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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Chris Riback: What is HER2-positive breast cancer?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Chris Riback: Is that AVIATOR?

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

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

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

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

Chris Riback: Wow.

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

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

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

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

Chris Riback: Wow.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Chris Riback: No, for sure.

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

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

Dr. Angela DeMichele: All of them.

Chris Riback: All of them.

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

Chris Riback: Of course.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Chris Riback: I read that.

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

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

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

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

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

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

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

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

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

Chris Riback: Yes.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Read the transcript below: 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Chris Riback: Were these initial results in 2019?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Chris Riback: Probably, yes.

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

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

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

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

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

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

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

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

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

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

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

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

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

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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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.

Can breast cancer be found with a blood test? What role do genes and proteins play in developing cancer? What, exactly, are personalized diagnostics? We spoke with BCRF investigator Dr. Joshua LaBaer to answer these questions and more.

Dr. LaBaer is one of the country’s foremost investigators in personalized medicine. He serves as executive director of the Biodesign Institute, director of the Biodesign Virginia G. Piper Center for Personalized Diagnostics, and the Dalton Endowed Chair of Cancer Research at Arizona State University. Dr. LaBaer’s research involves discovering and validating biomarkers to detect cancer and other diseases early.

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Read the transcript below: 

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

Dr. Joshua LaBaer: It’s a pleasure to be here.

Chris Riback: So, speaking of time, in reading about you, the absolute first question that came to my mind was did you have time to sleep at all in 2020? Were you awake for 366 days straight? I mean, you didn’t have enough diseases, different diseases you were working on, and then COVID came along?

Dr. Joshua LaBaer: 2020 was definitely a pretty busy year for us. Our usual research activities keep us pretty busy, but the advent of COVID-19 hit us here, in Arizona, pretty hard. At a couple points, we were leading the world in new cases. And there was not enough testing. And so, our lab was busy with that.

Chris Riback: Yes. Busy with that is just a slight understatement, of course. You were… preeminent might not be the exact word you might choose, but delivering the saliva-based testing among the many revolutions that many scientists contributed to our society, but that work of you and your team was obviously fundamental for all of us. So, thank you for that.

Dr. Joshua LaBaer: Thanks.

Chris Riback: Aside from that little piece of work, let’s talk about the many other areas. And we’ll have a particular focus on breast cancer. And maybe, before we get into your work specifically. Among other things, you are a scientist and a researcher, in a lot of areas, including breast cancer, but you have also received personally what you called the phone call.

Dr. Joshua LaBaer: Yes.

Chris Riback: And that changed not only your personal life, but I also believe, in some ways, the trajectory of your professional life. Tell me about it.

Dr. Joshua LaBaer: Absolutely. I mean, I’d been a medical oncologist. That was my specialty. And I was a physician at the Dana-Farber Cancer Institute when I got a phone call from my mom that they had found a mass in her breast, and that she was diagnosed with breast cancer. It’s one thing to treat patients. It’s another thing when it’s a family member. It’s a whole different feeling, right. And being a physician is a mixed blessing there. On one side, you know that, because you’re a physician, you can help in ways that maybe people who aren’t couldn’t, and especially because you’re a cancer doctor.

But at the same time, your mind immediately does all the math and you already start thinking worst case scenarios because you’ve seen them all. And so, all of that was kind of going on at the same time. And yes, it was not an easy situation having to sort of think that through and try to offer her help. Of course, she was across the country. I was in Boston at the time and my mother lived in the Bay Area, so you can’t immediately sort of come to her house and help her with all that. But yes, it definitely changed the way I thought about things.

Chris Riback: Yes, I would imagine so. It does for so many people, in so many different ways. The major difference, obviously, for most folks, is what you described. You’re in the business. So, relatedly to that, let me ask you a question that you once posed maybe more than once, but once that I’ve seen, that you posted publicly. Can we find breast cancer with a blood test?

Dr. Joshua LaBaer: That’s a great question, so not yet, but we are making great progress in that direction. So, we do have a screening test for breast cancer and that nominally is mammography.  It’s a special type of x-ray taken of the breast. And there are certain findings that indicate the presence of cancer.

It often can find cancer. It also though has its limitations. It does miss a fraction of real cancers. And a lot of the findings by mammography turn out not to be cancer. In fact, 80 percent of the time, that mark if you identify something, it’s not cancer, so most of the time it’s wrong. So, that puts a limit on it.

Chris Riback: Man, the false positives make for a lot of anxiety and maybe some unnecessary surgical work.

Dr. Joshua LaBaer: Oh yes, plenty of unnecessary surgery. Yes. It’s not just anxiety. It is unnecessary surgeries. Women have to go for biopsies, where they have sleepless nights waiting to get the pathology results back from those studies. So, it absolutely leads to procedures that might not be necessary. And then, there are some women who their breasts, because of density or other issues, are prone to false positive results. And so, they’re frequently going back to the clinic because someone saw something that they’re not happy with and have to get yet another procedure. And so, this is where a blood test could be very helpful. A blood test could help us find those cancers that get missed by mammography. And importantly, those blood tests could help us identify women who may have had a finding, but is unlikely to have cancer.

And so, that was an important direction that our laboratory sort of took off on, was could we help identify what we call biomarkers? These are things that are circulating in the bloodstream that indicate the presence of cancer. And the hope of course is to find those cancers early, because the earlier we find the cancer, the better chance we have of stopping the disease. In my mother’s case, for example, by the time it was positive in the mammogram, it was already pretty advanced. And so, who knows? If there had been a blood test for the earlier mammography, maybe it would’ve tipped people. When we went back and looked at the old mammogram, you could see something that was at the spot. It wasn’t enough to call it, but it was there. Maybe a blood test at that time might’ve helped.

