trials now in development.

Chris Riback: Excellent. And when you do work like that, does it involve, so there are so many clinical trials going on obviously. There are so many, let’s call them, banks where various samples are being collected. Do you do this type of work by connecting with those types of groups or other partners, or do you need to create a unique cohort and that one very hard part of the job is getting that cohort together? How do you attack the problem?

Dr. Adrian Lee: Yes, so I think that’s generally been the problem with lobular cancer. Because it’s only 10-15 percent of the whole of breast cancer, any one study doesn’t have enough to have the power because the study is powered on the total. And then if you take 10 percent of it, it’s never going to have the statistical power of the whole thing. And so you need the community to come together. And actually, that’s what happened in the last five to 10 years. It’s like studying a rare disease, yes? It’s not rare, 40,000 women a year, but it’s rare compared to the total. So basically what we’ve seen is this real coming together of those groups to say, “Hey, there should be a focus on lobular.” We’ve now had lobular cancer as educational sessions at the San Antonio Breast Cancer Symposium. BCRF was very helpful in that they were one of the main sponsors of our recent ILC Symposium. So we held a meeting here in Pittsburgh in September 2023. That was the biggest yearly meeting. We had over 220 people come.

Chris Riback: Wow.

Dr. Adrian Lee: The audience of that meeting was a third physicians, a third scientists, and a third lay patients and advocates. That’s pretty unique. Normally, that would never be that. And that was a great opportunity to share these ideas and concepts, like you said, to share knowledge, share models, talk about tissue banks, all of those things. All those things you said came together. And particularly for something that’s challenging, like a rare subtype of this, you need to have community to get those things done. No one is going to be able to do it alone.

Chris Riback: That’s super interesting. So the fact that this was at Pittsburgh, obviously I’m assuming that means that you generated and ran or led the conference. I mean, that would seem extremely rare for researchers, scientists, heads of major departments and medical efforts, such as what you represent, to include patients, or advocates as you say, at a symposium on the topic. And please, you’ll correct me if I’m wrong, I would think that frequently the incentive is for scientists to talk to scientists or maybe scientists to talk with pharmaceutical companies or potential funders. One, am I right? And two, regardless of whether I’m right or not, what’s the inspiration and the thesis behind including people who maybe, let’s say, have the most stake in the game?

Dr. Adrian Lee: Yes, so I think that last statement is you summed it up, is the patient has the most stake in the game. I think they had somewhat been excluded for a number of years. Stephanie and I were lucky to be trained at Baylor College of Medicine, where they were one of the earliest to incorporate [patient] advocates into their specialized program of research excellence in breast cancer. So we had a training in needing to do it. And when we came to Pittsburgh, we formed an advocacy group immediately called the Breast Cancer Research Advocacy Network. This is a Pittsburgh local group that meets every month, about 15 women meet every month to discuss research and help researchers. And then when we held the very first ILC symposium that was held in Pittsburgh in 2016, I think 35 advocates came to that because it’s kind of natural to us that advocates should have a say and be involved.

And there was a patient there, Leigh Pate, who drove a lot of what’s happened in lobular advocacy. She was a tour de force. She had an incredible ability to communicate. She was an incredible writer. She unfortunately passed away recently, and she does have a legacy. She donated money to BCRF to develop this legacy, which is a biobank we’re developing of models of ILC that we characterize and then we’ll make publicly available to everyone. So I think it’s kind of all come full circle. I think her spearheading advocacy in 2016 really drove a lot of these groups to form, and now you have this huge international advocacy. I mean, she really was the pioneer for this. And there were many others involved, but she really kind of drove the subject.

And I think patients, particularly when it’s been understudied, have really raised awareness through social media, through advocating, and I think that’s been good. And it’s driven a lot of scientists to think, “Yes, I should be studying lobular.” It’s easy to do that easy science. Science is never easy, but you kind of drift to the thing that’s a bit easier. And it’s hard to study a disease where you’ve got to collaborate. That’s not easy so I think that’s been a good thing.

Chris Riback: What a remarkable legacy. Isn’t that a wonderful thing? Tell me about you. How did you get into this? Was it always science for you growing up or did you just marry into the business?

Dr. Adrian Lee: I married my wife into the business, yes. No, I got my Ph.D. in London and came to San Antonio. San Antonio, at that point, was the mecca for breast cancer in the US. That’s where the San Antonio Breast Cancer Symposium formed. Nearly all the top leaders were in San Antonio. And Steffi, my wife, got her PhD in Berlin and was recruited around the same time when we met and married, had our kids there. Breast cancer has always been a passion. I think both of us feel we are lucky to have a job where we’re doing our passion. It’s one of those kind of rare instances where our job is part of our life. Obviously, we have a work-life integration, not a work-life balance like many scientists, and our kids would tell you the same. They didn’t become scientists.

But I think we get great joy particularly, like you just said, with the advocates of seeing patients and explaining. We do a lot of lay presentations. I run the Correlative Science Working Group for the [BCRF-supported] Translational Breast Cancer Research Consortium, and I gave a lay talk about biomarkers to advocates last week. I think you said this, you were the one that stated this, they have probably the biggest stake in the game and we should be listening to them around toxicities, all of these things. They’re the ones facing that. And so I think we take their comments seriously, and we appreciate hearing from them.

Chris Riback: And growing up, was it always science for you? Was there a chance that you might become a great musician or that literature was a passion? Or from day one, you were busy experimenting with chemicals or something in your parents’ kitchen?

Dr. Adrian Lee: That’s interesting you say that. There’s no science in my family. I have four brothers. They all do something incredibly different. None of them do the same thing. One’s an engineer. One’s in big banking. One’s in computer science. My dad was a painter and my mom worked, but there was zero science. I think like many, I got the opportunity to work in a lab when I was 16, and it was very transformative. I have this passion to learn. I do. Like most scientists, I am continually wanting to learn. I’m not very satisfied to stop at the status quo. Every day is a different day in the lab. There’s never a day that we are just doing the same thing. Every day is, most days, “This didn’t work and we have to figure out what to do next.”

Chris Riback: Now what?

Dr. Adrian Lee: When it does work and you get a grant and you get a great clinical trial or a great translational result, it can be super fulfilling. And as an example of how it’s changing, one of the biggest things that’s changing is computational biology.

Chris Riback: Yes.

Dr. Adrian Lee: In your life, you’ve already used AI 15 times this morning, yes? It’s integrated into everything you do. Some people don’t want to believe that, but it is. It’s driving everything you do now, from your use of the internet to everything. And that’s true in our research as well. We’ve really had to adapt to learn computational biology. That’s one of my newest things is I’m doing a lot of high-performance computing, supercomputing. I wasn’t trained in any of this.

Chris Riback: Yes, wow.

Dr. Adrian Lee: I’ve learned it on the fly and it’s not an easy data sharing and handling and wrangling. Data is not trivial, but it is exciting to have another kind of stage and another kind of thing to learn.

Chris Riback: Yes, what a terrific opportunity. And I couldn’t agree more. The field for someone who is, let’s say, genetically inclined to be a continual learner, where that is instinctively a passion, you’re obliged to do that. In fact, people like you are partially perhaps to blame for it because you keep discovering something new and that necessarily requires continual learning and learning something new. I can understand why that’s inspiring, and I thank you and your wife and others like you for that continual work, that inspiration for the rest of us. And thank you for taking the time with me today.

Dr. Adrian Lee: Thanks for having me. Those were great questions. It was a very nice conversation.

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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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.

The complexities of triple-negative breast cancer (TNBC) can sometimes make it hard to understand. It’s an aggressive form of breast cancer that is more likely to spread to other tissues––a process called metastasis. TNBCs currently have few biomarkers that can be used to detect, diagnose, and treat it, too.

Dr. Jill Bargonetti’s research into TNBC, various biomarkers, and more has put her at the forefront of discovering not only how these different variables might interact, but also how we might develop novel strategies to accurately identify and kill these cells.

Dr. Bargonetti is a professor at Hunter College, where she also is chair of the Molecular, Cellular, and Development PhD Program Department of Biological Sciences. A BCRF investigator since 2005, Dr. Bargonetti’s BCRF grant is supported by The Estée Lauder Companies’ Brands Award in Memory of Evelyn H. Lauder.  Dr. Bargonetti has received prestigious awards, numerous research grants, and served as a member of the National Cancer Policy Board and the NIH Tumor Cell Biology study section.

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Read the transcript below: 

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

Dr. Jill Bargonetti: Thank you for having me.

Chris Riback: When I started to research you and your work for this conversation, I’m sure you already know my reaction. I was like, “Oh man, here we go again. Yet another world-class molecular biologist who also is a one-time dance major and current day choreographer.” It doesn’t seem these days that you just hear about that combination all the time.

Dr. Jill Bargonetti: Very funny. I enjoy what I do. I get to do a few different things being a professor here at the City University of New York at Hunter College.

Chris Riback: You do, and I have seen it. I’ve watched and enjoyed some of the video on YouTube, but if you could explain it. We will get into your research, but obviously, the choreographing biologist was something unique in my experience. What is Choreographing Genomics?

Dr. Jill Bargonetti: Choreographing Genomics is a course that I developed where I teach the biology of cancer through postmodern dance. This understanding of the fact that cancer is caused by mutations of particular genes and different genetic pathways and relate the genomics of cancer development to the basic biology of the genomics of every cell, but how it can go wrong and how, when it goes wrong, cells can proliferate out of control. And that is basically what I take the students through from the beginning of the semester until the end of the semester, starting with an understanding of the central dogma, which is that from DNA comes RNA, and from RNA come proteins. And how these different protein products, when mutated, often result in tumorigenesis, we do it through movement.

Chris Riback: It was fantastic to come across, really interesting to watch, and got to the heart, a little bit for me, I felt like one of the reasons why we do these conversations is that communicating these ideas can be done in so many different ways, and to see it done through dance was really creative and really powerful. And I’m sure that your students get a great deal from that.

Dr. Jill Bargonetti: Thank you. I’d like to add that I would love to take it further. Before COVID, we had started a process which we called Touched by Cancer, where we invited people who had been touched by cancer, either as people who had survived cancer, family members of people who had cancer, to understand better what all of a cancer diagnosis means, what the understanding and the meaning of all these genes are. And we would have people who had been touched by cancer join us in the classroom for a few different meetings so we could get their perspectives on cancer and how it touched their lives, their perspective of their understanding. Because they are often undergoing all these different tests, getting to learn about their different sorts of treatment, their targeted treatments, and their understanding of what it means to them, but also perhaps their understanding of what might be going on that can bring a different perspective to the researcher, the student, a student’s decision to take on a particular life choice in a career. So it was very interesting to have them with us in the classroom.

Chris Riback: Another great example how connecting happens through all different kinds of sources and avenues and hearing directly from people who have been touched by cancer would surely be a most powerful way, especially for students, who I would assume are just getting into the field.

Dr. Jill Bargonetti: Exactly.

Chris Riback: The conversation, I’ve now hit the absolute peak of my ability to talk about in a quasi-smart way about dance. That wasn’t even quasi-smart how I’ve been talking, but I’ve reached my peak there. I’m way out of my field. So let’s talk about your research, and this part of the conversation obviously, like dance could, has the potential to get technical, so help me to keep it simple and help explain some of what I’m going to ask you about. Let’s start at what I believe is the top.

You are in the middle of extraordinary studies to offer novel therapies to attack triple-negative breast cancer. And to do this, you are studying three critical biomarkers, mtp53, MDMX, and MDM2, and we can get into those individually to the extent that it’s useful. And those three critical biomarkers, as I understand it, are known to drive triple-negative breast cancer and other types of breast cancer, and you’re looking to determine their role in this adaptation. First, so far, so good, is my characterization…

Dr. Jill Bargonetti: Perfect.

Chris Riback: Okay, terrific. Thank you. I will try to get at least a passing grade in your class. Given that, help me level set. Why is triple-negative breast cancer such a challenging cancer type? Secondly, what are biomarkers, and why are you so interested in them?

Dr. Jill Bargonetti: Okay. Let’s start with, first, why is triple-negative breast cancer so hard to treat, and what is it? By just listening to its name, the beginning of its name, triple-negative, it’s been classified as something that it isn’t, which is a very hard way to classify something, “Oh, you’re not this.” Or, “You’re not wrong, you’re triple-negative.” So what is triple negative? It means that the cell doesn’t have particular types of what are called receptors, and those are things that have targetable therapies. By not having one of those [main] three, it’s missing treatments that could target those three things. That’s basically it in a nutshell. Because it doesn’t have those three targetable things, it’s hard to target. What can we identify that it does have rather than saying, “It’s not this, what is it?”

Chris Riback: Yes.

Dr. Jill Bargonetti: When we talk about identifying biomarkers, “Okay, it’s not those, so let’s find some things that it is.” If we can identify those biomarkers for something that it is, then maybe we can target something at those. One of the biomarkers which you talked about in the beginning was, you said, mtp53, which stands for mutant p53. And in triple-negative breast cancer, about 80 percent of the time, they have mutant p53. And mutant p53 is a very stable protein in cancers. And in breast cancers that have mutant p53, they have lots of this protein that potentially we could target.

In the past, people have felt that they couldn’t target wild-type. Wild-type meaning normal p53. It’s been the nemesis of the biotechnology industry for a long time. They wanted to target it, they haven’t been able to target it. They have decided to call it non-druggable and forgot about it. But I think that the mutant p53 is potentially targetable, and certainly knowing that cells have a lot of it gives you an avenue to go down because having a lot of it appears to change the DNA metabolism of the cancer cell. That’s one targetable now biomarker, mutant p53.

Chris Riback: Yep.

Dr. Jill Bargonetti: Then MDM2 and MDMX are proteins that also interact with mutant p53, so they form a complex. If we use the dance idiom, you could think of it about three people holding hands together. Now you’ve got a circle as opposed to each one of them dancing off on their own, jumping into the sunset, they’re somehow coming together and running in the field holding hands. So, that’s what these three things can be together and then drive potentially differences in DNA metabolism for this cancer cell as these three biomarkers.

Chris Riback: Is part of the question how those three dance together? Is it a question of whether the three, in fact, are dancing together or whether any of them are acting alone? How does that connect?

Dr. Jill Bargonetti: Okay. It’s good. We have the dance idiom to talk about these things and we use a lot of the same language in dance that we do in science. While they interact together, they also often grab other partners. They might do some things together and they might, at times, leave the group and be asked to go move to a corner and do something different in a corner with another partner, but then be told in the choreography to go back to the center. That may change dependent upon where they are in the piece, if they’re at the beginning, if they’re in the middle or they’re at the end.

And cells, in their process of going from one cell to two cells in this division, they go through many different points in their choreography. So those partners may move around, be together for a while, find other partners, and then they may bring those other partners into the fray. If you didn’t have those biomarkers, those other partners may not come in, and some of those other partners may be evil. We might give them an evil personality, in which through that evil personality, they make the division happen more often. Sometimes they might be good, but somehow there’s been like a Dr. Jekyll and Mr. Hyde, their personality really changes for the worst, and they start to bring in more evil partners to the mix.

Chris Riback: Which type of partner, and is it a partner, is the PARP1 protein? What are PARP inhibitors, and how do those biomarkers connect?

Dr. Jill Bargonetti: I have a lot of different biomarkers and a lot of different partners that I do look at, and PARP is a protein that is very intimately involved in DNA metabolism. This would be the lover for DNA, just loves it to pieces and helps it stay around. But in cancers, very often, that PARP is working in a way that keeps the DNA there and together, when you would wish that the DNA would fall apart in a cancer cell.

Chris Riback: That confused me because I was reading about that. So it repairs broken DNA. As a layperson, I read, “Oh, broken DNA, that’s bad. I would want it to be repaired.”

Dr. Jill Bargonetti: Right.

Chris Riback: Talk me through that part of it, please.

Dr. Jill Bargonetti: In a normal setting, as I talked about, you’ve got this Dr. Jekyll and Mr. Hyde setting. In a normal setting, you would want the DNA repaired, you want that lover there taking care of everything. But in a cell that has undergone a terrible mutation that’s going to cause cancer, you want that cell to recognize, “Wow, there’s been a problem.” For example, when somebody gets a sunburn, “There’s been a problem, let’s slough those cells off. Let’s let those cells die and bring better cells to the top. Let them die. We don’t want them anymore, they’ve got all this damage.” Because that’s what happens with the sunburn, you get all this damaged DNA. “Let’s get rid of those cells.”

But what happens is, the PARP, in this setting, is allowing those cells to stay alive. So the PARP inhibitors, for example, have been used in the setting where people have a BRCA mutation, and they’re very useful at blocking that PARP from now repairing the DNA, being the lover there in a scenario where the lover should really go away. Maybe there’s a twist and there’s a pop.

Chris Riback: It’s a bad relationship.

Dr. Jill Bargonetti: A bad, bad. So, it inhibits it. And when it inhibits it, the cells die. That’s a great thing, because you didn’t want those cells because they had this mutation. But in the normal setting, yes, you do want it, but in the cancer setting, you don’t.

Chris Riback: Thank you. That makes sense. If we have now covered or at least introduced the various partners, lovers, dancers, and evildoers, and you’ve established some of the complexity of triple-negative breast cancer, biomarkers, and PARP inhibitors, tell me about your study. What are you looking at, and what are you looking for?

Dr. Jill Bargonetti: When scientists do their work, they come at it based on questions. And they have questions and hypotheses that they derive from small pieces of data that they get little by little. PARP came to us through a screen where we were not looking for it, we just were asking what did mutant p53, this one, partner in the dance, bring to the DNA? What was it doing when there was lots of it? And what we found was, it was helping to bring this partner, this lover, PARP. And it was like, “Why is it bringing PARP?” And the thing that we didn’t know about PARP was that PARP inhibitors were being used for cancers that had BRCA mutations but not being considered for cancers that had mutant p53, these mutations in p53, and in triple-negative breast cancer, that’s 80 percent of those cancers.

If that PARP inhibitor could be useful in a mutant p53 scenario, we would really bring a treatment paradigm to a large cohort of patients that currently don’t have a targeted treatment. Could we address and ask the question if PARP inhibitor-type therapeutic regimes would be useful in settings where you have a lot of mutant p53? A lot of our studies focus in on that question, can these PARP inhibitor therapeutics work to kill the cells that have mutant p53 while not really killing those cells that have the normal wild-type p53? So the Breast Cancer Research Foundation, really, all of the funding they’ve given us got us focused on this question. And that question is being developed in a number of ways, not just considering the mutant p53 but now considering these other players in the dance, the MDM2 and the MDMX, and how they all might be interrelated in bringing these DNA metabolism-type proteins to allow cancer cells to survive when we would be better off having them dead.

Chris Riback: There are so many permutations, it would seem impossible paths given these different players. What does it mean to define a novel gain of function mutant p53 pathway? In reading about that, why is that so exciting?

Dr. Jill Bargonetti: For us, it’s exciting in the fact that so many cancers do have mutant p53. And as I said, in triple-negative breast cancer, it’s 80 percent of that.

Chris Riback: 80 percent.

Dr. Jill Bargonetti: Wild-type p53 is a guardian of the genome. Wild-type p53 helps repair and keep that DNA in play. And when the DNA is damaged, it causes the cells to die. But it was thought for a long time that mutant p53 just lost that function. Now, there wasn’t this player to make the cells die, but it wasn’t doing anything else. Then it began to be clear that some of the mutant p53 that’s stable at present and high level has the ability to do other things, but it was unclear what those other things were. Now, the language gets a little bit more complicated, many people have studied what that gain of function is at the level of making the DNA become RNA. That step from taking DNA to become an expressed gene, and that RNA that becomes a protein.

But not many people have examined the gain of function for what the mutant p53 does to the DNA metabolism itself, what it does to those lovers of just DNA, not trying to make it into RNA, but just keeping the DNA successfully there in the cell, not to get sheared and fall apart, which would then allow the cancer cell to continue to exist, perhaps with an even more damaged genome, but a genome that can continue to be inherited in these cells that start to take over the body and become metastatic.

For us, finding that new gained function that was involved in DNA metabolism, it was a very exciting thing because it really hadn’t been evaluated before. Now, it’s been a number of years ago that our Breast Cancer Research Foundation funding allowed us to identify that pathway through an unbiased screen.

We weren’t looking for PARP. It had been something that people generally just used as a marker for cells dying. And here we were deciding, “Oh no, wait. We’re not looking at it for cells dying, we’re looking at it for cells living.” We’re now using this as a marker for cells that can continue to exist as opposed to, in the past, it had been used for when the PARP would get cleaved and cut up, it was used as a marker for cells dying. So we’re looking at a very different paradigm. We’re looking at mutant p53 allowing cells to stay alive, and PARP, allowing cells to stay alive.

Chris Riback: It really comes across in reading about the research, and I know I asked the question why it was so exciting, but in reading about it, it felt very exciting. It really came across that that was something different and something extraordinary. And as you said, looking at it with a different paradigm, what does your work mean in terms of various combinations of chemotherapy drugs?

Dr. Jill Bargonetti: PARP therapeutics are used in patients who have BRCA1 mutations. They are clinically used, but they are not clinically used for patients who have mutant p53. It’s not a diagnostic, “Wow, you have mutant p53, let’s see what combination therapy we can use to kill your cancer.”

Within that, I think that it has a lot of potential applications, and certainly we see that it has efficacy in our cell culture dish and that it has efficacy in our model. But unfortunately, we are not the ones who would be the people who would bring this to a clinical forefront. And how we get that information out there through the Breast Cancer Research Foundation is potentially a way that other people can then take these findings and use these findings in different ways.

And it was in those meetings of bringing us all together that I got to meet Funmi Olopade. And now we are collaborating on this mutant p53, PARP axis, in triple-negative breast cancer, but also trying to determine if we really see it more aggressively in women of African descent because they tend to, or we, people of African descent, get triple-negative breast cancer more often. So looking to see, is this a way that we can really target this breast cancer but would help everybody who gets triple-negative breast cancer.

But it brought us together, and we have a collaborative grant now through the National Institutes of Health, which would never have happened if it weren’t for the Breast Cancer Research Foundation funding starting the PARP work, getting me to meet Funmi Olopade, all these amazing breast cancer researchers that I get to meet every year. It’s just phenomenal.

Cancer studies and cancer research is basically a lot of different people adding to different pieces of the puzzle, so my little forefront of the world, my research, my lab is a small portion of what happens. There are other people who, hopefully, will find the research interesting and then investigate it in other ways and in other platforms.

Chris Riback: Understood. Maybe that’s why my questioning went in that direction because it feels like you’re doing something that then has the potential to affect those other areas. And yes, I’m sure plenty of researchers and scientists are looking for ways to take your work and perhaps start their own dance.

What does it feel like to make these kinds of discoveries? I ask because I imagine you must feel a wide range. On the one hand, a scientist and the wonder of discovery, almost like an explorer, is how I was feeling in reading about some of the work. And at the same time, pride and hope for what might be possible for people who have triple-negative breast cancer. What does it feel like to make these kinds of discoveries?

Dr. Jill Bargonetti: I like that you put everything with a positive spin, but sometimes making the discoveries doesn’t always have all that positive spin. Sometimes there’s frustration in the discoveries. I absolutely believe in this idea of using mutant p53, PARP, MDM2, and MDMX as biomarkers, but how does one get this translated to a clinical setting and utilizing these type of biomarkers and the ideas of the treatment in a clinical setting?

So sometimes it’s frustrating because I make these discoveries, I’m thinking things in my head. Sometimes it’s very complicated what I’m thinking, and I have these next steps and these next questions. But when I think about people who are struggling with the disease and how one gets these ideas into a clinical manifestation of using these biomarkers and people understanding having p53 roll off their tongue the way BRCA rolls off people’s tongue, I find it frustrating that mutant p53 is not something that’s discussed in that same way.

But meanwhile, you will say it to people who understand cancer, and they’re like, “Oh yes, that’s the most important cancer gene, but it’s undruggable or it’s untargetable.” Or “Yes. They all have mutant p53.” So it’s almost as if sometimes this pathway gets belittled because everybody’s like, “Yes. We know they have mutant p53.” or “Lots of stuff has mutant p53.” But it’s so important. It gets frustrating that more people aren’t trying to figure out a way to kill cancers that have mutant p53. So I get a little frustrated sometimes.

Chris Riback: Interesting.

Dr. Jill Bargonetti: Making the discoveries is nice, but I’ve been working on the p53 pathway, as you said, you looked at my research area, and I started working on wild-type p53 in 1990, which is frightening to say out loud. It’s a really long time that I’ve been working in this one gene pathway, although I wasn’t looking at gain-of-function mutant p53 at that time. I have devoted my entire professional career outside of getting my PhD to this p53 gene.

Chris Riback: Yes, you have. And yes, I can imagine that there surely must be frustration, and I’m sure on some level that, at some point, acts is fuel. I guess, it must, to keep one going, but yes, it could. It probably acts in both ways, but in the end, I’m sure it must act as the fuel because you’re the engine that keeps on going. So where are you going to next? Where does this research go next?

Dr. Jill Bargonetti: We continue to examine the players in the dance, and we keep finding new partners that come in and protect, perhaps, some partners that are more easily targetable. So we have found some that appear to play in the game with the MDM2 and the MDMX that are on the surface of the cell. And it is thought that partners that are on the surface of the cell are much easier to find than if you have to go into the middle. It’s much harder to go through this whole group of players. If they’re right on the outside, they’re much easier to grab.

Some of the studies are moving us to those players that are on the outside, where there are drugs that can potentially target those players on the outside. We’re thinking about those a lot. And perhaps by targeting those players on the outside, it can easily facilitate the destruction of some of these metabolic processes that are allowing the DNA to continue to exist when we would wish it wouldn’t.

Chris Riback: Dr. Bargonetti, you’ve been a BCRF investigator since 2005, and your BCRF grant is currently supported by The Estée Lauder Companies’ Brands Award in Memory of Evelyn H. Lauder. You’ve talked about it a little bit, but how would you describe the role that BCRF and Estée Lauder have played in your research?

Dr. Jill Bargonetti: Our research would not be where it is today if it weren’t for the Breast Cancer Research Foundation and The Estée Lauder [Breast Cancer Campaign]. They have really allowed us to do the kind of studies that are unbiased, to find this PARP pathway, which we never would’ve found if it weren’t for the funding. And to ask the questions in a way that allows the portfolio to continue to increase in its breath. As I talked about, we’re now thinking about things that are on the surface of the cell trying to expand. It gets a little frustrating thinking about this p53 engine that’s hard to target.

The Breast Cancer Research Foundation brings people together to think about all these various platforms at the same time. Every year, we get together and we’re talking about our research. It continues to allow me to think new ways. And The Estée Lauder Companies has been there every step of the way, including Evelyn Lauder, who really was there with me from the beginning and just supported, as she would call us, her researchers, her doctors, in our quest and in our creative questions. And had faith that our questions would help to eradicate breast cancer, and let’s hope that they do.

Chris Riback: Yes, let’s hope that they do. And yes, I think we’re all grateful that the Estée Lauders, the BCRFs, and the Cooney’s won out over the Alvin Ailey’s or whatever other company or companies surely would’ve wanted your talents there. I appreciated the dance metaphor. I think that, in particular, listening to you, it comes across why you would use that as an avenue to communicate. Not the only avenue, your work speaks for itself very loudly and very proudly. Thank you. Thank you for your time. Thank you for the work that you do.

Dr. Jill Bargonetti: Thank you for all of your very pointed questions. And thank you so much for allowing me to bring the dance idiom into my explanation of what I do. I really think that way. I think spatially and I think in movement perspectives, because cells are moving all the time and everything inside the cell is moving, so it really helps to explain the way I think about the biology.

Triple-negative breast cancer (TNBC) is an aggressive subtype of the disease, and treatment remains a major clinical challenge because it lacks the three major receptors (estrogen, progesterone, HER2) that targeted therapies can successfully home in on. Immunotherapy, which harnesses the body’s own immune system, is a major focus in TNBC research but questions and puzzles remain; namely, how TNBC cells can avoid attack by the immune system. Solving that could lead to new and better immunotherapies.

That’s just one of the many research challenges Dr. Hope Rugo has taken on. Another: Determining whether or how circulating tumor DNA in blood samples can be used to predict metastatic breast cancer or treatment resistance in patients with aggressive breast cancers.

A BCRF investigator since 2007, Dr. Rugo is the director of breast oncology and clinical trials education at the UCSF Helen Diller Family Comprehensive Cancer Center. She is a medical oncologist and hematologist specializing in breast cancer research and treatment, as well as a professor of medicine and an active clinician.

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Read the transcript below: 

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

Dr. Hope Rugo: Thanks so much for having me.

Chris Riback: Obviously, I want to talk with you about your extraordinary work and career, but in researching you, the most pertinent question quickly became obvious. Is it true that at eight years old you saved up your S&H Green Stamps to buy a children’s chemistry set from a Sears catalog because you knew even then that you wanted to be a scientist?

Dr. Hope Rugo: It is in fact true. I thought that science was the coolest thing at the age of seven and eight. Of course, I started saving those green stamps at seven.

Dr. Hope Rugo: Then, you could go to the counter at Sears and buy that chemistry set. That’s something I had wanted and worked towards for quite some time, and indeed, it was all it lived up to be.

Chris Riback: Yes. You’ve certainly graduated from that Sears chemistry set and done just a couple things.

Dr. Hope Rugo: It was amazing what they would let little kids have at that time. I don’t think they would now. You could make all sorts of fizzy things and things that went poof and that was very exciting.

Chris Riback: It sounds like it. I also read where you’ve described working in medical oncology as a tapestry of experiences. The word, of course, tapestry, brings such kind of harmonious visions to mind. What did you mean by that?

Dr. Hope Rugo: Working in medicine is already a tapestry of experiences and practices, but in oncology, in particular, there is a necessary melding of many different aspects of biology, science, personal aspects of care, compassion, communication, dealing with the early aspects of life all the way to the end of life by bringing in all of the different elements of medicine, science, biology, human interaction, and also by collaborating among professionals in many different specialties within medicine and the extended fields of medicine. I’m not working in other fields, but I think oncology, more than any other field, manages the whole person and you’re not organ-focused. You really are looking at the whole person, the whole biology of the interaction of that person with their environment and their family and their goals, as well as trying to understand what the cancer is doing to driving to both develop into dysregulated cells, and then what promotes that growth and changes that biology over time.

Chris Riback: Can I tell you in these conversations that I have had, perhaps the most surprising, but really, in a sense, the most uplifting and motivating comment that I have heard is the way in which so many different disciplines, the ways in which it brings almost literally everything together, psychology, emotion, biology, so many different aspects.

Dr. Hope Rugo: Yes, I think so. I think that one of the really tremendous opportunities and gifts that is part of clinical and translational medicine. Being a clinician is an incredible skill, but being a clinician where you can also interact with your laboratory colleagues and do clinical research, I think brings together the different aspects of medicine in oncology in a very unique and special way. It’s interesting, if you’re in the lab, you have to see the perspective from the laboratory into the clinic, and if you’re in the clinic, you have to be able to draw the aspects from the lab that aren’t yet applied to the clinic and think about novel ways that you can move forward, so there are those aspects on both sides.

When you’re a clinician, you have that additional aspect, which is just communication and understanding, which I think is a quite unique aspect of clinical oncology, where we really are talking about a scary disease and how to manage it and what the optimal treatment options are at each step of the way, and then interacting again with our psychologists, our social workers, our geneticists, et cetera, to try and provide that optimal care, so you have all those different aspects brought together in one area.

Chris Riback: Let’s talk about the disease, the treatment, and the care. Why don’t we start at the most basic level, because I think that understanding the risks your patients face will provide context as to the challenges around improving the response to immunotherapy and understanding the mechanisms of resistance in aggressive breast cancer. What is triple-negative breast cancer and how is it identified?

Dr. Hope Rugo: When I was training, we had something called Non-A, non-B hepatitis, meaning that it didn’t fit into any of the markers that we could identify, and it turned out to be hepatitis C and a number of other liver inflammatory conditions, but that’s how I first thought about triple-negative breast cancer, and indeed, we’ve evolved far from there, so we, in the 1800’s, understood that most breast cancers seem to be hormonally motivated, I think driven by hormonal mechanisms because if you had a woman who was premenopausal went into menopause, the tumor could shrink. That was the first understanding that the majority of breast cancers seemed to be driven by receptors for estrogen and progesterone and can be their growth, in many situations, can be driven by those hormones. Then, we identified that a subset of breast cancers, regardless of whether they had receptors, were driven by this amplification of a gene called HER2, and that story is a huge story of targeting HER2 and really completely changing the outcome of that subset of breast cancer that continues until this day. Then, what about all the other breast cancers? We identified those breast cancers initially as not having receptors for estrogen and progesterone, and then subsequently as not having HER2 gene amplification, and so once we had HER2, of course, that became triple-negative, where patients’ tumors do not express estrogen and progesterone receptors and don’t have amplification of the HER2-neu gene on chromosome 17.

That triple-negative breast cancer then underwent further characterization, and indeed, just like all subsets of breast cancer, triple-negative breast cancer is quite heterogeneous, so you don’t just have one triple-negative breast cancer. In the United States and in Caucasian patients, there seems to be a sort of a particular subset that predominates in triple-negative breast cancer, where most triple-negative breast cancers seem to be very rapid in the tumor growth. When I say rapid, it’s important to keep it into perspective. This isn’t leukemia, where it’s growing every day, but compared to the more indolent or slow-growing hormone receptor positive breast cancers, triple-negative breast cancer cells divide and turn over faster and are more efficient at invading and moving around. They also, and there are always exceptions within every subgroup, so there may be hormone-receptor positive breast cancers that act more triple-negative, so just to clarify that, but triple-negative breast cancer seem to be more plastic in their biology, so that under the pressure of treatment, they can develop mechanisms that allow them to grow under the treatment you’re giving that originally caused the tumor to shrink, so there’s more plasticity or instability, as well as the absence of receptors. Now, within the triple-negative breast cancer, there are subsets that are quite different.

There are subsets that look more like connective tissue, as opposed to looking like breast cells. In older women and sometimes in younger women, less commonly, we see a subset of breast cancers that are slower-growing, look a lot like hormone receptor­­–positive breast cancers, except for they don’t have the hormone receptors. Those cancers actually behave differently, and there may be differences between racial and ethnic subgroups in terms of the frequency of these different subtypes of breast cancer, but for all intents and purposes, when we’re speaking about triple-negative breast cancer, we’re talking about this more aggressive subtype that seems to predominate in the population we see.

Chris Riback: If I understand correctly, one of your set of studies is around trying to determine how the triple-negative breast cancer cells are able to avoid attack by the immune system with your goal, of course, being to develop new and better immunotherapies. Is that related to the plasticity that you just mentioned or is that related to something else? I know it’s at the heart of your own questions, but why are triple-negative breast cancer cells able to frustrate attacks by the immune system?

Dr. Hope Rugo: That’s an interesting question. It’s a little sort of to the side of our project because there are so many aspects to the answer to your question, so one is, “How can triple-negative breast cancers escape the immune system?” And there seem to be many mechanisms. One of which is part of our project, first project within the BCRF grant. One area is that as the burden of cancer increases, the cancer is able to turn down the host immune response, so the more cancer you have, and potentially this is related to these drivers of cancer growth, which is part of our projects, that drive the cancer to be larger sooner, and then suppress the host immune response. The mechanism of suppressing the host immune response is not simply the mutations within the cancer.

It has to do with multiple different mechanisms, and trying to overcome that with immunotherapy is a major aspect of treatment, I think, of treatment investigations now for a triple-negative breast cancer, and there’s a reason why immunotherapy works better in early stage breast cancer than as breast cancer starts growing and being larger, more invasive, and eventually metastasizing. Again, it has to do with this better immune response in smaller tumors, even the immune cells that can infiltrate the tumor decrease, as well as the immune markers as the tumor continues to grow. Why that happens is not clear, but it is definitely an important part of this escape of the immune system. Now, the instability of the cancer seems to come from many aspects, so we can’t just look at mutations, so looking at alterations in DNA or the RNA that comes from DNA changes in protein, that doesn’t by itself explain how the cancer becomes more resistant. Although, as the cancer becomes more resistant, it develops more and more instability mutations, et cetera, but there are major initial drivers that reprogram the ability of the cancer cell to grow and change the stops and the controls.

As those mutations occur, they make a lot of other changes in the cancer cell, and part of that is the ability to suppress your body’s immune system from recognizing the cancer and contributing to the ability to suppress its growth.

Chris Riback: Now, as I understand it in a parallel study, and I’m wondering to what extent this relates to the point that you were just making. You’re looking at not necessarily, let’s call it the front end of cancer that a patient is diagnosed, so now, how can we implement the most effective immunotherapies, but rather, what felt to me like the other side of the coin, how can we better predict metastatic relapse? What is the status of your work around the serial analysis of circulating tumor DNA, I guess ctDNA, in blood samples?

Dr. Hope Rugo: This is such an incredibly interesting and cool area and going back to my interest in that chemistry set, when you have tumor, and you have to have some tumor, but you might not have any visible tumor by imaging or exam, the tumor actually will put fragments of DNA into the blood, and we had started our evaluation of circulating markers of tumor, which might be much more sensitive to both detecting tumor, as well as providing a rich source of tumor to interrogate the cancer about what’s going on that’s making it act so differently, so we started that whole process looking at circulating tumor cells, so tumor cells that were shed into the blood. The problem with that was that it required special processing. These all do, but the cells themselves, they had to be analyzed very quickly because otherwise, they would fall apart, and then not everybody has circulating tumor cells, so only about 50 percent of patients, even in the metastatic setting where patients have quite a lot of visible cancer. The whole new field of looking at what happens when those cells fall apart and just in patients who have even early stage cancer is that you can find this cell-free or circulating tumor DNA in the blood, and using special techniques in the blood, you can actually find these cells even in patients who have early stage breast cancer.

Chris Riback: Wow.

Dr. Hope Rugo: You could understand in metastatic disease where you had cancer in the liver, lung or wherever the cancer was, that there would be shed circulating tumor DNA, but in early stage breast cancer, this has been really a remarkable finding, and it is something that we can then use to understand the tumor biology, what’s driving the tumor, but also, to try and figure out how therapies work and what we could do to intervene to change outcome in a more sensitive way than simply following the size of the tumor.

Chris Riback: Yes. Again, as a layperson in reading about ctDNA, it felt almost like a cancer thermometer of sorts, potentially like an early warning system. Is that an appropriate way to think about it or is that too simplistic?

Dr. Hope Rugo: I think that that’s a good terminology to use. I want to separate the use of cell-free DNA in metastatic versus early stage breast cancer.

Chris Riback: Please.

Dr. Hope Rugo: Cell-free DNA in the metastatic setting in cancers that are generally considered to be incurable, treatable but incurable, is used right now as a very important test to help us understand mutations that drive cancer growth that we could potentially target with new therapies, and that’s a way, for example, to find mutations that can be targeted by drugs called PI3-Kinase inhibitors or tumors that have mutations in the estrogen receptor, called ESR1, and the importance of ctDNA in this setting is that not only could it tell you new changes that are occurring in the cancer, but also, it means that patients might not have to have biopsies of their tumor that are more invasive, uncomfortable, and risky.

Chris Riback: Yes.

Dr. Hope Rugo: Biopsies still have a really important role, but ctDNA has been this tremendous advance in giving us a little bit more window into potential targets in the treatment of cancer. There are also studies that are looking to see whether or not if you were to change therapy based on ctDNA numbers alone, so the fraction of tumor burden evidenced by blood measurements. If you were to change therapy based on that alone, no evidence of cancer progression could you change outcome.

Chris Riback: Wow.

Dr. Hope Rugo: To date, there’s no evidence that that’s the case, but there are studies that are looking at this, but certainly would not change based on that now. In the early stage setting, we have one overlapping and one very different rationale, so one is, could the ctDNA give you a better window into the prognosis of the cancer compared to looking at the tumor shrink by itself? For larger, more aggressive cancers, we want to give treatment before surgery, called Neoadjuvant treatment, because one of the most frustrating aspects of treating early stage cancer have been you treat the cancer after surgery, so there’s nothing you can see anywhere, and then you just wait to see if it worked, right?

Chris Riback: Yes. Yes.

Dr. Hope Rugo: What you’re waiting for is, does the cancer come back? It never really made sense to me, and so now, we are treating before surgery because that response to treatment before surgery gives us a big window into prognosis, or what the potential outcome is, and more recently, it’s allowed us to individualize treatment based on response with evidence of improvement in outcome where we’ve changed that treatment approach in subsets of patients and subset of tumors, so how could ctDNA help us in addition to the response? Well, once you have a response to treatment and you go to surgery, you could have no cancer left, invasive cancer, or you could have a little bit left or a lot. Now, the ctDNA, we believe, adds into that information to give you more data about potential outcomes, so some patients who have cell-free DNA at the time of surgery won’t have recurrent cancer. Other patients, even those who have no invasive cancer at the time of surgery who have cell-free DNA, they might still have a substantial risk of recurrence.

This may give us more of an information that will help us tailor treatment for patients, and you could follow these tumors over time and get an idea of if something was going to be at risk for recurrence, maybe not today, but in two years or three years, you could potentially, and this is our pipe dream, change therapy to change outcome. Then, the second aspect of this is, could you use that cell-free DNA to individualize treatment? If that tells you there’s an emerging mutation, for example, that makes the hormone treatment that you’re using not effective, or does that tell you that a new mutation has evolved that would help you use a targeted agent more effectively? Those are the two aspects of looking at cell-free DNA. It’s been fascinating actually because, I think our early data suggests that this information may really help us in understanding prognosis, but more importantly, changing outcome.

Chris Riback: So much potential, and thank you for that really clear and, as you said, fascinating to hear the possibilities and the hopes. I have one other area that I want to ask you about quickly before I let you go, but before I get to that, is there anything else about your studies that I should be asking you about or that you wanted to cover that we didn’t get to talk about?

Dr. Hope Rugo: I think the studies that we’re doing are, I think, really exciting and forward-thinking. I’m so even more excited about the data that’s come out over the last year and our prospects over the next year. I think there are two things to mention that make this all possible.

Chris Riback: Please.

Dr. Hope Rugo: One is BCRF funding allows exploration of areas that wouldn’t be funded by other mechanisms, and I think that’s important to keep in mind because it’s actually a really interesting thing. I mean, you need data to get funding and to move forward, and many of these explorations, new information that’s kind about BCRF funding, would’ve taken decades longer without that funding, so that’s really important. Then, just in terms of my projects, nothing would happen without collaboration, and I’m so fortunate to have amazing colleagues in the clinic and in the laboratory, and my funding supports these really very smart people’s work in the laboratory, and then allows us to move that laboratory work into the clinic, and we wouldn’t be able to do that without BCRF funding.

Chris Riback: Well, thank you for those points, and yes, the people that you work with and the extension of what you are able to do surely connects with all sorts of innovation and scientists and researchers, and so yes, it’s a wide net that gets to be cast. I guess to close out then, I was also fascinated to read that you remained committed to education and regular lecturing, which is even more amazing now that you’ve discussed all of the studies and potential and the data and all the things that you’re kind of balancing/juggling on that hand, and that you run, I assume you still run the Breast Forum, an open bimonthly evening educational session for breast cancer patients, families and friends throughout the Bay Area. First of all, do I have that right? Is that still something that you do, but also, just your committed effort to education and regular lecturing?

Dr. Hope Rugo: Yes. The forum, yes, continues, and it’s actually been amazing, the few, little silver linings of the pandemic, and so we changed our in-person forum to a Zoom meeting in order to continue it during the pandemic.

Chris Riback: Of course.

Dr. Hope Rugo: I mean, it was kind of funny because we never would’ve thought about that or really understood we could achieve that, but we were able to open up the forum to people who obviously couldn’t drive in and park into San Francisco in the middle of the week in the evening, and so we now have a huge number of attendees who come, and we’re also able to focus on specific aspects of breast cancer that our audience is interested in, but the forum has been a great program where patients can ask questions and we have my tremendously gracious colleagues who will donate an hour and a half of their time to talk about their work and how it applies to the clinic to make the new information coming out digestible for our patients. One of the things we do in the forum, other than talking about specific areas of patient interest is we review the results from all major international meetings at the forum. My colleagues come. Again, they routinely donate their time.

They talk about the new data and how it applies to the clinics, most importantly, and patients can ask questions about these areas, which, I think is so important. Being knowledgeable gives people power and really helps them with hope, and also being able to ask appropriate questions of their own physicians. Then, the education for practitioners providers is as important because, I think the general oncologist is a tough job to have right now because there’s so much to learn in different areas of oncology, but if you’re practicing outside of an area where you have people talking to you all the time about the new advances and hearing these information and participating in these studies, you can’t keep up, so understanding how this data can be applied to the clinic when new studies result, but also, and really importantly, understanding how that data applies to the individual patient is the key importance of medical education, and medical education nationally and internationally is what drives excellence in patient care and allows new developments, and it’s not just drugs, but new understanding of treatment of cancer into the hands of the patients.

Chris Riback: Dr. Rugo, thank you. Thank you for your time, and thank you for the work that you do every day with and for patients.

Dr. Hope Rugo: Thank you so much.

There’s no one-size-fits-all approach to targeted breast cancer therapies. Breast cancer subtypes all behave differently from each other. We know better therapeutic strategies are desperately needed for triple-negative breast cancer (TNBC), an aggressive form that lacks targeted therapies, making it especially challenging to treat. 

To mark Triple-Negative Breast Cancer Day this year on March 3, we dove deep into the science of TNBC with BCRF investigator Dr. Elisa Port, whose BCRF supported research focuses on this subtype.

Dr. Port is chief of breast surgery of the Mount Sinai Health System and director of the Dubin Breast Center at Mount Sinai Hospital in New York. Dr. Port, BCRF investigator Dr. Hanna Irie, and their teams are working to combat drug resistance in TNBC by developing a drug for the protein PRKCQ—a promising therapeutic target that may make TNBC more responsive to chemotherapy.

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Read the transcript below: 

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

Dr. Elisa Port: Thank you for having me. It’s always a pleasure to be here.

Chris Riback: First, you’re a very well renowned surgeon, of course, and scientific researcher. So obviously it only makes sense that in college, you double majored in Spanish and French. I’m sorry. Dr. Port, did you take a wrong turn when you walked down the stage to get your diploma?

Dr. Elisa Port: So, I was not one of these people who was so goal-oriented, driven, directed early on in life. Yes, I was very achievement-oriented. Of course, I got good grades all through high school and college, et cetera, but I actually did not start out knowing what I wanted to do. My father was a doctor and I had of a cousin, who’s more like a big brother to me, who’s a doctor as well. So I definitely had my role models, but I wasn’t sure. I spoke Spanish growing up and I thought that was a were important skill to have. And I found that I had a facility with languages and wanted to develop that. And the college I went to, Dartmouth, had a really incredibly well-developed language program. So I really wanted to take advantage of that somewhere along the way the pre-med courses sort of fell off the language courses. I know this sounds incredibly passive, but it’s the truth of how it happened and the language courses just kept getting added on. I really enjoyed them more and more.

And in the end, I graduated as a language major and I had not really completed my pre-med requirements. I just kind of let them ebb way, which meant that a year or so later after floundering around in the real world, when I decided maybe medical school was a more directed approach and something that I would want to do. And yes, I can always use my language skills in that. I actually did have to go back to school to complete pre-med requirements and I did that in an extra year. And, I did that in kind of an expedited plan and then applied to medical school. And obviously, the rest is history.

Chris Riback: It’s a terrific history. And I mean, that’s a great and helpful story for many of us, I think of all ages. First, how many of us can empathize and recognize that there’s not a straight path in life and that often happens. And the patients that we’re going to talk about that you deal with many may, if not all of them, might be facing situations that don’t offer the straightest path that they thought that they might have had. And there’s a lesson there. And two, and maybe we’ll talk about this as the conversation goes on, but among your skills, and you’ve written a book outside of just a scientific medical textbook, is your ability to connect with patients and understand that human component that goes beyond the purely scientific, purely medical, purely here’s your diagnosis. Thank you very much. See you later. And I can only imagine that on some level that all connects and goes back to your earliest days of hola and bonjour.

Dr. Elisa Port: Well, listen, I had a very clear understanding early on, I grew up in San Diego, California. My house was about a 25-minute ride from the Mexican border. And there was an incredible Mexican influence. And we would go down to Mexico for dinner. And a lot of time there, vacation there, had many friends. And when I say Mexican, I don’t mean of Mexican heritage. I mean, people who, my family worked with whatever, who lived in Mexico and would come across the border every day into the states for work and vice versa. so that was a huge cultural influence for me, and I just found that thankfully speaking Spanish and learning Spanish came naturally, but I just also found it to be, I think for a doctor in the United States, speaking Spanish is one of the most useful skills you can have practically speaking again, to your point Chris, connect with people and meet them on their own terms.

I don’t use one iota of organic chemistry or physics anymore, but I can tell you, I use my Spanish on almost a weekly basis, and I love that and I love that we’re able to connect. I just think, this is a bigger statement, but I just think in America, we are so used to everyone speaking English for us. And if you get outside the United States, it’s just incredible how you can travel anywhere and, thankful for Americans that most people do speak English because most of us don’t speak a second language. And I think that’s a shame.

Dr. Elisa Port: And I found that when we travel and we speak the native language, whatever that is, even my very rudimentary now French is a use it or lose it kind of scenario. And let’s just say, I have not had the opportunity to use it the way I do Spanish. It’s just lovely to be able to, again, when you travel to these countries to speak the native language.

Chris Riback: Well, there’s another great lesson out of that that comes from many of these conversations that I’ve had with other scientists, researchers, doctors like yourself is this work is going on all over the world. I want to get into your research, particularly around the triple-negative breast cancer patients, but there was another item that struck me slightly more on point was a quote of yours that I came across where you said in, “In 2020 women diagnosed with breast cancer should have every reason to be optimistic.” It’s now two years after that statement, I’m betting you stand by it. Tell me why?

Dr. Elisa Port: Yes. More so than ever before, because what we’ve seen. One of the statistics, Chris, that kind of backs that up is between the year 2000 and 2010, the death rate from breast cancer dropped almost 2 percent each year. that’s crazy numbers. That means that if you were diagnosed in 2011, 2012, you were 20 percent more likely to survive than if you were diagnosed in the late 1990s. That is a lot of progress in a very short period of time. And that trend just has continued strongly and it’s owed to a variety of different factors, which continue to develop and title wave, which are improved diagnostics, improved technology and earlier diagnosis, so that we can catch these cancers earlier when they’re way more treatable, way more curable. And then the second part of course, is research that has led to better treatment options than ever before.

At any given point, like at my center, I think we have 20 clinical trials going on in breast cancer, and that’s just our institution where we’re very, very heavily invested in research and cutting-edge care, the Dubin Breast Center and at Mount Sinai. Not all of those trials are going to translate into meaningful improvements, but some of them will. And so if you’ve got that many irons in the fire and that many options that are being explored, even a couple of them are going to translate into big breakthroughs for improvement for a group of patients that otherwise might have had might not have had other options.

Chris Riback: So, let’s talk about the research and let’s start with the broad perspective and what you are facing. Why is drug resistance such a particular challenge in triple-negative breast cancer? Why is the response to standard chemotherapy so highly varied and why do so few targeted therapies exist?

Dr. Elisa Port: Oh my gosh. These are our philosophical questions that if I could answer, I would probably be on the short list for some very big prizes.

Chris Riback: Well, we look forward to nominating you?

Dr. Elisa Port: God, no. This is like lifetimes of work. So let’s just look at what triple-negative breast cancer is. Let’s talk for a second to your point right before, which is the optimism related to breast cancer. And what I said about the improvement in survival between 2000 and 2010. So much of that, Chris was hinged on the develop of HER2/neu targeted therapy. When we say triple negative, what is the triple, and what is the negative? We now have moved past the one size fits all for breast cancer. We know that breast cancer is not just one disease. It’s multi-different, what I call, subtypes. And each one of these subtypes behave so differently from each other. They’re almost like comparing breast cancer with colon cancer or colon cancer with ovarian cancer.

So, these subtypes are so different from each other and their treatment pathways and the option for treatment can really diverge wildly. So, the first order of business, when a patient comes into my office, newly diagnosed with cancer is, I say, the first thing you need to understand is that there’s different subtypes of breast cancer. And how do we figure out what subtype you have? And the answer is it’s really easy. Once a biopsy is done and it shows cancer, they run three tests on that tumor. They run a test for what’s called estrogen receptor, progesterone receptor. And the third one is called HER2/neu. And together those three, that’s the triple, help tell us and define for us what is making that cancer grow or tick.

So, when a tumor is said to be estrogen and/or progesterone positive, that means that hormones are feeding that cancer. It’s helping the cancer grow, almost like hormones to a cancer is like water to a plant. And the reason why that’s super important is that let’s just agree, and it’s super intuitively obvious that the more you know about what is making a cancer grow, the more options you have to intervene on that level. So, we have multitudinous different drugs that block cancer cells from seeing hormones that they need to grow. So, if your tumor is hormone positive, there’s all these different me medicines you can choose from to block that stimulation from happening. So, it’s like stopping to water the plant. What’s going to happen if those tumor cells don’t see these hormones? Many of them will wither up and die or implode. That’s why being Esther and progesterone positive is a favorable thing because we know that that’s the way the tumor is growing. And we have many of those options for treatment.

Chris Riback: You have ways to try to turn off the water.

Dr. Elisa Port: Yes, and target it. As you said, to your point about targeted therapy that is targeted therapy, this cancer is being fueled by hormones. We are going to block that. That is targeted to your tumor. The third one, the third component, HER2/neu, which is lesser-known is a protein that sits on a tumor cell. And when HER2/neu is positive, it used to be a very bad thing, because those were considered aggressive cancers. But flash forward to that decade we talked about 2000 to 2010. When a couple of, as you said, targeted therapies were developed to latch onto that HER2/neu protein and cause those cells to implode. That drug, the first drug of its kind, was called Herceptin and there have been others to follow. And basically, what that did overnight, Chris, was it used to be we’d see someone with HER2 positive breast cancer and go, “oh, oh no, that’s kind of an ominous sign. We’re going to treat you, but we don’t know how this is going to turn out.” Twenty years later, we’re like, “We’ve got this medication that will most likely melt the tumor away so effectively that when we go to do your surgery to follow, there might not even be any cancer left.” And so that’s a third targeted therapy.

So, we have estrogen, we have progesterone, we have HER2/neu and we have very targeted therapies for all three of those markers. So, triple-negative breast cancer means estrogen negative, progesterone negative, HER2/neu all negative. That means that none of those things are known to be working or at play with the growth and perpetuation of this cancer. Doesn’t make it not a cancer. The problem is we just know less about what is making grow and that’s why the targeted options are more limited. And really the only option we have for those patients is a more generic form of chemotherapy.

Triple-negative breast cancers make up about 15 percent of all the breast cancers we diagnose, but they’re disproportionately more common among certain groups like African American women. Black women, when they get breast cancer, 30 percent of their cancers are triple negative. Big problem. Women who have the BRCA1 gene, the BRCA1 gene, not the 2. If they get breast cancer, 75 percent of their cancers are going to be triple negative. And so, you have very specific subgroups of people who are at high risk for developing triple-negative breast cancer. And from me, that’s sort of the last group where we don’t have as effective options as the ones I described for the other groups. And that’s where we still need to make more progress.

Chris Riback: What then is the protein PRKCQ, and why are you focused there?

Dr. Elisa Port: This is what we’re researching, which is ways of figuring out and mechanisms of figuring out whether or not there are other tests we can do on the tumor to define, number one other targets that are drugable. And number two, if there’s a way to predict which tumors in advance are going to be chemo-resistant and whether or not that chemo-resistance can be overcome. So together with my amazing researcher partner, Dr. Hanna, who we call Yoko, Irie, who’s an MD PhD, and she’s truly the brains behind the operation as it relates to the science recently discovered a compound that when given together with certain chemotherapies, that in certain tumors that were resistant to chemo alone. When you give this compound in combination, it almost like unmasks the tumor and makes it sensitive to chemotherapy.

One of the reasons why this work has been so important and is funded by BCRF, which we’re incredibly grateful for, is that what our actual grant has allowed us to do is develop this incredible resource, Chris, which is these, what we call avatar models. So, what we’ve done is when a woman comes into our office and she has a diagnosis of triple-negative breast cancer, with her permission, we put her through another biopsy to retrieve tissue, additional tissue from the tumor, these before she gets any treatment. And usually what we do with that is we try to grow that tumor out and try a number of different chemotherapy agents biologically.

And what we’ve been able to do with our research has been in the patient we go ahead then and give chemotherapy. And what we’ve done is, of course, at the conclusion of chemotherapy, these people all get surgery. And that’s when we see and measure the response to treatment, some women will have what’s called a CR, the complete response, meaning we go to take the tumor out and it’s all just scar, dead tumor cells. And some women will have residual cancer. And those are the people who, to varying degrees are what are called chemo resistant. And so now imagine you can take a piece of that tumor that’s left over and compare it to the original and you know which patients are chemo resistant. And you can focus on those as a model for research in overcoming that chemoresistance.

Chris Riback: And in what stage are you at in this research. My understanding, and you’ll correct me, please, if I have it wrong, is it’s still lab work. Is that accurate? What is the status of the research?

Dr. Elisa Port: A hundred percent correct. It is lab work, but now that we’ve identified these druggable, these compounds, we are working toward developing a clinical trial.

Chris Riback: As I was thinking about that, and I don’t know if this is a scientific question or an emotional one: How do you balance, perhaps in your own mind, the speed and urgency needed? You’re trying to help triple-negative breast cancer patients with the care and time required to do research right. I know there are standards and rules and guidelines, and you have all of that. Still, getting that balance right, I’m sure you want to help every patient yesterday. How do you balance that tension?

Dr. Elisa Port: I don’t think it’s possible in the sense that the processes is the process, and there’s only so much time that all of these processes take, and those are sort of the built-in limitations. You know, there’s also resources too. Think about what’s been done in public health, as it relates to, for example, look at how quickly a vaccine for COVID was developed. Billions of dollars were at it. And it does make me wonder, if you put a hundred of the best and brightest scientists in one room and threw some unquantifiable, ginormous amount of money at them to come up with one or two or three therapies for triple-negative breast cancer would it happen any quickly?

I do think all of us share a sense of urgency, and I don’t think there’s any complacency on our part or on the scientific community part. But, I would just look and say, yes, if breast cancer is the sum total of a whole circle and triple-negative breast cancer is sort of the last bastion of 15 percent, look at how much we’ve done with the sense of urgency over the last 10 to 15 years to improve outcomes. And yes, this is the remaining piece of the slice of the pie that require requires a lot of effort, energy, attention to have better options.

Chris Riback: You mentioned earlier, as well, the importance of recognizing, finding, identifying cancers early. Tell me about your research and for our listeners, we’re doing this conversation via video using only the audio and I don’t know how it [the conversation] could have gotten better, but it just did because Dr. Port just brought a terrific looking dog into the-

Dr. Elisa Port: This is my rescue. This is my Rooney, the rescue

Chris Riback: Rooney, the rescue. We are going to have to make this video because Rooney the rescue, think our audience would love to see Rooney.

Dr. Elisa Port: It’s called pet therapy. I’m a big fan.

Chris Riback: Excellent.

Dr. Elisa Port: Both for me and our patients.

Chris Riback: Okay, well, if we hear a little bark now everyone will know why and it’s no problem. Tell me about some of your earlier research and the role of MRI in patients at high risk for breast cancer and the role of PET scanning in breast cancer.

Dr. Elisa Port: So early on when I was in practice in the late 1990s and early 2000s, there was a huge explosion in tech technology and imaging. And I was very, very interested in, wanted to play a role in figuring out how to optimize the use of those technologies in our breast cancer patients and PET scanning was one thing. PET scanning is really whole body imaging to figure out if cancer has spread to other parts of the body. We don’t use it in all patients, people with very early-stage breast cancer do not need a full-body scan. People ask that all the time to find out if the tumor is spread, but people with more later-stage diagnosis can often benefit from them to define how of the diseases and whether or not it has spread to other parts of the body.

PET had been used in other disease types and I was really interested to see if it was effective in breast cancer. I did a study really early on looking at the comparison of PET scan to, at that point what was standard of care imaging, which was CAT scan and bone scans, kind of old school. And what we found is that PET scans were a little bit better as it came. They were equal in detecting systemic disease, but they were better in the sense that it was one test instead of two tests. So putting patients through less hassle and all of those logistical nightmares of coming in for testing. It was also more, what’s called, specific, meaning if the PET scan was positive, it was way more likely to be accurate, in that sense. We definitely also discovered that there were certain kinds tumors that it wasn’t so great for. There’s a subset of breast cancers called lobular cancers and PET scans don’t work as well. Those tumors tend to grow less like a ball and more like a sheet. So, they could be really sneaky and PET didn’t pick that up so well.

Those were all things we helped to define and then PET scanning came into, as a result of our work and many others, PET scanning did become kind of standard of care for a subset of patients with breast cancer. So I think I just played a small part in helping define what the utility was of PET scanning in breast cancer patients. As it relates to MRI, MRI has definitely now become one of the most common tests to be done in women with breast cancer.

And I looked at it in one study I did as how useful it was in screening women at increased risk for breast cancer. And we found in terms of picking up cancers that mammograms might miss. And like many, many studies that have been done, we added to the body of literature, showing that in certain more high-risk groups, MRI is very helpful in additive and screening. And mammograms alone are probably not enough. In other groups that are slightly elevated risk, but not as high, then MRIs may not be as much added value. And so it’s really just all about exploring some of these new things that were coming online and trying to not one size fits all and throw the kitchen sink at everyone and really help figuring out who can benefit the most.

Chris Riback: Well, it was certainly interesting to read about that set of work that you did. And now the work with PRKCQ, which to a layperson feels totally different. But, then again, as we discussed earlier, you started your life in a totally different area, languages. So perhaps it’s not surprising you have a flexible mind that can transition.

I have two questions that remain in my mind. One is positioned perfectly behind the delightful rescue [dog], Rooney, is your book, The New Generation Breast Cancer Book. That book now is, I think a couple of years old, maybe four or five years old?

Dr. Elisa Port: Yep. About five.

Chris Riback: About five, I’m sure, just as relevant today. Why did you write it? Who were you writing it for?

Dr. Elisa Port: Thank you for asking the question because the book was really a passion project. I never said, “Oh, I want to write a book and I want to do that.” Really, it started because I felt like there was an unmet need and that there was a hole that kind of needed to be filled. And what I saw, Chris, was that as you and I talked about, the prognosis for breast cancer patients was getting better and better and better. and we had more and more to offer. And yet there was a total disconnect between that and women coming into the office newly diagnosed with more doom and gloom than ever before. For a very long time, it took me to process to figure out what was going on, why was everything I was talking about: We’ve done better than ever before, we have so much to offer you, and yet women were really, really coming in, like at their wits end.

And the answer I figured out was this exploding thing called social media and the internet which really is now 10, 15 years old as it relates to the level of access. And so what I started noticing is that the internet in particular is sort of a clearing house for, yes. Everyone says when you’re diagnosed with breast cancer, get information, get information, but starting to be the problem was not lack of information. It was actually too much information with no filter. So when you are that person with early-stage breast cancer, as many are diagnosed with going online, you are seeing kind of the worst of the worst. And I equate it to like Yelp or like Expedia any of these places where you’re having reviews. For the majority of women who have been breast cancer and go on and get their treatment and do really well, you don’t see those people blogging and chatting anymore. They go on to live their lives.

So, by definition, what I was seeing is that if you aren’t newly diagnosed and you are going online, there was a very curated selection of people who either had bad outcomes, more likely, who were desperate, who were filling these pages with really, really negative stories. And so when you’re newly diagnosed and you’re reading that and that’s all you’re seeing, it’s a very bad place to come from. Onto top of it, of course, with email and texting and all those things, what was happening I found is that women would email a friend and that friend would send out an email to 10 friends and they would-

Chris Riback: Post it on Facebook.

Dr. Elisa Port: Yes, post it on Facebook, see this person, see that person, I heard this, I did a lumpectomy, I did a bilateral mastectomy. You need to use my doctor. And again, it’s done under the: everyone’s just trying to help. But to the point that we made earlier, one of the huge improvements with breast cancer is there is no one’s size fits all. And so women were getting a lot of feedback and a lot of intel about other people’s cases that may have nothing to do with theirs. And they were coming into the office saying, to the point about PET scanning, my neighbor told me make sure I get a PET scan. My sister told me tell your doctor to do genetic testing and not realizing again, under the auspices of everyone’s trying to help, but not gets everything and all cases are different.

So, the book came out of the need for what I consider the hardest part for patients with breast cancer, which is from the moment they get the diagnosis, which is usually a phone call from their internist, primary care doctor, radiologist to the time where a set up an appointment with a breast surgeon to get a plan. And that’s sort of the dark, the black hole, of scariness and lack of information where women are their most vulnerable and are at most risk for being taken down a rabbit hole of doom and gloom.

And so, I wrote the book. It is truly not at all patronizing, intense or paternalistic saying, don’t go to the internet. It really was written as a kind of insulator, or a framework to give women sort of an overview and to give them sort of a calming background against which they understand that if they seek out this information, it may have nothing to do with them and to understand that until they get in to see a doctor, who can give them advice about their particular case, all of this stuff is kind of just background noise.

Chris Riback: What an outstanding insight that I’m sure all of us listening are extrapolating to all other parts of the internet and life and society, et cetera, but will hold that aside. But the insight that there’s no longer a lack of information. On the one hand that’s great, but what that has created though is a lack of a filter. And in particular, breast cancer, it is all about the personalization. There’s a lot of information out there, but it’s not filtered, it’s not customized, it’s not personalized. And that’s a great insight and a great help. To close out: BCRF. What role has BCRF played in your research?

Dr. Elisa Port: Well, BCRF has played a huge role in my research. Number one, of course, the funding of this research, which I think is going to be groundbreaking over time. I think some of the discoveries that my partner Dr. Hanna Irie has made, and that I’ve been privileged to be involved with really have legs. And I think that that’s obviously number one, two, and three on the list, the funding of really critical research and the idea of the cache of the BCRF researchers selecting out the top performers and the minds that have the most promise and the most likelihood of changing the playing field and delivering transformational options to our patients. And they’re really selecting those people out.

And I think the second part is actually what some people don’t get to see is the collaboration between us. I think the sad part of COVID is obviously we haven’t all gotten together and reunited in the way that we did, but the summits and the retreats and the discussions and the collaborations that have been developed out of these things, those are priceless. And those are incredibly important to furthering the end goal, which is more options for treatment, better options, a cure. People say, “Well, when will breast cancer be cured?” And the answer is: It is already being cured. Lots of women, the majority of whom get breast cancer are cured. Our goal is to cure all women. And we’re not there yet.

Chris Riback: Not yet, but with the work that you’re offering, Dr. Irie and others, someday. Dr. Port, thank you. Thank you for your time. Thank you for the work that you and your colleagues do every day.

Dr. Elisa Port: Thank you so much for having me. I really enjoyed speaking with you and thanks for getting such important information out there.

Effective medicine has always relied on clear and verifiable diagnoses. Of course, for patients, the wait and uncertainty of diagnostics can be especially trying.

Dr. Connie Lehman is among the scientists and practitioners trying to change that. And she’s doing it in myriad ways—from leveraging both new technologies like artificial intelligence (AI) to conducting old-fashioned operations management fixes—to drastically reduce wait times and detect cancers earlier.

With more than 250 peer-reviewed publications to her name, Dr. Lehman has led meticulous studies of advanced imaging tools to identify breast cancer at its earliest stages—when it’s all but guaranteed to be cured. Dr. Lehman, a BCRF investigator since 2019, is a professor of radiology at Harvard Medical School, and chief of Breast Imaging and co-director of the Avon Comprehensive Breast Evaluation Center at Massachusetts General Hospital.

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Read the transcript below: 

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

Dr. Connie Lehman: Oh, thanks for having me. I’m glad to be here.

Chris Riback: So, let’s start with the area, the word, the procedure, that everyone knows about, mammography. Is mammography still the gold standard? What are the benefits of mammography and other imaging techniques? And what do you wish were better about the process?

Dr. Connie Lehman: You know, it’s so interesting, because almost every new grant that I review or read, in the area of early breast cancer detection, they start by talking about the challenges of mammography, and we all know those. There’s human variation, some people are really great at reading mammograms, others can miss cancers that are on the mammogram, there’s a lot of human variation. We have challenges with access, any women will tell you that she doesn’t look forward to having her mammogram, the compression, women have concerns about the radiation. So it is a test that’s fraught with challenges, but it is absolutely the best method we have to detect breast cancer early when it can be cured, so we’re working very hard in all kinds of domains [like] liquid biopsy. Wouldn’t it be great if there was a blood test that could let you know whether or not you needed more intervention or whether or not you were harboring a small, tiny pre-clinical breast cancer? So, a lot of fantastic research, but at this time, without any question, screening mammography is the best tool we have to detect cancer when it can be cured.

Chris Riback: One of our recent conversations in the series was on liquid biopsy and yes, that would be fantastic. Not wouldn’t it be, won’t it be fantastic.

Dr. Connie Lehman: Exactly, it will be.

Chris Riback: It will be. As we’re waiting for that, what is an immediate-read mammography, and how in the world did you and the team reduce the median time to report finalization from 61 minutes to just 4 minutes?

Dr. Connie Lehman: So, I love that you asked the question, with what my team and I did, because it took a team effort. It was really our entire community of our administrators, technologists, our fellows in training, our faculty saying, “We need to do screening mammography differently for our patients.” What really stimulated us to start thinking differently was the pandemic, and many people have talked about the challenges of the pandemic. But that silver lining, where we all found we could be more nimble than we realized, and we could tackle some of our challenges, they were actually there before the pandemic, but that the pandemic sort of opened our eyes to the problems. And one problem was the differential experience that our patients had in that first screening that would show an abnormality, to the final diagnosis of cancer and becoming engaged in treatment. And those differences we saw across our patients were really worrisome to us, and we feared that they were getting even more exacerbated with the pandemic.

So, we decided to do something about that. We said, what if we could treat every single patient that came through our doors for a screening mammogram as a VIP. Let’s make sure they have their result while they wait, if they need more imaging, whether for a simple technical repeat or for actually an evaluation of a lesion, let’s just do it while they’re there. Let’s change our workflow, let’s work together as a team to figure out how, rather than having the patient go home and have that screening mammogram sit on our pack station, where we store our images, waiting for a radiologist to review it. What if we flipped it all around, made it totally patient-centered, and said, “We’re going to read these real-time, immediately, while the patient’s still there.” So, for that percentage of patients that need more, more imaging, more workup, we do it right then rather than have them come back, days, weeks, unfortunately for some of our patients, even months later.

And so that’s what we did, and it was really fantastic, not just for our patients, for individually, for them to be so grateful. But also we completely eliminated the disparities we had seen before this program, across differential races and ethnicities in our patient population.

Chris Riback: Why is that? What happened there?

Dr. Connie Lehman: Well, we found out that before we implemented our immediate read screen, the amount of time for patients that we had, our patients of color, whether they were African American self-reporting as Black, Asian, Hispanic. The amount of time between having an abnormal screen and having that confirmation of a breast cancer diagnosis was significantly longer than for our white patients, and that really concerned us. And we have lots of hypotheses on why that might be, but we just knew that it was there. A lot of groups have said, well, we need to educate these groups better, they need to understand the importance of coming back in. But how amazing when we just changed our workflow that we got rid of the problem. So, it became something where we thought, Oh that’s something where you can actually change the system, rather than expect the individual to change their behavior.

Chris Riback: As an outsider, listening to this, among the things that struck me as so remarkable. So we all think about, what can be the breakthroughs in improving breast cancer diagnosis care, all of the things that you were talking about, and we all think about. I think about the extraordinary innovation that is going to take millions of dollars and years. And we do need all of those, liquid biopsy, I mean, there’s an example. And yet still while doing that, there are the things that can be done thinking about workflow. It’s almost like a Harvard Business School case that you just described. Like, how can we improve the internal operations of our manufacturing plant, and on some level, that’s what you did, creating a tangible difference in care, without tens of millions of dollars and five to 10 to 20 years of research.

Dr. Connie Lehman: You know, I’m so glad that you’re highlighting that. In fact, we should do a little shout-out and kudos to the Harvard Business School. Because I was fortunate to take a year-long program for healthcare leaders at the Harvard Business School, and it was exactly what you said. It was like these case studies where someone would say, “Well, wait a minute, can’t we do this better, can’t we just change and question the way we’ve always done things and do it a little bit differently.” And, certainly, in other industries out of healthcare, we have innumerable examples of people just thinking differently and really having that, customer-centric approach. And we’re bringing a lot of those processes and those paradigms and those approaches, into our healthcare system. It’s been really exciting to see how quickly a group can actually change their thinking and change the healthcare delivery paradigm or model.

Chris Riback: Yes, the mindset. But what happened on the workflow change that we were just talking about in the immediate read mammography? What happened to the accuracy as you cut the time to final reporting?

Dr. Connie Lehman: Well, this is a great question because many radiologists who I had talked with said, we’re a little bit worried that if we’re doing immediate reads, we might get a little stressed, we might be tempted to race through looking at the mammograms. We might get distracted, someone needs us to go do a biopsy or to look at a diagnostic mammogram. And when we read our screening mammograms, we are not distracted, we’re doing it in batches and we don’t have anyone else bothering us. So we set up our immediate read using those same critical elements of the best reading conditions. So, our radiologists that are reading the screens in real-time, they’re in a room where they close the door. All they’re doing is reading the screens.

We also have these monitors up. So, all of us that are in the clinic that day can see the unread screens, and if the number starts to creep up, [say if] I’m doing diagnostics, I can jump in and read a few of the screens real-time. So, it was not just saying, “Well, we’re just going to start reading these as fast as we can.” It was actually building a full system to support all the good things about, quiet, protected, batch reading, but timed so that it was happening while the patient was still there.

Chris Riback: Interesting. Part of me is wondering, did changing the operations, and cutting down the time dedicated, or available to that read, or focusing the time, I guess I should say, on the read. Did that change the mindset of the people reading it? Maybe you were even more focused, because they knew that they were trying to do it in a tighter period? Anyhow, for all the Harvard Business School professors out there listening, I think we’ve got their next case study and, get ready Dr. Lehman, now you’re going to get to be the star of an HBS case study. Unless they’ve done it already. Have they done it already and I’m late to the game?

Dr. Connie Lehman: No, no, not yet. Yes, we definitely should. And I do like it. We’d studied very carefully, and published our findings and our results, showing that our accuracy was equivalent. That we weren’t calling back more patients, we weren’t seeing fewer cancers. But that we have the same performance level, and obviously that’s critical for this type of program to be successful. So we didn’t have that downtime, where the images were just sitting in our storage system with nobody looking at them. That’s where we really adjusted the timing.

Chris Riback: Thank you for clarifying. Let’s turn to AI. What role does AI play in breast cancer detection? How does it work in terms of identifying personalized risk?

Dr. Connie Lehman: So, I am obviously incredibly excited about this revolution in healthcare with artificial intelligence, the possibilities are limitless. We have had such an exciting two decades of what I refer to as -omics. Genomics, proteomics, radiomics. We have so much data, so much information, but all the information was outpacing our human ability to analyze, to process, and for me, as a radiologist, certainly for my human eyes and my human brain to be able to take in. And thank goodness along came the unbelievably fast computers, and the entire revolution of artificial intelligence and deep learning, and we’re leveraging those tools to have the highest impact as possible on our patients. And it’s going to be in every domain, from risk assessment, to intervention, prevention, early detection, diagnosis, treatment, returning to surveillance. But it’s going to be up to us humans to use them well, and use them with a real attention to rigorous science, to quality, to equity, to all of those things that we’re trying to carry forward in this revolution, in this new domain.

I think one of the things that’s challenging whenever there’s something as exciting as AI, is everyone can a little bit get ahead of themselves. So we have some claims out there that, computers are reading mammograms better than radiologists. This is still early, it’s mainly retrospective studies, reader studies. We all learn from the story of CAT and mammography, that reader studies don’t always translate over into actual clinical practice. So we’re not going to repeat those sort of sins of the past, and we’re going to do this in a really smart way.

The specific area that’s so exciting for me with AI, is risk prediction. So we’ve always been using the mammogram to try to find a cancer. But as a mammographer reading mammograms all the time, I always notice the things you can tell about a patient from her mammogram like, oh, this is a woman that has actually gained a lot of weight since her last mammogram, or wow, this woman lost weight since her last mammogram. We can see that the woman has had a prior needle biopsy, or an excisional biopsy, or even cancer treatment. We can see that a woman has started to go through menopause. Maybe she’s gone on chemo prevention, or maybe she started hormone replacement. Maybe she’s lactating, all of these different factors and features, which we know influence the breast tissue, and impact the risk of future breast cancer. We can see that on the mammogram, but all I could really do is observe it.

But now with deep learning, we’re taking that data out of the digital mammogram, and we’re using it to predict a woman’s future risk of cancer. And that has been incredibly exciting for us to start to explore, it’s something that the Breast Cancer Research Foundation has been equally enthusiastic about. Not only allowing us to do investigations in new domains, novel applications of AI that others aren’t doing, but also create those environments for partnerships. So we’re not just doing this with, amazing computer scientist at MIT and fantastic breast imagers at Mass General Hospital. But also medical oncologists, surgical oncologists, epidemiologists from all the different groups and teams that the Breast Cancer Research Foundation brings together.

Chris Riback: Yes, cross-disciplinary work. These conversations that I’ve been so privileged to have with people like you, so often that’s what comes up.

Tell me, my understanding is that the study that you are working on, the one that you were just talking about. I don’t know if you are still in year two of three, if you are now in year three of three. You’re taking, if I understand correctly, a collection of digital mammograms from the participants of the Nurses’ Health Study II, which I think is data that I’ve talked about previously in other conversations. And this pilot study, you just talked about, that it’s predictive, and you talked about the model. How did your colleagues, your team create the model? How do you anticipate what the model should show? You talked a little bit about some of those factors. And what are you finding? I know it’s early days, but the predictions that the model is developing, how does it compare with actual results?

Dr. Connie Lehman: Exactly. So well, first your question about what year we’re in. We are in the early phase of our year three. And we’ve been able thankfully to make an incredible amount of progress, even despite the pandemic.

So the model was trained on a large population of mammograms that we had within the Mass General system. And then we just, as you said, wanted to evaluate and test it in other data sets. So, an external validation, so Rulla Tamimi and others that were heavily engaged in the Nurses’ Health Study, worked closely with us on this Breast Cancer Research Foundation project, and we learned so much. One thing we learned is some of these older databases of mammograms aren’t what we refer to as AI-ready. It took a lot of work for those mammograms to be saved and stored, but they weren’t always saved and stored in the exact ways that we need to be able to test and train our models, etc.

In research, everything’s not always a win the way we might think, some of the areas where we find it didn’t work the way we thought, it leads us to greater understanding.

I was lucky to have an early, early mentor when I was getting my PhD at Yale. And I would do the ‘Gosh, darn,” when the research didn’t turn out the way I wanted. It was like, this is what’s fun about science. Like it’s, the data are friendly, they’re going to guide you. They won’t always show you what you thought you were going to get or what you wanted, but they’re going to guide you in the right direction. And so Rulla and I just sort of picked ourselves up, brushed ourselves off and said, “Okay, now we’ve learned and know where can we go for the next phase,” and I think that’s going to help a lot of people.

Dr. Connie Lehman: So, we pivoted, and we had partnerships with seven hospitals around the world, and we did our external validation, and we also had a real eye for making sure that we were going to be able to see that this model worked across various races and ethnic groups. And the reason that was so important is we found that our traditional risk models perform extremely poorly outside of European Caucasian women. So for example, Emory was one of our validation partners and almost half of their women undergoing screening mammography self-identify as African Americans. So we were really pleased and excited to see that the model validated very well, had very robust performance at these seven hospitals around the world from Brazil to Asia, in the US, Europe. So we published on that and then we continued to work in other domains, and now we’ve built a very robust infrastructure so that every mammogram at Mass General is processed through the AI model.

And we’re starting to evaluate that now more. Now we’re set up more to do prospective evaluation, which is going to be critical because the bulk of AI work today in this domain has been retrospective studies, and we really need to shift towards prospective evaluation. And then the most exciting, for me, part of this third year is we’re bringing in the other areas of information on patients, biological factors, other tests, very rich databases that we have on patients. Now, we had expected to do this in the Nurses’ Health Study, and we’re still looking at different ways that we can bring that information in. But we also have a very rich source of databases within the Mass General Brigham system, and so we’re pivoting and moving forward into that next level of, what if you had both the biological information about the patient, as well as the imaging information and data.

Chris Riback: And just so that I’m understanding you correctly, that additional data will help evolve and inform the AI model that you will then apply. So you’ll be able to bring in not only that initial set of data, but also this biological data.

Dr. Connie Lehman: Yes. What we’re hopeful is that all of these sources of data are going to be additive. So we can move further in being even more targeted and more precise for each individual woman. Traditional approaches with risk is, you can say, “Well, this whole group of women has a higher risk of breast cancer than this other group of women.” But getting down to being able to tell an individual woman more precisely what her own individual risk is, has proven really challenging.

Chris Riback: Yes.

Dr. Connie Lehman: When we looked at our AI values in this Breast Cancer Research Foundation project, we had the AI values of all of our patients that had undergone screening MRI. And there was a significant group that had known genetic mutations for breast cancer. We were surprised, and I always like it in research when we find something that surprises us because it’s one of those, eureka, a-ha, kind of exciting moments.

Maybe it’s because those women with genetic mutations are on chemo prevention and maybe that chemo prevention, which is reducing their risk, is making their breasts on the mammogram look like, their neighbor that doesn’t have a genetic mutation is bringing that risk down, and we can actually see it with AI on the mammogram. But see it with AI in quotes because I’m not seeing it. So we’re excited about that. It also suggests that there might be multiple sources of information that can help guide us, in more precise prediction, that the genetic information is distinct, does not totally overlap with the imaging radiomics AI-assisted information.

Chris Riback: Yes. I’m curious as well for you personally. I assume that you were trained as a radiologist. You are now getting neck-deep into computer science and artificial intelligence. Is that something that you always were interested in? How has that transition been for you?

Dr. Connie Lehman: Well, when I was younger, I was just interested in everything. In fact, I thought I was never going to be able to decide what I wanted to do because I just wanted to do everything. I was certainly always interested in biology and the sciences and human behavior and the brain. I decided to pursue a PhD in psychology at Yale. It was my first mentor that said, “Ah, you have to combine this with medical training. That’s really what you want to do. I can just tell.”

So, I combined my MD and PhD training at Yale, and then when I was going into radiology, my friends were a little bit surprised because they thought, Oh for sure you’ll be doing the neurosciences or something. They knew I was really passionate about women’s health as well. But for me, radiology’s been just the absolute perfect sandbox to do my work in, because it provides us so many opportunities to have a very high impact on human health and all the domains that are interesting to me. How the brain works, how we change patients’ cognitions and behaviors, and how people make decisions, whether it’s a radiologist, making a decision that a mammogram is normal or abnormal, or a patient making a decision on whether she wants to undergo breast MRI or not. Whether she wants to know more about her risk or not, or if she’s going to come back for a screening mammogram.

So I don’t know, I just keep finding these incredible opportunities. And to me also, my career has always been about relationships. So it was when, Regina Barzilay at MIT had just completed her own treatment and said, “Do you want to work on a project together? I’d really like to make a difference in this domain.” That started this really intense exploration.

Chris Riback: Yes. Well, that would be a hard person to ever say no to. And I assume, I found myself wondering with all of those different interests and potential occupations, French scholar, was that ever on the table?

Dr. Connie Lehman: Do you know, having French as a language never seemed like it was going to bring any added value to any part of my work. Until I was working on a project in Uganda, with some absolutely fantastic colleagues at Makerere University, there in Kampala, and I was walking through the hospital and there was a man who was clearly confused and no one could understand him. And I felt so sorry for him, and the closer I got, then all of a sudden, I thought, Oh, he’s speaking French. And I was able to translate from French to English, with my Uganda colleagues, who then helped the man find out where he was going to go. And there’ve been two other experiences where all of a sudden French was helpful, but many a time I had wished in the US, I’d just learned Spanish way back. But anyway, and then of course travel and fun. French is always going to be a good language to have.

Chris Riback: It’s always good for that. Just to close out the conversation, you mentioned it earlier, but the role that BCRF has been able to play. I know that you’re affiliated with a range of organizations, and you’ve mentioned some of them, and working with MIT and different institutions as well. But how would you characterize what role has BCRF played in your research?

Dr. Connie Lehman: The Breast Cancer Research Foundation has been so critical to the work that I’m doing. And I will tell you, one of the things that really resonates with me is the culture that they set for their community. It is such a culture of inclusiveness, of being excited about partnerships, about being excited about creativity. I’m never worried that when, for example, Rulla and I realized the Nurses’ Health Study mammogram data didn’t work the way that we thought it was going to work, like, “Oh, they’re going to be so upset.” We pivoted, we started to explore other areas. It allowed us an opportunity to do new regions and new areas that we hadn’t even anticipated.

And so that culture of work together, partner together, ask the challenging questions. There’s going to be successes, there’s going to be setbacks, but we’re all in this together. Our patients have been through layer after layer of challenges that we didn’t wish on anyone, and yet you have this organization that the entire time was like, we’re right there with you, and it goes a long way.

Chris Riback: So actually, as we come to the close of the conversation, are there connections? I mean, we talked earlier about the immediate read. We’ve been talking about the AI work, does it all tie together in some way?

Dr. Connie Lehman: You know, it really does, and I’m so glad you asked that. Because it’s easy for us to state our mission statement, that we want to provide equitable access to high-quality healthcare for the full diversity of patients we serve. So we say that, but then we start to think about, well, where do we fall short of that? Certainly when we reopened after we had to shut down during the pandemic, when we found that of our six screening centers, the screening centers that we’re serving our more vulnerable patients were slower to open on Saturdays when more of our patients needed access. And they were slower to open to full capacity, than those screening centers that happened to be in neighborhoods that served our less-vulnerable patients, we knew we had to change. And by studying that, we pivoted quickly, so that early on, we saw those changes and then we corrected by the end of the year. But it really took a lot of effort and a lot of attention that was part of the immediate read screen.

Let’s get more people in and get them fully taken care of. So we don’t have this inequity and who is able to talk their way into, like, “Oh, can you have the doctor read it while I’m here,” and another patient might be less comfortable in asking that, or have a harder time coming back to the hospital. It was a really challenging time. So the whole immediate read screens, we also had our same-day biopsy program looking for equitable access across all of our centers for weekends, for evening hours. That was a big part of the work, but also in the AI, it was so exciting for me to see how the AI risk model worked, and it worked better than our traditional risk models. It was chilling for me to see in my own patients that I feel responsible for taking care of, how inequitable the traditional risk models were.

We found and will be presenting in Chicago at the Radiological Society of North America [annual meeting], that our Caucasian patients are two-and-a-half to three times more likely to be given access to risk prevention, and risk reduction based on the traditional risk models. Even though we don’t see a difference in the rates of cancers in those populations, and that’s really chilling. And there was a beautiful article written in the New England Journal of Medicine, not only tackling these inequities with race across risk models in breast cancer but across everything from renal disease, cardiac disease. So, we have a real opportunity, and I think you may have heard some people say, “Well, we’re worried that these AI tools are going to have even a greater divide in the haves and the have nots, or even greater inequities.” So in healthcare we’ve got to double down and really make sure from the beginning to the end, we’re training the models in the right way. We’re testing them across the full diversity of our patients, and we’re bringing the AI tools into delivering on that mission we have of equitable healthcare for all of the patients that we serve.

So, we see that it all comes together. We’re humans and we know what our mission is, and we are grateful to have so many different tools to make things better, not just for some, but for all of our patients.

Chris Riback: Yes, it sure does, it starts with the patients, as you just mentioned, and then the folks like you. Dr. Lehman, thank you. Thank you for the conversation. Thank you for the work that you do.

Dr. Connie Lehman: Thank you so much. It’s been a pleasure.

While breast cancer is not typically caused by inherited factors, as many as 10-15 percent of people diagnosed with breast cancer carry a known genetic mutation. The most well-known mutations are in the BRCA1 and BRCA2 genes. But these only account for 5-10 percent of inherited breast cancers, so what about the many other gene mutations that increase a person’s risk of breast cancer?

One major BCRF-supported cross-institution study, CARRIERS, found—among other results—that some mutations that had previously been linked to breast cancer were found not to increase the risk of disease.

What does this mean not only for genetic testing—but also how we should consider results? More significantly, what effect might this have on the personalization of risk?

BCRF investigator and cancer geneticist Dr. Katherine Nathanson was one of the study’s principal researchers. She is deputy director of the Abramson Cancer Center and the Pearl Basser Professor for BRCA-Related Research in the Perelman School of Medicine at the University of Pennsylvania. She not only runs a prominent research laboratory but also maintains a clinical practice. 

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Read the transcript below:       

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

Dr. Katherine Nathanson: Glad to be here.

Chris Riback: Let’s start by understanding some of the background of hereditary breast cancer and the mutations. Most of us have heard of mutations in the BRCA1 and BRCA2 genes. But those aren’t the only mutations, obviously, associated with breast cancer, are they?

Dr. Katherine Nathanson: No. So we think about breast cancer susceptibility as a spectrum of susceptibility. So, you have your high penetrance genes, in which mutations are associated with a relatively high risk. So usually BRCA1 and 2, for example, that’s associated with a high lifetime risk. Then you have your genes in which mutations are associated with what we call a moderate lifetime risk, usually in the range of twofold. There is a gene that’s sort of in between, which is called PALB2. But there is a gene that’s associated with a moderate lifetime risk, which is CHEK2, ATM, and things like that. And there are a set of what we call normal variation. Sometimes those variants are associated with minimally increased risk, but when we put all those variants together, we get what’s called a polygenic risk score, or lots of variants together to try to think about risk.

So the way that I talk about it, which hopefully is helpful, is everyone gets dealt a hand of cards. And sometimes when you get dealt a hand of cards, you get the ace of spades. You know what the ace of spades is. It’s a really high card. It means something really important. That’s your BRCA1 or 2. You have a moderate penetrance gene. You get dealt a hand of cards. Queen of clubs, it’s helpful card if you’re playing Bridge. But it’s not the best card. It’s not the greatest card, but it’s there. And then you get everything else. Your six of diamonds, your eight of spades. And those are your normal variation. But when you put all those together, sometimes they can make a very powerful hand of cards.

And so if you think about the different genes in which there are mutations, you can think that everybody gets dealt a mixture. Sometimes you get different hands than others. Everybody gets dealt a mixture of those sort of hands. And some of them are high, some of them are moderate, and some of them are low combinations. This is the way I sort of think about an analogy to help people out.

Chris Riback: It’s really helpful, and it makes me wonder. Which hand is the most common, and which hand is the most worrisome?

Dr. Katherine Nathanson: So the hand that’s most common is probably the hand, I don’t know if anyone plays Bridge. Right. The hand that you get the bunch of dreck [trash]. And it’s like, you’re just playing it defensive. That, in fact, in this sense is probably the better hand. Right? And the more unusual hand is when you get the high cards. And it’s much more unusual to carry a BRCA1 and 2 mutation than it is to get the sort of regular hand of assorted not-so-great cards.

Chris Riback: And so, how would you characterize the extent to which those mutations, the extent to which they increase breast cancer risk or are associated with breast cancer risk, compared to the BRCA1 and BRCA2?

Dr. Katherine Nathanson: So like the queen of clubs in the analogy that we were just using.

Chris Riback: Yes.

Dr. Katherine Nathanson: So those increase your risk modestly. So, it depends on the gene, but instead of for example, you have to remember that any woman in the US has a 12 percent lifetime risk of breast cancer. So just to point that out, right? So, these increase your risk potentially to 20 to 25 percent. That’s higher, and we can show in large studies significantly higher. But it’s not nearly as high as a BRCA1 or 2 mutation. And in that context, actually, the other cards are much more important.

Chris Riback: Why is that?

Dr. Katherine Nathanson: It’s because we talk about modifiers. So we know that in addition, it’s a hand of cards. Right? So in addition to having that ace of spades, your other cards matter. But when you have something like a queen of clubs, the other cards matter more. Because it’s really, there’s not such a dominant, we say, mutation in a gene. The other things matter and affect how that works. The moderate penetrance genes more.

Chris Riback: The interplay among them.

Dr. Katherine Nathanson: Yes. Exactly.

Chris Riback: So earlier this year, you and others published a population study of more than 64,000 women in the New England Journal of Medicine. You analyzed the data from the CARRIERS study, cancer risk estimates related to susceptibility. What did you find, and why was it so groundbreaking?

Dr. Katherine Nathanson: So the reason it was groundbreaking was because it actually was a population-based study. So much of our estimates of risk actually don’t come from people in the general population. They come from women who have a family history, who are collected on the basis of family history, or some of the recent studies from women who have had genetic testing. And usually you don’t, maybe not these days, but [it] used to be you didn’t just walk in and get genetic testing. Right? Anybody. And so they were biased estimates. Biased in terms of who was high-risk. So-

Chris Riback: And self-selection of who was going and getting the testing.

Dr. Katherine Nathanson: Exactly. Exactly. And so these were a number of, and I just want to emphasize, huge team of people worked on this project. Really would not have been possible without collaboration. The senior author was [BCRF investigator] Dr. Fergus Couch from Mayo Clinic. I’m on the executive committee after meeting every week for five years, but we got somewhere. But the people who ran the studies and the most important people who collected samples from patients, and the patients who contributed to those studies. So hugely important. You can’t do it with any aspect of that.

So the point was that these were very large, mostly older women, who had breast cancer, who either actually were followed prospectively and then got breast cancer. So there is some cohorts of studies, something called the Nurses’ Health Study, where they look at all the nurses and they follow them prospectively over a number of years. And then some of them get breast cancer, for example. And those studies are very helpful to understand, if you’re in the general population, what’s the risk of these mutations in someone who doesn’t have a family history or doesn’t present to a high-risk clinic. And so that’s actually why it was particularly important. And not surprisingly, it showed that people with a family history have a higher risk of having mutation.

So, the idea was that we found that women with breast cancer from the population, about 5 percent of women overall, and mostly these were older women, had mutations. Whereas about 1.5 percent of women without breast cancer had these mutations. So it was significantly more frequent, but not high numbers, right, of women. And then we were able to identify what the risk associated with each of these mutations is, or mutations in each of these genes, I should say, more accurately is. And I think, actually, I’m going to tell you what I think is really important about this study, which I think is very hard to get from the news coverage.

Chris Riback: Yes please.

Dr. Katherine Nathanson: So I think that there are two parts that are very important. One is, this is 3,200 cases and 3,200 controls. Despite only five genes overall were significantly associated with breast cancer risk. So the number, actually, of genes wasn’t all that high. Now there are some additional genes, if you looked at ER-negative and triple-negative disease, that were associated [with] disease. But the other part is that we routinely have women who are getting these huge gene panels for breast cancer susceptibility. And many of the genes on the panels were not associated with breast cancer susceptibility in this study. And I think the negative aspect of this is actually really, really important. We really-

Chris Riback: What do you mean by the negative aspect?

Dr. Katherine Nathanson: So for example, I’ll give you a good example. So there’s been a lot of discussion. Are mutations in a gene called MBN associated with breast cancer risk? And there’s back, forth, is it associated with disease? Our study and the accompanying study BRIDGES, which was done in a European group, definitively showed no association with disease. So one of the things that is really important is that especially when you’re looking at these women who are getting, because it’s easy to do the testing, these big gene panels. Some of the genes who are basically ruled out as being associated with risk.

And that, actually, honestly, to me is the most important part of this. Because most of the ones that we associate with risk, we knew were associated with risk. But some of the other ones where some people said yes, some people said no, were more borderline. And we were able to really definitively say these are not associated with risk.

Chris Riback: And I would have to assume that in terms of levels of anxiety, intrusion of hair that may or may not have been needed, I would think. You correct me, please, if I have it wrong. That for years, probably, you had women who would get those results and there was uncertainty and stress, anxiety, and perhaps even more.

Dr. Katherine Nathanson: Right.

Chris Riback: And you were now kind of able to say, “We don’t need to worry about that.”

Dr. Katherine Nathanson: Exactly. And to me, that’s actually in part the most important part of this. That we were able to really definitively show that they are not associated. I think it helps us tell us a little bit about who, although it doesn’t really change the guidelines substantially about who should be tested. That’s important too, like who should be tested. Women with ER-positive breast cancer over the age of 65 should not be tested. And those kinds of things, that’s important too. I think there are another series, I’ll say, of follow-up studies, some of which are out, some of which are not out.

So there was also a study that looked at the rate of mutations in Black women. And one that looked at the rates of compared within the CARRIERS [study] group, the rates of mutations in Black and white women. There were no differences, which is also very important to say. No, the rates, there was some variation within the genes. But overall, there was no significant difference between Black and white women. Very important to say. And we have some studies that are accepted, which are coming out soon, actually looking at the non-, what I call the lower cards, but the polygenic risk scores. And how the polygenic risk score looks in this dataset, how does it influence risk.

It’s clearly much more important in, as I said, if you have a lower or a moderate penetrance gene than it is if you have a high penetrance gene. So those things are important. And looking at the rates of mutations in women over 65, very important mostly if you have triple-negative disease. Not so much if you don’t. But to my mind, I think that part of the thing that people, for me, as someone who clinically sees patients who get huge panels, having really good negative data is really, really important. Because it helps tell people, we don’t think this is causing your disease. And you don’t need to have surgery, you don’t need to have other kinds of interventions, because we think this is good.

Chris Riback: This has to significantly alter the way one thinks about the personalization of risk.

Dr. Katherine Nathanson: Right. And the personalization of risk, I think, is really, really interesting. I mean, lots of people are very interested in personalization of risk. And there’s lots of ways to approach personalization of risk. So first of all, do you carry a high, moderate penetrance gene? What is your polygenic risk score? So we know that in women with a high polygenic risk score, their risk of breast cancer is as high as someone who has a moderate penetrance gene. If you have a low polygenic risk score, one of the things that they’ve thought about is decreasing mammographic screening in women who have low polygenic risk scores. Very hard in the US, particularly, to de-escalate things like that.

But it is definitely something that I think, in other countries, may happen. That if you have a low polygenic risk score, a low score, low risk of breast cancer, you may de-escalate or decrease screening. So you think, now we have genes. The genes and the variants sort of affect each other. So they’re not independent. Mammographic density is a known risk factor. Obviously things that we also think about, smoking, alcohol, physical, all those kinds of things are risk factors. And even within genes, the different mutations don’t all have the same risk. And so there’s lots of ways that people are thinking about how can we better personalize risk. But I think the thing that we have to think about along with personalizing risk, is what are we going to do with that personalized risk? Do we feel comfortable, if we say someone’s at a really low risk, saying, “Well, you need less mammography.” I think that’s something, as a…

Chris Riback: Yes. Very hard to do.

Dr. Katherine Nathanson: Very hard to do. These are complicated questions I don’t have the answers for.

Chris Riback: Yes. Well the complicated questions, you understand, doctor, are your fault.

Dr. Katherine Nathanson: Right, exactly.

Chris Riback: If you had to participate in these studies, we have simple questions and very unclear answers. Instead, we’ve got a couple.

Dr. Katherine Nathanson: Well, yes. I mean, it’s complicated questions.

Chris Riback: The complicated questions. You mentioned a moment ago some of the either currently ongoing or potentially beginning studies. And I believe, and you correct me, please, if I have this wrong. That one of them is one that you and your team are launching around a study of very high-risk women with early-onset breast cancer, to identify more about what drives the risks of breast cancer in these women. Do I have that right?

Dr. Katherine Nathanson: Yes. So we know that, even though we’ve done this large study, we know there are several things that are probably some rare, identified variants that are associated with disease. Now those could come in several flavors. So is it possible that there are additional breast cancer susceptibility genes that are rare and unidentified? Definitely possible. But you need to really look at very high-risk women who have been screened negative, and that’s something that we’re interested in, or doing, I should say. And I think that the other thing that we’ve also thought about is, there are some limitations to the way we currently look at the known genes.

Technological limitations. They’re not state-of-the-art changes over time. I think that’s really important. And so, are there variants in those genes or associated with those genes that might be associated with risk that we’re missing? Which is definitely possible in women with breast cancer. And so, that’s something that we’re also interested in looking at. And we were starting to do something called whole genome sequencing. So not just looking at the genes, but looking at the sequences between the genes to see if there is variation that might potentially be associated with risk. There are also what we call rearrangements.

So we know, for example, in BRCA1, that if you think about it like a sentence, you can have misspellings in the sentence. But you can also have missing words or missing phrases. And so, we’re very good at getting the misspellings. We’re pretty good at getting some of the missing words. But sometimes we’re not so good at getting the large phrases or rearrangements. Or if they’re, for example, between the words or something like a comma. How far can I take this analogy, right? That we don’t pick those up so well. So we’re looking to see if some of the families have variants that are associated with that. Those are harder to prove as being functional, so that’s one of the things that we think about.

Chris Riback: How did you come to focus your work so significantly on high-risk women? And I know you deal, as well, in other types of cancer. But in high-risk areas, is what I have taken.

Dr. Katherine Nathanson:  Oh sure. So I’m a geneticist. So I decided very early in my career, actually when I was in medical school, that I wanted to go into genetics. I was always fascinated by genetics growing up, and I thought it was really interesting. And I decided in medical school to go into genetics. So I’m actually double-trained in internal medicine and clinical genetics, which is wild, still. Pretty unusual. There’s probably less than 50, maybe less than 100 people in the country.

Chris Riback: Wow.

Dr. Katherine Nathanson: And so, then when I decided to, I trained in genetics. I did research training. And so, I ended up doing cancer genetics for a variety of different reasons. And that’s where I’ve sat ever since. But I really approach it or come to it from someone who’s really trained as a geneticist, rather than an oncologist kind of perspective. So I’ve been doing it a long time. And my clinical practice actually deals with a lot of other hereditary cancers, as well. So that’s-

Chris Riback: And there are two. So first, fascinating to me that even as a kid, genetics was what interested you, drove you. So, it was never going to be opera singing or—

Dr. Katherine Nathanson: Oh God, no. You wouldn’t want that.

Chris Riback: So as well, there’s an intersectionality as I’m learning about you and reading about you, that you do. One is, you just talked about it. The translational medicine. You run a lab, but you also see patients. In addition, you don’t focus, it seems, on just one type of hereditary cancer. You focus on several. Are there learnings? Is that just because you get bored easily? Or are there learnings and insights that you gain from?

Dr. Katherine Nathanson: So I would say, it isn’t because I get. I think it’s more historical. I sort of ended up doing lots of different things for various historical reasons. And I’m actually doing things that are a little different now, because I’m very interested in really trying to improve genetics generally. I think we really have to be prepared for genetics for everyone, and that’s something that’s really important to me. I have found in my science, however, that you never know what you’re working on comes back to what you were working on before.

I think the biggest analogy, I worked on, actually, a study that actually has led to a drug, down the road, but for renal cancer. But part of the study, all of a sudden we found BRCA1 in this study of renal cancer. And it has to do with DNA damage, and it happened to be important there. And I thought, my God, I try to do whatever I do, and it sort of all comes back together. But it is important. I see neuroendocrine tumors, and one of the things that’s really happening clinically to me is that people are getting these big panels. They get mutations in a gene called SDHA. SDHA is associated with pheochromocytomas and paragangliomas, but all the women that I see have breast cancer, and they got this big panel.

So we’re now trying to figure out and make sure. They don’t think it’s associated with breast cancer, but we’re doing some large-scale studies to make sure that I can confidently tell a woman who comes in with SDHA that that’s not associated with the breast cancer risk. So I feel like it all links back together, because I can do that, because of all the work that I’ve done on breast cancer already. And I want to make sure that I’m counseling my patients appropriately. So I feel like it all seems to intersect and come back together on some level.

Chris Riback: Yes. It seems like it. And I would be remiss if I didn’t ask you. What role has BCRF played in your research?

Dr. Katherine Nathanson: As I say, I will tell this to anybody. BCRF has been the most important thing to my research. I had a difficult early career for lots of reasons, but BCRF provided funding for me at a critical juncture in my career. I would not still be sitting here doing what I do if it wasn’t for BCRF. I absolutely feel that that’s true. I feel like they have been incredibly important over my career in terms of the support that they have provided. Like when I was an assistant professor, sort of struggling, and now, I mean, I don’t think of myself as that much. But now I have a deputy director of a cancer center.

Chris Riback: Now you’re a big poo-bah, yes.

Dr. Katherine Nathanson: And I wouldn’t be there if I wasn’t for BCRF.

Chris Riback: Well, we all benefit from the work that you do. Thank you for that. Thank you for taking the time today with me.

Dr. Katherine Nathanson: More than happy. It was great.

For so many breast cancer patients, radiation therapy can bring extraordinary benefits—top among them improved survival rates and reduced recurrence. But there are also challenges and questions: Why do some people experience a recurrence after treatment? How can we reduce side effects? How can we ensure the right patients receive radiation therapy—and that the treatment works as well as possible?

These are among the many medical mysteries to which Dr. Lori Pierce has dedicated her career to answering. Dr. Pierce and her colleagues are currently trying to determine why, after surgery and radiation therapy, breast cancer can come back and whether blocking the androgen receptor can lead to increased radiation sensitizing.

Dr. Pierce is a radiation oncologist, professor, and vice provost for academic and faculty affairs at the University of Michigan. Among many other leadership roles, she also serves as president of the American Society of Clinical Oncology (ASCO). A national leader in breast cancer research, she has published more than 180 manuscripts and book chapters and has received numerous teaching and leadership awards. She has been a BCRF investigator since 2003 and is a member of the Foundation’s Scientific Advisory Board. Her current BCRF grant is supported by Ulta Beauty.

In this episode of our podcast, she talks about her work in the lab, the importance of BCRF, and, more recently, as ASCO president.

Subscribe to Investigating Breast Cancer here:

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Read the transcript below:                    

Chris Riback: Dr. Pierce, thank you for joining.

Dr. Lori Pierce: Glad to be with you, Chris.

Chris Riback: If we could start at the highest level with radiation therapy, how important is its role in helping breast cancer patients after surgery?

Dr. Lori Pierce: Radiation is a very key component to the successful treatment of women with breast cancer. Lumpectomy and radiation is a standard treatment for patients with early-stage breast cancer and so radiation is given not only to reduce the risk of the cancer coming back in that breast. But we now have seen through a lot of trials that by doing that, you improve a patient’s survival. So, radiation is very important in breast conservation, and it’s also important in those patients whose tumor requires them to have a mastectomy, but there may be some patients who have a mastectomy, who need radiation as well, and that also has been shown to improve survival. So, radiation is a very important component of care in early-stage breast cancer.

Chris Riback: And you mentioned one of the key and really just very challenging areas, I’m sure. I mean, so many aspects of breast cancer are frightening and emotional, and frankly sad. And one area that you just mentioned and that you do work on, is around recurrence. A patient has surgery, has radiation therapy, hopes she or he has “beaten” cancer, and then it comes back. How devastating. How challenging is recurrence in the whole spectrum of breast cancer?

Dr. Lori Pierce: Yes, so we do everything we can to minimize the chance of recurrence. All of the trials that we do, they’re trials help to identify the latest advances in breast cancer to further reduce the risk of recurrence, while maintaining quality of life. So that’s a very important concept. Having said that, despite the very best care, there are a few cancers, breast cancers, that will come back despite getting the appropriate care. And if you look at the trials that have been done that have included radiation, patients who’ve had radiation following breast conservation, roughly about 10 percent of patients will have a recurrence in the breast. And so, the vast majority of them do very, very well, but there’s about 10 percent that have recurrence. And that’s actually been the focus of a lot of the work that I’ve done, thanks to funding and support from BCRF. 

Chris Riback: And so, let’s talk about the work that you’ve done across your career and focus in on some of the recent work and recent research that you are focusing on. There are, of course, so many areas of radiation oncology that one could discuss with you, including some incredible work going on globally around not identifying who would benefit from radiation therapy, but rather gaining greater clarity around who wouldn’t benefit and therefore, doesn’t need radiation therapy.

So maybe we can talk about that in this conversation, as well. But I want to ask you first about what I believe is your current research, what is the androgen receptor, and what role might it play in resistance to radiation therapy?

Dr. Lori Pierce: So, great question. Let me give you a little bit of background. So, for those patients who have a recurrence in their breast, we think it’s probably due to resistance to radiation, that that breast cancer cell has found a way to resist the effect of radiation. And so, we’ve tried to focus on strategies to be able to lessen that resistance and, at the same time, again thanks to BCRF, we’re trying to come up with molecular markers that can predict those cancers that may be resistant to radiation. Because if you can pick out those cancers, you then can know which patients should receive some of these strategies that we’re trying to come up with, that can decrease the resistance to radiation. So that’s kind of a two-pronged approach.

And so, getting to the question that you asked, many years ago when I first started working in this area of radiation resistance, I did a trial with a chemotherapy agent, gemcitabine, with radiation, and I did it and I won’t bore you with the details, but it was a trial that was done in patients who had had a mastectomy and had a recurrence after a mastectomy, and had really, really difficult disease to control. And the good news was that trial showed that all the tumors were controlled with gemcitabine and radiation. So that was a home run. What wasn’t a home run, is that it caused a lot of side effects. There were a lot of skin problems in patients who had that treatment. And I must say the patients that we treated, they were fine with it. I wasn’t fine with it because, there are probably ways that we can achieve the same outcome, but have it be more tolerable to patients.

And so, then we started working with another class of drugs, something called PARP inhibitors. And again, not to bore you with the details, but PARP inhibitors, they inhibit an enzyme called PARP, and PARP basically helps cells to repair DNA strand breaks. So, DNA, of course, is the control. It dictates what the cell is going to do, and it has all of the genetic material in the DNA. And, luckily, cancer cells have some difficulty in being able to repair damage to the DNA. And so if they need PARP and then you inhibit them from getting PARP, then they have even further difficulty repairing their DNA damage. And radiation causes DNA damage, so it’s a marriage made in heaven, to have radiation and a PARP inhibitor.

So, long story short, we did a lot of studies early on to show that it was safe. We did it in the lab first, and then we did a phase one study, thanks to BCRF. So the phase one study was a clinical study, which multiple institutions participated, in which we tested that PARP inhibitors could be safely given for breast cancer, and we showed that. And now, again, thanks to the work that BCRF funded, there is now a national study that is looking at radiation with or without PARP inhibitors in patients who have inflammatory breast cancer, which is a very aggressive type of breast cancer. So, it just shows that when you have an idea and you have BCRF behind you, you can take a concept from the lab and do the appropriate clinical trials to be able to bring it into the clinical arena. So that’s the full story with PARP.

And you mentioned the androgen receptors. So that’s a receptor that is on the cell that is a hormone type receptor. And we know that about 50 percent of triple-negative breast cancers—cancers who don’t have an estrogen receptor, don’t have a progesterone receptor, and don’t have a HER2/neu receptor—which means our therapies that fight ER, estrogen receptor, and progesterone receptor-positive tumors, and HER2/neu positive tumors won’t work in triple negatives, because they don’t have the ability to bind.

Chris Riback: Yes, they can’t catch it when it comes in.

Dr. Lori Pierce: They can’t catch it when it comes in, that’s right. And they’re also a very high rate of having androgen receptors on the cells of cancers that are estrogen receptor-positive. And that’s very good too because even though we have incredibly effective hormonal therapies for estrogen and progesterone receptor-positive cancers, not all cancers will be controlled with them. Not all estrogen and progesterone receptor-positive cancers will be controlled. Sometimes cancers find a way to evade drugs that bind to these receptors. And so knowing that androgen receptors are also on these cells, gives us another way of being able to sense whether that can increase radiation sensitivity.

And sure enough, in our laboratory data, we’ve shown that for estrogen receptor-negative and triple-negative cancers that have the androgen receptor, that when you give radiation, if you have a drug that blocks that androgen receptor, and then you do radiation, that makes them more sensitive to radiation. So, you get more bang for the buck, if you will, and more sensitization with that androgen receptor. And so, we are now working toward trying to do a clinical trial. And the good news is that there are a lot of drugs out there that are used in prostate cancer that we know are safe and have been used for many, many years for prostate cancers, generally. Most of them have androgen receptors also, and we know these drugs are very safe, so we can bring them into the breast cancer arena and, actually, some of them are already used for breast cancer patients for those who have disease that has spread. And so, we know that they’re safe drugs and we’re looking at how to combine them safely with radiation.

Chris Riback: Can I tell you, in so many of these conversations among the many things that amazed me in several of them, is how often learnings, insights gained from one type of cancer, get translated into another type of cancer. And so, how did that actually work, the connection between the androgen receptors that are noted in prostate cancer to possibly addressing them in breast cancer? How was that connection? Were androgen receptors not previously recognized in breast cancer? I kind of assume they must have been, or was there some advance in prostate cancer and then people, like you said, “Well, wait a second. There’s something that connects here.” How was that connection made?

Dr. Lori Pierce: Great question. So, we have known for quite a while that androgen receptors were on breast cancer cells, but it’s clear some of the significant advances that have been identified in prostate cancer, that made us all take a look at that. And then also, there are so many similarities between prostate and breast cancer. They’re both hormonally driven cancers, to a large degree. And then some of our gene expression data from some of the trials that we did earlier in the lab, and some of the cell lines identified some of these androgen receptor compounds as being compounds that would be very active in some of these cell lines. So, it was kind of like the sun and the moon were aligned and also, it helps that earlier on, one of the investigators who were working with me, who was at Michigan at the time, who’s now left to go to UCSF is a prostate cancer researcher. And so, so it was kind of just the right idea at the right time.

Chris Riback: Now why in the world would anyone want to leave Michigan, especially to go out to San Francisco? You’ll have to do additional research on that problem.

Dr. Lori Pierce: You know, I agree with you, but I think it’s worked out to be a very good move for him.

Chris Riback: I’m sure.

Dr. Lori Pierce: So, I don’t begrudge him that, but he is Dr. Felix Feng. He is an amazing researcher and he’s gone on to do great things.

Chris Riback: Especially talking with you in the middle of winter in Ann Arbor. I’m sure there are several reasons right outside your window, why going to San Francisco might make sense. So, to quickly finish up on this research that you’re doing, I’m trying to just confirm, where are you in the research? Have you been able to start the clinical trial, or did you say earlier that you recognized as you’re doing some lab work and now, you’re getting ready to do the clinical trials on this?

Dr. Lori Pierce: We are getting ready to do it. We’re actually writing a concept, even as we speak, and hopefully, you’ll see something in the not-too-distant future.

Chris Riback: Excellent. We will keep our eyes out.

Dr. Lori Pierce: And I’ll also add, I mentioned that we were doing preclinical work in the estrogen receptor-positive cell lines, and interestingly, although the receptor-negative cell lines if you have the androgen receptor inhibitor, and then you do radiation sensitization, we didn’t see that in those that had the androgen receptor that were ER-positive. So, we’re trying to figure out mechanistically what is the difference? But what’s interesting, you study one question, and another question comes up, especially a question from years ago. We’re looking at the sensitivity of radiation with your common estrogen receptor inhibitors like Tamoxifen, the aromatase inhibitors.

Many, many years ago, I wrote a paper in the Journal of Clinical Oncology. Long story short, it was about the timing of giving, let’s say Tamoxifen and radiation. Should you give them at the same time? Should you do your radiation first and your Tamoxifen to follow? Because there were reasons, and I won’t bore you with the details, that there were theoretical concerns that doing the two together would lessen the effectiveness of the radiation. So many places would do the radiation first and then start the hormonal therapy. Well, now that we’re into this studying of androgen receptors, ER receptors, why do we see sensitization? Why don’t we see sensitization?

We’ve started to run some lab tests, and we’re actually seeing that you get sensitization just by having the hormonal therapy at the same time as radiation. And, actually, this is the subject of a couple of trials that are currently ongoing about the sequencing of hormonal therapy and radiation. But this is something that, coupled with the laboratory data and depending on how the clinical data comes out, will be something very fundamentally important, potentially, to cancer patients who have ER-positive cancer, who get radiation, and how best to sequence these therapies. So, it’s just interesting. Again, the paper I wrote was in 2005, and so now we’ve come around from the clinical paper to the laboratory exercise and actually finding that there may be sensitization just from using our very widely utilized hormonal therapies with radiation.

Chris Riback: Yes, that is wonderful, and it is a terrific insight how questions can then lead to additional questions and to additional questions. And I am sure we could have a whole conversation on that, I’m sure, and I would imagine that’s part of the fuel of what keeps people like you going with the energy and pace that you keep up every day. It’s got to be that curiosity.

Dr. Lori Pierce: It is because these are basic clinical questions. These are questions that our patients need answers to. And those that are the most important incentive for what we do. It has to be relevant and it has to be something that will favorably alter a patient’s course, for sure.

Chris Riback: Were you always curious, were you a curious kid?

Dr. Lori Pierce: Extremely. Extremely, always, always. I have a couple of broken bones when I was a kid to go for it. I was always getting into things.

Chris Riback: Yes. I’m getting that sense about you. Yes, so you found out your limits the hard way, but fortunately at least as a scientific researcher, medical professional, no limits yet that we know of. None that we’ll talk about at least right now.

Before we move on, because I want to ask you a little bit about your work with ASCO (the American Society of Clinical Oncology), and you don’t need me to tell you that you were the president there. But you kind of reacted earlier, when I mentioned the importance of some of the work going on globally, around gaining greater clarity of who wouldn’t benefit and therefore doesn’t need radiation therapy. What’s the status of that work generally, and why does that excite you so much?

Dr. Lori Pierce: So, for any type of therapy for breast cancer or any type of cancers, there are potentially positives, [and] there are also negatives. You don’t want to offer treatment to a patient who really doesn’t need it. And so, it’s important to be able to discern those characteristics about a specific cancer that tell you whether that patient needs treatment now. It’s the ultimate individualizing treatment, to know which patients don’t need treatment. But the other side of the coin, is you have to do this very carefully, because there have been many advances [in] the use of radiation. And just like I said, we know that radiation not only reduces the risk of a recurrence, but also improves survival, so it has to be very, very carefully studied.

Similar to medical oncology—having the Oncotype DX test, being able, through a series of trials, be able to discern those patients who would do well in the absence of chemotherapy—we’re doing the same kinds of things with radiation, and there are currently trials. So, the short answer to your question, is the trials are currently ongoing. Looking at selected patients or patients who have specific aspects of their cancers that are, and I’m doing air quotes here, “that are favorable,” so those that are certainly estrogen receptor-positive, those who have small tumors, patients who may be older, as opposed to 35-year-old patients with cancer, and trying to then see within that selected group, whether they would do equally well without radiation. So, the trials are currently ongoing, very important studies. And hopefully, in the next two to four years, we’ll start to have some meaningful data from those trials.

Chris Riback: Excellent. Look forward to that. I want to talk to you about all the free time that you clearly have because with not enough on your plate, you decided, “Well, why don’t I add a little role like ASCO president,” with all the extra time that you have? Was that your thinking in taking that on?

Dr. Lori Pierce: Yes, that on that summarized it pretty well.

Chris Riback: It seems like it. So in that role, what does the theme, “Equity: Every patient. Every day. Everywhere” mean?

Dr. Lori Pierce: So yes, I have the honor to be ASCO president, and when you’re voted to be president, the first year you’re actually president-elect, and during that year, you get to select the theme that you want to focus on during your year as presidency, and you just name the theme. “Equity: Every patient. Every day. Everywhere.” This is so important to me. It’s important to all of us as clinicians. I am African-American and for just about every endpoint, oh gosh, almost every endpoint that you can look at, people of color do less well and cancer is no exception. And the reasons there are so complicated. If this were a slide show I have a word cloud where I have all of these terms that have to be considered when you think about equity, and it’s such a simple word, but it seems to be so complicated to achieve.

And certainly ASCO, by nature of what ASCO does, ever since ASCO was created, it has focused on equity of care. It’s what it’s all about. And so, there were a lot of initiatives that ASCO already were doing full force, in terms of equity. And some of them included some of the young investigator awards, career development awards, focusing on health disparities, in which BCRF has provided funding for multiple of these grants. So, this has been something that ASCO has been doing. But, for my year, I added additional initiatives to ASCO’s portfolio because this is so important. I mean, care has to be given equitably to all. It shouldn’t make a difference of their financial situation. Shouldn’t make a difference of their age. Shouldn’t make a difference of if they’re in a rural community or inner city. Shouldn’t make a difference what color they are. Everyone is entitled to high quality care. And so, there are many initiatives that ASCO has and new initiatives to focus on equity of care.

Chris Riback: And as I read some of what you’ve written and said about this, it’s also about directly impacting outcomes, isn’t it?

Dr. Lori Pierce: Oh, for sure. And, yes, the short answer to that question is absolutely yes. And you can look at it from so many different perspectives. How do you directly affect outcomes? You affect outcomes by the therapies you give. You affect outcomes by the workup, to be able to adequately stage patients. You affect outcomes by some of the social determinants of health that really impact people on every level. You affect outcomes by survivorship issues, prevention issues, modifiable risk factors. All of those components affect the outcomes of our patients.

Chris Riback: Yes. I don’t know exactly where I read this, that you said, but it gets to exactly what you were saying, that some of the disparities are due to social determinants of health, which you just mentioned. I’m quoting you here, “like where people live, their level of education, where they work, their financial resources,” and it’s hard for us to directly impact those, but we can impact how we give care and that it is equitable. And that struck me because it has such an awareness, obviously, about the entire range of social determinants of health. Obviously, you would love to solve all of those, and maybe in due time, you will. But you make very clear what you and your role, what doctors, researchers, scientists, clinicians, caregivers, can directly impact right now, and that’s the care.

Dr. Lori Pierce: The care, that’s correct. You can also advocate for your patients, with local members of legislatures and state and national. We need to be able to understand cancer through the lens of our patients and what are the barriers that they see. We have all of these incredible therapies, but if there are barriers that prevent a patient from receiving it, then all those therapies are for not. So, it’s important that, as caregivers, we actually spend some time asking questions to understand what are the barriers to a patient receiving the care that we recommend. So, one of the initiatives that we have this year is to create a social determinants of health set of podcasts and videos. And it will educate. It’s really geared primarily for our fellows and early career oncologists—because they’re our leaders for tomorrow—to really understand what the social determines of health are.

And there’s one episode that is being taped this month about how to take a social determinants of health history. It’s so important to find out if Mrs. Jones doesn’t have transportation, can’t come in for radiation, she can’t come in for chemotherapy. Mrs. Jones has to work and can’t get time off. So, they’re just things that we’re all taught in medical school. How to do an H and P [history and physical examination], but we need to kind of also how to solicit in our history, taking those barriers. And that knowledge will help us, in some cases. We can’t do it all, but in some cases will help us to be able to help our patients better. Does that make sense?

Chris Riback: That makes a ton of sense. That’s terrific. I would look forward to getting to learn more about that. I know you’ve mentioned it a couple of times, but broadly speaking, what role has BCRF played in your research?

Dr. Lori Pierce: So, BCRF, it’s just a special organization. You know, it brings together breast cancer researchers who are doing incredible work to be able to cure breast cancer. And it has meetings, it has ways that we can interact with one another, and we learn from one another, and we collaborate. BCRF establishes this amazing collaboration of researchers. You know, some of the cell lines that we used for some of the work as I talked about earlier, were from other BCRF investigators. And then a few years back, some of the work I was doing then, which is different than what we talked about, was looking at radiation in women who have a BRCA1 or two mutation. And it involved bringing together a collaboration network of investigators, in order to have enough numbers of patients, to be able to make some clinically relevant observations.

And I was able to connect with other BCRF researchers to be able to establish these collaborations. And this work, even though it was a few years ago, is still being quoted. I just helped to co-lead the ASCO, ASTRO [American Society for Radiation Oncology], SSO [Society of Surgical Oncology] guidelines on hereditary breast cancer, and a lot of the work for the radiation part was from the work that I had done with this collaboration. So, BCRF essentially creates a family of breast cancer researchers. And it’s just an honor to be able to be in that family and to be able to learn from others and to collaborate.

Chris Riback: And if I could, mindful of time, close out this conversation with my own question on history. How did you get into this? I mean, going back, for you was it always science? Was it always research? Did you ever think, perhaps you’d be a fiction novelist or world-class skier? I will confess, I have read about a Doc Weaver in Ahoskie, and I don’t know if I’m pronouncing the –

Dr. Lori Pierce: Ahoskie!  You’ve done your homework, oh, my gosh!

Chris Riback: North Carolina. So, what was Doc Weaver about?

Dr. Lori Pierce: Yes, so I’ll just summarize it. And I have a lot of family in a small town called Ahoskie, and so in the summers, I would spend quite a bit of time there. And, in the sixties, you’d come to Ahoskie and the care was segregated. I mean, most of the people of color received their care from a physician of color, and his name was Dr. Weaver and he was wonderful. He was absolutely wonderful. And I noticed that. I noticed how he had the answers, how he was the doctor for everyone. Everyone looked up to him. Everyone realized just how special he was and certain things, when you’re a kid, stick with you and that stuck with me. And that certainly was one of the seeds that led me to where I am today.

Chris Riback: And so, had you decided. I mean, was it pretty clear? Were you science-minded?

Dr. Lori Pierce: I was always science- and math-minded. I was always very inquisitive, which you stumbled upon earlier. And, as I mentioned earlier, yes because I was so inquisitive and I was pretty thin, I broke a couple of bones along the way. So, I ended up needing to get X-rays and all, and I was fascinated by X-rays. Absolutely fascinated by X-rays, to the point that I asked so many questions to the X-ray techs, that they would go get the radiologist to answer my questions. The radiologist went over the films with me, and I just thought that was just the coolest thing. And I decided then I wanted to be a radiologist, and that didn’t change until I got to medical school.

And I won’t bore you with the details, but while in medical school, I realized just how much I love working with patients and radiologists are wonderful, but they don’t have that close of an interaction with the patients that they take films of. And I found radiation oncology, so that gave me the X-rays, it gave me the chance to work with patients, it gave me the chance to do clinical research, and it’s just been a wonderful career.

Chris Riback: I sure hope you don’t take this the wrong way, but the rest of us are so glad that you broke bones. That’s excellent for the rest of us. Thank you.

Dr. Lori Pierce: That’s how it all happened.

Chris Riback: That’s how it all happened. Dr. Pierce, thank you so much for your time and, obviously, for the work that you do every day for patients.

Dr. Lori Pierce: It’s so good to talk to you, Chris. Good to be able to talk about the work that we’re doing, and hopefully it will resonate with some of the patients who hear this.

While genetic testing and counseling for breast cancer has been available in the U.S. for many years, accessing these services in Mexico and the rest of Latin America is more challenging due to limited resources. This disparity is particularly concerning because hereditary breast cancer has been found to be a serious problem in this population of women.

Leading genetics researcher and oncologist, Dr. Jeffrey Weitzel, has devoted his career to decreasing these barriers. He led a groundbreaking study that revealed BRCA mutations may be present in 25 percent of U.S. Hispanic women, leading to calls for increased genetic testing and counseling.

Dr. Weitzel, a BCRF investigator since 2013, is director of the Clinical Cancer Genetics Program and professor of oncology and population sciences at the Beckman Research Institute at City of Hope. Dr. Weitzel is pioneering low-cost genetic screening materials and training doctors and nurses working with underserved populations in Peru, Colombia, and Mexico.

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Read the transcript below:

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

Dr. Jeffrey Weitzel: My great pleasure.

Chris Riback: There are so many places a conversation with you could go and I certainly hope that we get to go to all of those places or at least most of them. I’d like to start with your work that centers on improving access to genetic screening and breast cancer prevention in Latin America and Mexico. Let’s start perhaps with a laying of the geographical land. How big is the screening and prevention problem in Latin America and Mexico?

Dr. Jeffrey Weitzel: I don’t think we have to go beyond our own borders to get some sense of that as well. Really, our project is about, started at its heart, to address disparities. I’m an oncologist and a geneticist so this onco-genetics realm. Certainly there are many BCRF projects that relate to the causes of breast cancer. People come to mind like Dr. Mary-Claire King and others who are just absolutely stellar leaders in identifying hereditary forms of breast cancer.

While it’s not the most common cause of breast cancer it is perhaps the most impactful. The risks are so extraordinary that people really deserve to be identified and given guidance as to how to take care of their risks. So, over 20 years, it’s been over 20 years that we’ve been able to do commercial gene testing for breast cancer pre-disposition that there are still groups that are left out in the United States.

This really goes to my own back yard. I’m living in Los Angeles and we have a very rich Hispanic fabric. A lot of people with ancestry that might originate in Latin America. This goes back to the year 2000 and to one of my dear colleagues. If you don’t mind, I’ll tell you a story.

Chris Riback: Please.

Dr. Jeffrey Weitzel: Dr. Feldman was the chair of oncology at one of our safety-net hospitals. This is one of the LA County hospitals. 89 percent of their indigent service population is Hispanic and or has Spanish language as even their first language. She came to me when we were at a breast cancer retreat talking about science and she said, “We’re dying out here. I have 32-year-old women coming in with easily palpable stage-three breast cancers, and they have a family history of breast cancer. Why weren’t they identified, given access to genetics and the opportunity for prevention.”

This is something that’s so obvious. We know the story. We know what hereditary breast cancer looks like but these people weren’t getting access. So, I said well, let’s look at that. We literally created an infrastructure right off the bat. We’re going to open a free clinic, we’re going to provide the care but we still have to figure out how to get the testing done because in those days the test cost 4,000 dollars for two genes. Medicaid did not provide coverage for testing.

First, we had to say okay, what do we need to do special for these individuals so that we can make them feel comfortable. If you build it, will they come? If they come, will they learn? If they learn, will they do the right thing? If they do the right thing will they be free of cancer and live longer.

Chris Riback: Was that conversation the inspiration for you for your groundbreaking study that revealed the BRCA mutations may be present in 25 percent of US Hispanic women? Is that what drove you to do that research?

Dr. Jeffrey Weitzel: This is the thing, when you go to do the right thing, sometimes you learn other stuff. So, again from a friendship level we started this program to address a disparity. I’m honored that I also have Conquer Cancer professorship in breast cancer disparities in part because of this legacy. But we first published on the beliefs and interest in risk-assessment in Latino cohorts we said, if you build it will they come? We literally put that in the title. We started the clinic and said, are people coming in? Are they learning? And they were.

By hook or by crook we got funding and created our own funding to try and get testing done and in the process we discovered that, wow, these people had a high prevalence of mutations, this is in our study, just at the county hospital, which we published on in 2005. Further, we saw the same mutation repeatedly, which suggested a population level impact of history, anthropology, and epidemiology.

I’ll tell you more about that story in a moment, but we, kind of, through the backdoor, learned the epidemiology and that’s because nobody else was taking care of these patients. So what happened in the intervals, I have a large research network. This is something I’ve built over 25 years. I have 39 sites in the US and now we have 7 in Latin America. We’re all running the same protocol, which is everybody we see for risk assessment we enroll and we study.

The 2013 paper that you’re talking about, which at that point was published in the Journal of Clinical Oncology which is a high-level journal because it was a novel observation of 746 individuals, all of whom had breast cancer, presumably at a young age they met the criteria for testing and we got testing and it represented mostly Mexicans and Latin Americans and Central Americans based on our service area.

Chris Riback: Was it that 52 percent of them had the same mutation? I might be getting the fact wrong. What was the data there?

Dr. Jeffrey Weitzel: Of all the women with breast cancer 25 percent had a mutation. Of those mutations we found that there were two specific mutations in BRCA1 that had counted for a large proportion of cases and then multiple other mutations were seen. One of the things we discovered, because this was work I did again, on this initial cohort from the county hospital. First we found a bunch of mutations, then were new technologies coming along which was to look for specific mutations that couldn’t be detected by just sequencing.

They’re called large genomic rearrangements. So, big dilutions. Ironically, you can find a misspelling in the gene very easily with sequencing but if a whole chapter is missing, you don’t see that, because everybody’s got two copies. One copy is normal. One copy is not. You’re just reading through and you think they’re all normal but they’re actually just completely missing that stuff.

It turns out that we were one of the first observations of a large genomic rearrangement, so a very specific type of mutation that was repeating in this population, had never been reported in Spain or any other country. So, we surmised that this was what we call a founder mutation. Any geographically or culturally isolated population can have this.

We further went and found out that not only was this frequent in the population, it looked like it was in Mexico. We found it once in Venezuela but it turns out that individual was Mexican. It turned out to be exclusive from people who originated in Mexico, and it was frequent. We did what we call haplotyping to determine how old the mutation was, kind of like carbon dating, and we found out it was 1,500 years old.

This long predated the colonial Hispanic influences. So the colonial influence of the Spaniards, et cetera, and really reflected origin in an indigenous population, indigenous American population likely in central Mexico.

Chris Riback: Not brought from Europe.

Dr. Jeffrey Weitzel: That’s right. Now we found a lot of other mutations that were frequent. So the other one that was a very interesting observation we first published in 2005, one of the first times it was documented, was multi-generational Catholics, we found the 185delAG mutation of BRCA1 which is a known Jewish founder mutation. What we published on then, in 2005, was that they shared the same chromosome as my Jewish patients from West LA.

This shows an ancestral origin and that links it immediately to history and to anthropology. This is where I get just completely excited because we start talking about the impact of history and humankind and the consequences of diasporas. Think the Spanish Inquisition, 500 years ago, It’s about 500 years ago this year. They basically caused a mass disposition of Sephardic Jews, so Spanish Jews, who moved to Portugal and then to the new world.

We’re able to establish that there was a much larger diaspora that was of conversos, people that converted to Catholicism to survive than had been anticipated. That mutation and this founder mutation that we found in the indigenous population were the two most common mutations in the whole cohort. So, that was really illuminating and it helped me understand the impact of world history, and not surprisingly we saw a bunch of Spanish mutations too. There are other mutations that are common in Spaniards that are seen in this population.

One last population this represented, and again bringing together our world history view is, there was an African founder, and that reflects the impact of the slave trade. Especially in Central America and in Mexico on the gulf coast, because remember that was where a lot of the slave trade entered. We saw exactly what you’d expect for the admixture, the type of blend of cultures and ancestries that you see in Mexico. Again, I learned a lot about ancestry, anthropology, and epidemiology by trying to do the right thing. That is, take care of people who have no access to care.

Chris Riback: I was just going to say, you’re raising one of the most fascinating parts of these conversations for me is the intersections. So often the intersections I come across are from oncologists who are studying or have worked in one type of cancer and from working in one type of cancer, lung cancer, stomach cancer, and other areas they take those findings and apply them in other areas of study and that mix has not stopped fascinating me.

What I’m hearing from you is, you’re not a historian by study, and you’re not an anthropologist by study, but is the fact that you are an oncologist and a geneticist, was that mix of your background part of what enabled you to really go forward on the type of investigation that you did there?

Dr. Jeffrey Weitzel: Yes, absolutely. I think that geneticists follow lineages and sometimes those lineages go way back. That’s a natural interest on that side. The oncology side of me is all about, what’s the problem? What do we need to help with? Where are we having a problem that we need to take care of people?

So, you’re right. I’m sort of a junior anthropologist as a result of this. Really, I’ve read the books. I’m starting to read the books and the things that relate to these historical angles and then it actually provokes new scientific questions. You look at these ancestries but what was important at the time, let me just add one other thing, is remember we were talking about disparities in the access to care and the absolute limitation because of the economics.

The other thing we tried to do is we said, okay 75 percent of the patients who have a mutation have one of them that we’ve determined were on our shortlist. They were recurrent. They’re historical, ancestral. We already knew these genes didn’t mutate frequently, meaning new mutations aren’t quite found that open. We said, can we do a cheaper test.

I actually turned around and created in my laboratory, I like to call it the pragmatic research, which is can I get testing done cheaper for my patients without having to spend $4,000 a test? And we did. We created then a platform that uses mass-spectroscopy, a $20 test that picked off 75 percent of the true mutations. That allowed me, even in my county hospital population in the US, before Medicaid started paying, we were able to figure out the 10 or 15 percent who are carriers based on this very cheap test. Turned around and converted it with a commercial test at a cheap cost to now have a tool for the whole family.

We were leveraging science to be pragmatic and literally translate directly into access to care based on knowledge of epidemiology. What’s happened since then is that we started to raise that flag and really push that theme, that don’t leave anybody out, any population that looks like it has hereditary breast cancer probably does. How do you take care of these people? We need people who are trained in genetics and oncology, so we married this to what I will call our, we have an award-winning doctor training program. So doctor, nurse, and genetic counselor training program.

Chris Riback: Is this the cancer genomics education program with Dr. Blazer?

Dr. Jeffrey Weitzel: You’ve got it. Dr. Blazer.

Chris Riback: So please go ahead.

Dr. Jeffrey Weitzel: So Dr. Kathy Blazer was a genetic counselor. She was one of the first genetic counselors that I hired when I got my first education grant back in 1997. She was obviously quite young when I hired her. She’s Dr. Blazer because along the way we had gotten really involved in, really brought our education program because we realized post-medical school training, and even fellowship training of oncologists was completely deficient in understanding how to apply genomics and cancer.

That’s become even more so the case. I’m sure you’ve had other podcasts where you’ve talked about precision medicine, so this whole intersection of genomics and oncology is just so stimulating and so fascinating. People need that training that they didn’t get. Not only that, but she championed what we call situated learning. We’ve taken practitioners who are in practice and use their own cases to help them learn and it turns out that it’s the most profoundly effective way to train practitioners is to make it situated, it’s relevant to their practice today, and use their own cases in that learning.

Suffice it to say we developed a program that’s over 100 continuing medical education hours and involves a lot of immersed learning. She’s Dr. Blazer because she went and got her educational doctorate at UCLA, while she continued to work at City of Hope and has raised the bar even further on our program. I’m very honored that last year the American Society of Human Genetics recognized us as a team to award their education award.

Suffice it to say, we’ve taken this award-winning program and said, okay, how can we increase access to care, and how can we leverage this epidemiology. Because even though we continue to expand access to this care in the US. I will say there are still deficits in the underrepresented minority populations, and disparities there. Also, among Hispanics in the US. We have made a lot of progress there. We now have trainees in every state of the union and 26 countries.

How do we then take what we learned and maybe take it to Mexico? This is where, really BCRF, has been so instrumental. These things take a while to develop. We have to be patient. Even though we’ve been doing testing for 20 years in the US they still don’t have a fundamental access to genetic cancer risk assessment in Mexico, Central America, and most of South America. This can be said also for, probably, Africa and a few other places.

We said, hey we’re training people, but it doesn’t do them any good to get trained if they don’t have tools. So, I have a registry protocol, that allows return of results that are clinically actionable to the patients and the clinicians who are participating in this research. So, what we’ve done is created an implementation intervention so, there’s a whole science of dissemination and implementation, I’ve had to learn multiple sciences beyond oncology and genetics to do research.

Behavioral research, will they show up? What are the social-cognitive aspects of Latinas preparing to undergo risk-assessment. I’ve learned so much from my colleagues and embraced my colleagues who are multi-disciplinary, it’s so important. Again, genetic counselors are so key to that process.

In any event, we, embracing all these various specialties and things, and learning how to do dissemination and implementation which is really, how do you take this practice that you feel is medically important and will help to save lives, how do you get other people to adopt it and what are the barriers?

It’s a whole study. They’re the PIs of their own registry but they send the biopsy specimens to my laboratory at City of Hope where Joseph Hertzog and Danielle Castillo both work in my lab and they’re just awesome. They do all this work.

They receive all the samples, we extract the DNA. Even though I didn’t want to be a service lab. I have no intention of being one of the major commercial genetic testing laboratories. I realized, if we did it cheaply using a number of different tools, what we can now do, BRCA testing plus another 30 genes all for under $100 per case. That puts it into the realm of research funding, and into the realm of plausibility for these other countries if they can pick up the technology.

It’s partly tech-transfer too. In the meantime we said, well you don’t want to just give them the tool and tell them to go, test people, you want them to take care of them appropriately. So, we trained them in the course. They get the high-level training in cancer genomics and how to apply it in the clinic and they go back to their own setting, they create their own clinic and we help coach them on creating clinics, which is part of what dissemination and implementation is about.

By putting them in our registry we accomplish two things. We now, continue to grow the body of knowledge about epidemiology. So, what are the country-specific patterns that will help to convince their own health care administrators that it’s important. And second, they’re really giving that care to their patients and helping to find ways to take care of that risk when they find it.

I’ll give you an example that is so pragmatic. Unfortunately, most of these people still have cancer when they’re identified, we’re not quite at the identifying the at-risk relatives, but if a woman at 35 years old or 40 years old comes in with breast cancer, at whatever stage… I will tell you the stage distribution in countries without good screening is dismal. It’s like stage three. But, they have big families. And so, if we can identify the risk in that woman, she gets good care and survives, and we find out that because she is a BRCA carrier she has an extraordinary risk for ovarian cancer that could take her life. With almost no chance of early detection there.

That’s an intervention, remove her ovaries and tubes out after the completion of childbearing that could save her life. Then, on top of that, we now have the anchor for that family, we do what’s called cascade testing. Now we can go to her sisters. Even if we can’t provide comprehensive care for everybody in that family, at least half of the individuals won’t carry the mutation so we can give them reassurance that they’re average risk. The other half we can focus what limited resources we have.

This is about allocation of limited resources in low and middle-income countries. If I looked at it, at a population level, how do we help in a bigger way? Our goals are nothing short of changing entire counties’ plans for the care of high risk individuals at risk for breast and ovarian cancer. At the immediate level, I believe we are saving lives now by not waiting until genetic testing is somehow implemented by commercial firms at an adequately low price that the countries with such limited resources are willing to pick them up and integrate them.

We’re really creating the infrastructure to implement these cares and getting immense experience for the people locally and for our general knowledge of epidemiology to help guide these directions. Again, the BCRF funds have been so important to be able to have the patients. We literally develop these programs one city at a time. We’re in Mexico City, Guadalajara, Monterrey. We just opened up a clinic in Tuxtla which is in Chiapas.

Even in a poor country or a low and middle-income country, this is like the poorest.

Chris Riback: And historically there’s been real danger there.

Dr. Jeffrey Weitzel: That’s right. Real danger, and historically disparities even within that setting. The more indigenous people, and there’s a lot of disparities. We’re partnered there with Francisco Gutierrez and his clinics. He trained with us. We went and did a site visit back in January before COVID-19. He was a most gracious host but we got to see where they’re going to do their work, we got them logistical support and we’ve already tested over 50 patients for his clinic.

That will serve people in Chiapas all the way down to Guatemala and into Oaxaca, so a very large area that they’ll help to serve. We’re also in Bogota, Columbia, Medellín, Columbia, and Lima, Peru. This is the nucleus of the network. I will tell you that overall supported by Breast Cancer Research Foundation. We’ve helped to test more than 4,000 women over the last five or six years. That means 4,000 families with access to care. At least 15 percent are carriers of a significant mutation that influences their care.

We’re starting to create a legacy in terms of publications as well. We have one publication from 2014 on triple-negative breast cancer, and out of 190 women with triple-negative breast cancer we found that 27 percent had a mutation on our quick screen. We screened 190 women in two weeks for $5,000 and came up with 45 carriers that quickly.

You just can’t do it on a scale when we’re being nimble, we’re doing what we can. We found out just recently, we got some really exciting data coming out that we’re writing right now, so it’s unpublished suggesting that there may be a difference between the mutations. That the mutation that’s that founder mutation while it confers great risk, also may confer some survivor benefit if given chemotherapies. We’re actually starting to get into the patho-biology of breast cancer, not just who’s at risk but what are the outcomes? We’re also studying what’s the uptake of risk reduction surgery.

Do the women who we identify get access to the care? Remember this is all on the backs of those saints, those clinicians, at each of these sites. We said, we’ll help you define the risk, but you’ve got to figure out how to take care of those patients. Rather than saying it all had to be lined up before we started we said, let’s get this going and the natural experiment, which has been just amazing, is that when given the opportunity, we give the patient the information, let them be empowered. Give the doctors the information, let them be empowered. They find ways to work the system and get the care.

This has been really remarkable that they’re going to figure out how to provide the care where they are and it’s respect for cultural and situational circumstance. We aren’t promoting US guidelines, we’re promoting locally relevant guidelines in terms of the care that they provide.

I’m becoming more adept and understanding of all of these very important, I’ll call them, cultural humility is I think the new word. Understanding how…

Chris Riback: Yes, it’s a terrific phrase. In listening to you so many key ideas and such important concepts jump to me. When you say you’ve tested 4,000 folks. It goes beyond that. The cascade effect of what you’re learning is all of a sudden, the folks within that testing environment who do discover that they have a genetic mutation, I know you already know this, you’ve just now positively affected at least with arming them with information about themselves, their whole families. Every member, sisters, granddaughters, nieces. The list goes on.

Dr. Jeffrey Weitzel: Absolutely.

Chris Riback: That’s number one. Number two the thing that occurs to me, so tragic, I’m certain you feel the same way. You mention that so often in some of these locations in the US, in other places where there is disparity of care and disparity of access that the person who comes in, comes in because the risk identifier that has come up in her life is the actual cancer. You described it as so often they come in and it’s stage-three cancer, they haven’t been identified before that. Obviously that’s tragic and sad and you wish to goodness that somehow you’d been able to identify them earlier.

That said, same thing, then they go through the process and all of a sudden you’re now able to arm the rest of their families, yes maybe, you phrased it, maybe you’ll be able to find some other type of cancer that they might have been, might have come across, or had ultimately. By doing this care you will have identified that. You mentioned ovarian cancer as an example.

Lastly, and this is kind of my question, one question is, please correct me if I’m not interpreting the lessons that you’ve been describing because I’m just trying to communicate back to you what I’m hearing in getting to hear the work and the study and impact that you’ve made. Going into this conversation, one of my main questions was, okay Doc you’re worried about disparities, where do you begin. Is that a money question? Is that an access question? Is it a social question? Is it a health care professional question? Is it an education question? Is it a science question? When you talk about disparity what exactly does that mean, and what I’m hearing from you is, yes. It means all of that and that probably, is what defines one of your current research programs, the multi-modal approach to address these disparities. It really is multi-modal isn’t it?

Dr. Jeffrey Weitzel: Absolutely. It’s creating infrastructure, generating knowledge, being able to help influence health policy decisions, so a truly global profile. Right?

Chris Riback: Yes, yes, it’s a public policy.

Dr. Jeffrey Weitzel: It’s a public policy. Again, by demonstrating the impact. By going and not waiting for little pieces to come together, but to put it all together and allow my colleagues to take the lead. They really do take the lead. They’re extraordinary in their efforts. We’re publishing locally. We’re publishing globally. The idea is that they will establish that the problem exists and that there’s a pathway to some solutions.

We’re laying the groundwork. One of our colleagues we were working with Alejandro Moja, he was the former director of the National Cancer Institute in Mexico City, and he was at one point or another also working as an agent of the Ministry of Health. One of his charges was to create a national cancer plan. We were able to at least, get his ear because he was one of our earliest collaborators, probably our biggest critic, but once convinced [he was] our staunchest ally.

I appreciate my friendship and my collegial relationship with him to date, but he had written in, to this national cancer plan, allowed us and my partners in Mexico, to help write a component of the plan that started to integrate the concept of genetic risk assessment and the need for scale-up. To be able to take the lessons that we’re learning from the BCRF project, expand them, and now apply them to other parts of the country beyond the major population centers.

I think we’re already seeing the path we need to take. It’s also sobering, I’ll tell you. We went there in January, had a physician round table and all the same things were still there. What’s even worse was at the time, because of political changes, and we know that well in the US as well, that things change. Support for different programs change. They were in the process dismantling their safety net program called Seguro Popular which threatens our program so we actually talked about starting a social movement.

I’ve got to tell you it’s so inspiring to see them standing staunchly to support their patients and those families and realizing that they’ve got tools that can make a difference and finding a way. Just finding a way. As they say, nature will find a way. Humankind will find a way. If you are respectful and understand that.

Chris Riback: If humankind will find a way, and you may have just answered the question that was going through my mind, which is, listening to you, it is beyond obvious that you are inspired. It’s beyond obvious that you are enthusiastic. Are you optimistic?

Dr. Jeffrey Weitzel: I am passionate and I believe, yes, you can’t do this kind of work without being an optimist. If I had been a fatalist we never would have started. We would have said there’s too many barriers. In fact, we did some focus groups and things and things. There was a fairly, concern about, there’s so many elements working against the integration of this care but we put a wedge in there.

You put the wedge in, which is knowledge, the teaching, the training, and then you let them be inspired and find a way. Again, we just started building tool and putting them together and hence the multi-modal intervention. The recognition that it’s the registry because I have to do the testing in my lab now. Eventually that’s not going to be the case, it’ll be available commercially but cheaply and good quality. They’ll already have in place the structures for the follow-up care. Again, it’s not just getting the risk assessment done it’s what do you do with them once you know they have risk. It’s so inspiring to just follow my colleagues.

I give them the tools they’re the ones who are really doing the hard work. It’s easy enough for me, well it’s not easy to write grants. We write grants, we sit back, it’s not an ivory tower. I get out into the field. I do travel. We do site visits at these sites because we want to see what they’re up against. We want to see what they’ve done. We come in, not like an audit. It’s a friendly audit. Here’s what you’ve done. Boy, these other sites in Peru they got over this barrier by adopting this. So, we help them adopt those practices and share it among this group and we have a cohesive group of people who recognize common goal. They’re in multiple different countries and we’re innovating together.

We publish together. We innovate together. I try to never stop learning and listening. I tend to talk too much. I get that all the time. But I do listen. My absolutely spectacular colleagues in Mexico, Dr. Yanin Chavarri Guerra in Mexico City Dr. Cynthia Villarreal Garza in Monterrey, they’re some of my longest-standing colleagues and partners and I think they are brilliant. They are the future of oncology and prevention in Mexico––absolutely so. Julio Abogadas who’s in Peru at the National Cancer Institute in Peru, a breast surgeon. Again, the future of prevention there along with Pamela Amorra.

That’s where I get my inspiration and I think it helps me understand our impact well beyond the walls of the City of Hope. I mentioned also, here’s something interesting. We’re trying to help them through strategic allocation of limited resources. So at the end of the day if you’re just a healthcare policy wonk, we have a limited amount of money and so many needs, how do you do this? I would tell you that there’s a big drumbeat for can we get breast cancer screening for all women?

I don’t want to offend anybody, but for many women they might be a 1 in 10 chance at most, maybe less, we’re being able to stratify that more, but the BRCA carrier’s an 8 out of 10. If I have only a certain amount of money to apply for screening and people are not getting regular screening, only 19 percent of women are getting breast cancer screening in Mexico despite the fact that it’s technically a covered benefit. As a basic limitation there, if I could only screen one set of people. It’s when Willy Sutton was asked, why do you rob banks in the 1940s.

Chris Riback: I know why. That’s where the money is.

Dr. Jeffrey Weitzel: That’s where the money is. Okay. The same applies here. If you apply the strategic allocation of limited resources. If you can cheaply identify those at highest risk you’ll make the biggest impact with the least amount of money quickest there. I’m certain when I look at the uptick of the risk reduction removal of the tubes and ovaries, and the other side, mastectomies that are being done as prevention for some of these BRCA carriers with breast cancer, I’m confident that we’ve already prevented a bunch of ovarian cancers and probably quite a number of breast cancers.

This is prevention in the moment while we’re still working on the implementation, and that’s exciting. Think about this, is that they’re teaching us how to get limited resources to work for a population, we can take that home and start to address disparities in the US and in low resource settings. It’s reverse-engineering. It isn’t that it’s just a one-way street where we’re just bringing stuff to them. We’re learning from them and I hope to bring that to disparities in the US.

Chris Riback: I am certain that you are. I knew coming into this conversation that you are recognized as a world-class oncologist and geneticist what I didn’t know and what I’ve learned is you’ve got a bunch of other titles, historian, anthropologist, sociologist and I would dare say a potential for a novelist because not only do you tell a great story but there’s a remarkable story that you’ve uncovered. There’s something multi-cultural and extraordinary there. Thank you. Thank you for the work that you do and thank you for taking the time to tell me about it.

Dr. Jeffrey Weitzel: Well, thank you for your interest. I’m so pleased that you would take an interest and willing to help to share this. I’m always in great debt to the Breast Cancer Research Foundation. I’ve been a long-standing scholar with them. I’m so grateful that they’ve had the patience and understand the mission. They’re one of the few organizations in the world that’s truly global. They have global impact. I just can’t say enough positive about that and how important their funding is.

I think they are the largest public or private funders of breast cancer research in the world and I truly see a global understanding on their part. Everything from absolute basic biology to what I would call pragmatic translation. I’m probably from the middle of that curve on over to pragmatic translation. Really honored to be one of their scholars, so I can’t say enough for my gratitude for their support.

Chris Riback: That’s wonderful. Thank you.

Advances in cancer therapy have dramatically contributed to the decline in breast cancer deaths over the last three decades. But even with these advances, drug resistance—when tumors stop responding to anti-cancer drugs—remains a serious clinical challenge. So how exactly do cancer cells evade the drugs designed to kill them? What’s next in developing strategies to prevent or overcome drug resistance and improve outcomes in breast cancer patients? And what role can new technologies like liquid biopsies play?

In this episode of BCRF’s Investigating Breast Cancer, we talk to Dr. Sarat Chandarlapaty to answer these questions. Dr. Chandarlapaty is a laboratory head at the Human Oncology and Pathogenesis Program at the Memorial Sloan Kettering Cancer Center. He’s also a BCRF Scientific Advisory Board member and has been a BCRF researcher since 2015.

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Read the transcript below:

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

Dr. Sarat Chandarlapaty: Thank you, Chris. It’s a pleasure to be here.

Chris Riback: Of course, I want to talk with you about resistance to therapy and the progress that you are making, that can be made, that you hope to make in those areas, but given our times, I think I should start and would love to start with a very brief Coronavirus update and really just in terms of what are you hearing? What are you hearing from the breast cancer community and what are you hearing from your patients?

Dr. Sarat Chandarlapaty: Yes, Chris, this is obviously an unprecedented time. As an oncologist, I think, I get these phone calls, really there are two sort of streams of questions. One is, “What can I do to avoid getting Coronavirus? I have breast cancer and I don’t want to get Coronavirus,” and then on the other side is, “Are we ignoring my breast cancer?” The answer to those, in some ways, competing questions is: “We’re here to care for your breast cancer and to treat it as the disease that it is, but to recognize there’s this unprecedented risk out there, and we do your care in a way that’s tailored to this moment.” But we’re still very much in the business of trying to make sure that we offer the very best treatments for breast cancer.

Chris Riback: Let’s talk about those treatments and let’s talk about your research in particular. So your area of research I have seen described as solving the mysteries of drug resistance and improving response to targeted therapies. Is that how you think of it? Are you trying to solve a mystery?

Dr. Sarat Chandarlapaty: Yes, it’s interesting, I mean, one of the first things we want to figure out about cancer is how can we cure it, how can we treat it and make those tumors shrink? And with breast cancer, we’ve solved a little of that problem, right? We’ve developed therapies over many years through the work of many, many people. We’ve developed some basic understandings of what makes some breast cancers tick and when I’ve come in, I’ve seen that and the question I struggle with is why does it work and then stop working? What is happening there?

Chris Riback: Yes.

Dr. Sarat Chandarlapaty: Because if we could just make those treatments work indefinitely, then I think we would have a far better solution. Yes, resistance lies at the heart of the research that I do.

Chris Riback: What defines or describes resistance to therapy? So for a lay person like me, we always hear about resistance, generally, I’ll hear it in terms of antibiotics. “Don’t take too many antibiotics, because you’ll increase resistance to their effectiveness.” Resistance in a tumor, resistance in breast cancer is something different.

Dr. Sarat Chandarlapaty: That’s right. There are similarities to antibiotic resistance, but I would start by saying, there are two classes. First, there are cancers that we give a treatment to and those cancers clearly don’t care. They just sort of proceed on as though we didn’t treat them. That’s a sort of intrinsic resistance and that’s less common overall. Then there is the so called acquired resistance, that is a cancer that for six months, for three years, was treated with a drug and seemed to be well behaved under that regime, maybe shrunk some, and then suddenly started to grow, started to go into new places. That change in behavior is really the resistance that my lab has really focused in on, because it’s so common— such a common occurrence for patients who have had, particularly, the more advanced breast cancers.

Chris Riback: How common is common? And I found myself wondering, are there any signs in advance, any commonalities where you kind of getting a hint that resistance might occur. So I guess, let’s start with the beginning part, which is how common is it?

Dr. Sarat Chandarlapaty: Yes, so we think about it mainly in the setting of where patients have advanced disease, so called stage IV breast cancer, where cancer has spread outside of the breast, and we’re predominantly treating with drugs, oral drugs, IV drugs.

Chris Riback: But has it metastasized because the resistance was there? Meaning, if the resistance didn’t occur, it wouldn’t have gotten to the state that you just described? And I know metastasis can occur for all sorts of reasons but when you’re looking at it, are you talking about the type of metastasis that has occurred because there was a resistance in the first place or is there now resistance now that you’re finding the cancer in the different organs?

Dr. Sarat Chandarlapaty: That’s a good question and a little complicated. If a cancer presents for the first time, as a cancer that’s not just in the breast but is in the breast and, say, the bone, that’s a cancer that’s never been exposed to a therapy, so it may have that so-called intrinsic resistance, but it certainly wouldn’t have acquired resistance. It didn’t get exposed to a therapy and change or adapt or evolve, but sometimes we actually do see that. We see a patient who presented with a primary breast cancer, had it removed surgically, received hormone therapy, for instance, and after years on hormone therapy, a breast cancer arises in a new site. And that’s one that is resistant, did the resistance fuel its spread?

Dr. Sarat Chandarlapaty: Probably not but we don’t know if sometimes the resistant cancer takes on new properties that allow them to spread, but I tend to think of this, to answer more simply, as separate processes. The cancer spreads and the cancer that has spread is resistant …

Chris Riback: To therapies at that point?

Dr. Sarat Chandarlapaty: To therapy, right.

Chris Riback: And getting back, I think I might have cut you off in terms of how common is it, because I would assume that this is an area of concern for someone and I want to ask you about that in a moment, but how common is it?

Dr. Sarat Chandarlapaty: For cancers that have spread, that are stage IV or metastatic, most of them, I would say, on the order of 80 to 90 percent will eventually figure out and become resistant to the therapy we give. The timing of that is quite variable, and remarkably so. So for one patient, on a very common regimen of a hormone and a targeted therapy combined, one person, their cancer might respond and then develop resistance in six months, and another person treated with the same regimen with the same characteristics might respond and then develop resistance six years later. So one is six months, one is six years and that’s obviously, there are some intrinsic property is different about those cancers and we want to understand that.

Chris Riback: And are there signs or is it like a light switch? Is that resistance gradual and from your perch, you can, you see it coming or is it sudden and all of sudden, one day it’s working and the next day it’s not?

Dr. Sarat Chandarlapaty: Well, that’s a really important question, whether we can develop technologies that can tell us when it’s coming so that we can sort of be ahead of it. Right now, the standard way that we find this out is because we do serial imaging and blood tests like what we call tumor markers. Or we sort of listen to the patient for what symptoms might be happening and so it’s somewhat crude that after three or four months, we’ll see if the treatment’s working. So things might be happening in a much earlier time point but we don’t have ready access necessarily to technologies that can tell us about that, but if we could find it out earlier when it’s just a few cells as opposed to a large number, then that may enable us to develop treatments that work better for the resistant cancers.

Chris Riback: Listening to you, I find myself, the word that keeps coming to my mind is uncertainty, and I’m thinking about kind of the emotional challenge of that. I’m imagining that you’re working with patients who have already gone through what they have gone through and who like any of us would be looking for something that resembles … I put the word in quotes, “control” or “certainty,” we all seek that in our lives and we probably can never have that, as I think maybe even this current pandemic is showing us. Having control over life is pretty tough to get, but I assume that’s the goal but then there’s this uncertainty that a certain percentage of cases, this resistance occurs and then there’s the added uncertainty that the timing can be different. It’s just emotionally, I would think this has to be something of a challenging area. Am I kind of imagining the situation correctly?

Dr. Sarat Chandarlapaty: No, I think you’re right that we want to be able to have some understanding of the processes that are happening and not just that they’re happening, but when they’re happening and be able to plan accordingly and to have control. I agree, and having, I think, measures of what’s happening, that are telling us about … in more detail whether someone is more likely to be, have a cancer that’s in the type that’s likely to develop resistance in six months versus 10 years can be helpful, particularly to the one who’s in the 10 year group, right? And also gives us tools to be able to give us the insight that we might want to do something different for those that are more likely to be six months kind of group. I think understanding better that being able to make it a little more granular, I think is helpful for patients and it’s helpful for obviously physicians as well.

Chris Riback: Now, this I assume is one of the hard parts in the quintessential $64,000 question which is why some tumors would be resistant. Maybe this is obvious but in looking at your research, and looking at the work that you’ve done, so I realize potentially, and maybe this is just simple question and I just wasn’t getting it. But, for example, in the ER-positive patients, if the aromatase inhibitors, or that the inhibitors that prevent the production of estrogen and thereby starve the cancer of the fuel that ER-positive patients, that defines that, how does that cancer metastasize if it doesn’t actually have the fuel that it needs to grow? I mean, I guess, is that the core of the question that you’re trying to discover?

Dr. Sarat Chandarlapaty: Yes, what is it exactly that makes the cancer tick, and what allows it to start ticking again? You know, the two things that I think we’ve elaborated better is, first, that when the cancers for the ER-positive cancers that are treated with hormone therapy, and this is what we’ve worked a lot on, when they become resistant, they don’t suddenly turn into a cancer that resembles a melanoma or a lung cancer, and starts looking for other sorts of fuel if you will. They actually try to reactivate that hormone program and the way they do that is just by developing mutations in the DNA, very specifically for those genes that work on estrogen program. And so they’re addicted, in a way, to this program, and they try to reactivate it, rather than trying to turn themselves into something completely different.

Perhaps that’s surprising but that’s what, by learning that, we’ve then developed new drugs that can target that pathway in different ways. So if one hormone therapy doesn’t work and it’s because of mutation in the hormone pathway, then we can potentially use another drug, specifically in the hormone pathway, and that will work again. So it’s targeting that core addiction of the cancer.

Chris Riback: I’m curious about liquid biopsies and I know many folks are curious about liquid biopsies. What should folks understand about how they work and how they should think about them or potentially could think about them in their own situations?

Dr. Sarat Chandarlapaty: Yes, it’s a great question. This is a new area and didn’t exist really 10 years ago. The idea that tumors secrete stuff into the blood, including their DNA and that can then be detected is really an amazing new technology, and it allows us potentially to understand properties of the cancer and follow them through blood tests rather through removing the tumor or biopsying the tumor. It isn’t yet a complete replacement for tumor biopsies because there are things we can do with the tumor biopsy that we can’t yet do with plasma. But we’re increasingly learning much more of what we can do. It’s an area that technology is developing quickly. I think research is going to enable us to use liquid biopsies to replace a lot of what we do with tumor biopsies in the future.

Dr. Sarat Chandarlapaty: It’s a really important area of research because I think the upside of liquid biopsies is that it’s relatively easy to collect things over time and as I mentioned, cancers evolve, cancers change, and we want to be able to track that. Moreover, the liquid may be sort of collecting from … if let’s say a patient has a liver and a lung metastasis, well, the liquid, the blood is really sampling from both so we may be able to get information that’s more comprehensive. So there are reasons why I think this is a very exciting technology, and I’m thankful that BCRF is helping to support research on it.

Chris Riback: Do you still remember what the reaction was? You presented that in San Antonio. It’s, I think, about four and a half, five years ago, at this point. What was the reaction like for you around that work?

Dr. Sarat Chandarlapaty: Yes, I think people were very excited about the potential for this technology, and we just had another paper come out a month ago on following patients serially over time.

Chris Riback: Yes.

Dr. Sarat Chandarlapaty: On a clinical trial and seeing the evolution of the cancers through these liquid biopsies, through a blood test and just to know that we could use that to follow how the cancer was changing was really very powerful and we couldn’t have done it otherwise.

Chris Riback: Yes, and the result of the most recent study was?

Dr. Sarat Chandarlapaty: That we saw these new mutations arise either in the estrogen receptor or in this other gene called P10. So this was a study where we were combining two drugs, an ER drug, and another drug, again, something called PI 3-kinase so a gene that’s mutated in about 30 percent of breast cancers and this two-drug combination, which has been recently approved, we were finding that mutations were arising within a few months to either ER or PI3K and it told us that the cancer, if it could figure out even one of those two, that that might be sufficient to cause resistance and so we learned a lot about the timing of resistance and about the nature of it, what types of things were causing it.

Chris Riback: Yes.

Dr. Sarat Chandarlapaty: And so that’s really informing us now about how to move ahead with a better sort of combination.

Chris Riback: Yes, I mean the liquid biopsy work can really guide treatment for women with metastatic breast cancer.

Dr. Sarat Chandarlapaty: Yes, I think that’s right. It can enable us to know what mutations are present, which can guide our therapies, and can tell us when, why things aren’t working when they aren’t and perhaps more in the future.

Chris Riback: And where’s the heart of your research right now?

Dr. Sarat Chandarlapaty : Yes, there’s two kinds of I’d say big streams of research that are going on in my lab. First, we are trying to understand: What is the full sort of program? That is, estrogen talks to the estrogen receptor, the estrogen receptor talks the cell cycle, the cell cycle talks to the transcription program. Now I know that’s a lot of terminology but there’s a program, it’s not just one gene. It’s a whole pathway to change a cell from normal to cancer. What are all those steps, and in a resistant cell, wherein those steps did they become resistant? Because that tells you where you can attack with another drug, maybe a second drug.

So we’re trying to understand the program better so that we can deal with resistance because I think if you can give two drugs in the program, it’s very hard for the cancer to outsmart that. If you can give three new drugs in the program, it’s almost impossible for the drug to outsmart that, and we’ve learned that with anti-microbial resistance, anti-bacterial resistance, that if you can really target things in a way that make it harder for the cell to evolve out of, then they don’t come up with the solutions, yes.

The second is what I just said, there’s this evolution that’s happening. The cancers are developing new mutations. They’re changing. There’s this whack-a-mole sort of phenomenon, right? You hit the cancer with one drug, and then another tumor pops up and then you hit that one with another drug, and another pops up. Why? Because the cancer’s evolving. It’s changing and there’s some basis for that. The other cells in our body aren’t evolving, the cancer cells are evolving. How are they evolving, what’s the process that’s allowing them to change and adapt to our therapies? If we can figure that out, if we can develop anti-evolutionary sorts of medicines, then maybe we can just stick with the one drug and then block evolution.

Chris Riback: What’s the hypothesis, what’s the status of the anti-evolutionary drugs?

Dr. Sarat Chandarlapaty: We’ll we’re not at a drug stage yet, but we are increasingly understanding better, what are the sort of trajectories of cancers, how do they evolve. What we’re doing is doing essentially a lot of human genome projects on cancer cells. We’re doing lots and lot of DNA sequencing, not just once, but over time to say how did this cancer evolve, what were the changes? Then if you look back at those changes, you might interpret and understand what processes fueled them. So not in the realm of breast cancer commonly, but if you look at a lung cancer, you’ll often see the imprints of smoking on the DNA. That is the types of mutations that smoking induces, leaves a signature. Similarly, if you look at melanomas, you will see an imprint or signature of UV sunlight damage and so we’re looking for those kinds of imprints to tell us what kinds of things are changing. How is this cancer changing, compared to that one? Ultimately that’s leading us, I would say, to knowing the evolutionary process, and then we can go after it.

Chris Riback: And is the work you’re describing, is this around the FoxA1 gene mutation? Is that the work that you’re talking about right now or is that separate work?

Dr. Sarat Chandarlapaty: I’d say that’s related. More of the work is on, for instance, this ESR1 mutation. Again, that’s something that evolves. That doesn’t happen at the beginning of breast cancer, that happens over time, typically with therapy. And another are these mutations in something like called FAT1, for instance, that’s another one that seems to arise over time and the third one, I would say, is PTEN, that’s another that we recently published on but these are all things that seem to be induced and not present necessarily at the very get-go.

Chris Riback: And is there any guidance or is there any practice, anything that you’ve seen where if the patients can do that can reduce risk of resistance or it’s irrespective, that type of activity is just it’s irrespective, just talk about another thing out of one’s control. This is another that’s out of one’s control.

Dr. Sarat Chandarlapaty: Yes, this is not something that it’s because we ate something or because we exposed ourselves to this that we see these things happen. These are intrinsic to the cancer and unfortunately, no, this is sort of out of control, but also I would say, not something one also should blame themselves for, so to speak and sometimes people do that. They’ll blame themselves, “Oh, I shouldn’t have done this or that,” and that’s not the case. This is unfortunately just the nature of these cancers.

Chris Riback: Yes, I think that’s an important lesson for all folks to keep in mind. About you, how did you get into this and I mean going back, where did you grow up? I saw that you were educated, I think, in North Carolina at Wake Forest and then maybe another school in North Carolina as well, but was it always science for you? Was it always research even going back before university? Was this always where you knew you would end up?

Dr. Sarat Chandarlapaty: Yes, I’d always had interest in science, and my father’s a physician. He did nuclear medicine when I was growing up in Miami, so I was exposed to that from the get-go. Then in college, I was really fascinated by chemistry and biology and so I actually pursued a PhD in biochemistry as my first stop. I didn’t go to medical school. Then while I was in my graduate training, working on yeast cell biology, we were studying this pathway and at the time we were studying this pathway, it was also being found that that same pathway that was controlling yeast mating, was also being mutated in cancers. I was like, “Wow, that’s pretty interesting. The same exact pathway, same set of proteins, and it plays a role in some cancers. I wish our understandings could inform that.” I think that’s when I realized I wanted to have a medical research sort of bent towards what my career end. Then I went to medical school and always with the intent of really doing sort of patient-centered research.

Chris Riback: And you know that insight that you just had that inspired you, the seeing an activity in one area of work and of life and applying it or making it, having it make you wonder about another part. I’ve got to say, one of the most interesting things that I’ve learned in these conversations is how leading researchers like you connect work across cancers and across different types of medicine. Do you find that … I mean, I understand that was at a different stage in your life and you were taking one area of research, it was taking you in one direction, and it opened up a whole other door for you. Part of your work today, requires you to be aware of and interact with different types of cancers. Is it the same thing? Items that you’re learning about one area of cancer is that helping inform your work in breast cancer as well?

Dr. Sarat Chandarlapaty: Yes, absolutely. I mean, I think, we’ve really benefited so much by that sort of multi-disciplinary approach to science, and so there are countless examples. I mean one huge area in cancer has been the sort of understanding of immunology and then the potential for using, understanding immunology toward developing immune based cancer therapeutics. That’s now become its own field. I think a lot of these are sort of these bridge fields that as you study very carefully, one area, cell biology and then you study another area, you realize that some of the findings in one area will inform the other. So it’s what’s exciting, and it truly brings innovation to what we’re doing.

Chris Riback: What role has BCRF played in your research?

Dr. Sarat Chandarlapaty: Yes, so BCRF has been really essential in, I’d say two big ways I think about right now. One is just giving me a platform to explore new and innovative ideas. So if we have an idea and want to try something, BCRF recognizes that the only way we’re going to develop really new technologies, new treatments is the spark of an idea, and so BCRF, by the way, it funds us. Obviously wants us to find really rigorous and good science, but it wants us to do things that are a little outside the box, too.

Dr. Sarat Chandarlapaty: And so as an example developing technologies to study cancer via blood test as opposed to via tumor biopsy, that was something that, you know, I didn’t have a great deal of prior work on but we had an idea, and others had the technology and we worked with them and just having that funding from BCRF, to be able to explore that allowed us to find, for instance, the ESR1 mutation, was something that we widely see in blood tests and now blood tests are being used a lot for following cancers. But early on, many years ago, that was not something that was I could get a lot of funding for, so to speak. So I think innovation is one big area.

Dr. Sarat Chandarlapaty: And the second is just providing a network of investigators who can help each other out. So if I need, I’m studying a type of cancer, well, someone else might be developing models and that’s what they do. They’re developing all sorts of different models, and they’re BCRF investigators, so they’ll give me access to all their models and that’s happened multiple times for me where I didn’t have the specific type of mutation in the cancer models I had, but a BCRF person had and so we’re all on the same team in trying to collaborate. That’s been really a phenomenal resource for my lab and our work.

Chris Riback: Well, thank you, thank you for that collaboration.

Dr. Sarat Chandarlapaty: Yes.

Chris Riback: Thank you for the work that you do in your lab and every day.

Dr. Sarat Chandarlapaty: Thank you. Thanks for the chance to talk about all this.