Chris Riback: I saw, at one point, a statistic you’d noted that the blood tests, or at least in a trial, and you’ll correct me if I’m getting this slightly wrong, reduced the biopsy rate by 63 percent, which kind of knocked me off my chair. I mean, that’s a… What a massive percentage. So, where are you on the trials? And what do you see ahead on this part of your work?

Dr. Joshua LaBaer: Right? So, the markers that we identified were licensed out to a company called Provista [Diagnostics]. And they ran a number of prospective clinical trials. What they found in those trials was that the test that included these markers was… had what we in the business call a strong negative, predictive value. That is to say that, in women who don’t have cancer, the test said they didn’t have cancer most of the time, 90-something percent of the time. So, that was looking very positive.

Unfortunately, Provista ran into some business challenges. And so, right now, they don’t exist anymore. And so, the test has now been transferred to a new company. They plan to offer the test at the end of this year. So, the test is right now not on the market, it’s kind of waiting. This is where science meets business.

Chris Riback: I was going to say, I mean, you’re solving all the scientific problems. Perhaps, for your next trick, you can solve all of our business problems as well.

Dr. Joshua LaBaer: Right, right. Diagnostics is always a funny space in medicine because if you offer a drug, people are willing to pay for a course of therapy. But that’s not always the case if you order a diagnostic test. And sometimes the diagnostic tests are critical because they can save you all that therapeutic stuff. And the clinical trials you have to run for diagnostics are not that different from the clinical trials you have to run for a therapeutic.

So, it’s often very expensive to get a diagnostic to market. So, this is a battle that we in the diagnostic space are always fighting. We’re always trying to remind people how important it is to be able to find something, because you can make such a difference if you can find it early.

Chris Riback: Yes. Well, boy, this surely could be a whole separate conversation, but it feels to me like you may have just described a metaphor for the US healthcare system overall, and some of the challenges. This could really change the way we treat cancer in the future, couldn’t it?

Dr. Joshua LaBaer: A lot of us agree that a key element of cancer management in the future is the ability to find it as early as possible. Cancer typically takes many years to develop. Many studies that have been done here suggest that it may take well over a decade for cancers to develop in our bodies. So, the key is, can we find them when they’re still small and before they’ve spread?

Because most of the time is where the damage occurs, is when the cancers breakout and spread around our bodies, something that we call metastasis. And oftentimes, cancers may form initially in the breast, for example, or if it’s a lung cancer in the lung. But where they cause their damage is when they spread to the brain, as it did in my mother’s case, or when it gets to other parts of the body, critical organs, and such.

Chris Riback: Yes. And I’ve had the privilege of having conversations with other researchers like yourself, some of whom are focused really specifically on the metastasis issues, and how to recognize when it’s starting to travel and if it’s arrived someplace else. And yes, particularly with breast cancer, metastasis is just among the massive challenges, which actually may help describe some of what I want to ask you about next, which is, what are personalized diagnostics?

Dr. Joshua LaBaer: Right. So, personalized diagnostics is an interesting term. On one hand, those of us who are physicians always know that, from the day we became doctors, we always personalized our care. In the very early days of medicine, people described symptoms. People would say that the patient has a fever or the patient has diarrhea. And that was the diagnosis at the time. In the 17th and 18th centuries, people recognized that there were different causes of those things, and that, by recognizing the cause, you could be more precise in the treatment of that thing.

And then, I would say, in the 19th and the 20th century, the dominant tool to look at that stuff was the microscope. Doctors would get specimens from patients. They would look under the microscope and they would make a diagnosis. And when I went to medical school, a diagnosis might be something like ductal adenocarcinoma of the breast, and it looked like something under a microscope. And that was the diagnosis. What emerged in the last bit of the 20th century, and it’s certainly dominant in our 21st century, is the addition of molecules to that process. So we now know that ductal carcinoma of the breast can actually take many different molecular forms, something called luminal A, or luminal B, or HER2-dominant, or triple-negative. These are all terms that you’ll hear doctors use now.

And what they’re referring to is molecules that they see in the cancer. And the pattern of molecules in those different cancers tells us that they behave differently, that they respond to different drugs, and that they may have a different prognosis. And so, by recognizing those different molecular forms, we can be more precise in what we know the patient has, and we can be more precise in treating the patient. And so that’s what we’re referring to as personalized. Some people now use the term precision diagnosis to kind of more referred to that molecular form. And the better we get at understanding those molecular forms, the better we can get at treating those patients by knowing how to tailor our therapies to the specific molecular form that that patient has.

Chris Riback: And what is the p53 protein? And why does it demand so much of your attention?

Dr. Joshua LaBaer: Well, p53 is a protein that was identified well back in the 20th century. And it’s the most commonly mutated gene in cancer in human cancer. It is mutated in many, many cancers. It was controversial when it first was identified because initially it was thought to be what we call an oncogene, a gene that drives cancers. And then, later was found to be the opposite. It was a gene that prevents cancer called a tumor suppressor gene. And then now it’s come around full circle. And there are elements of it that act both as a tumor suppressor gene and as an oncogene, which may explain why it’s so commonly mutated in cancer. People have referred to it as the guardian of the genome. It’s a gene that somehow prevents mutation in its activities. But when it gets mutated, it can definitely cause trouble and lead to cancer.

It is commonly found in breast cancer. It’s especially commonly found in a type of breast cancer called triple-negative breast cancer.

Chris Riback: The triple-negative, yes.

Dr. Joshua LaBaer: And triple-negative refers to the lack of the estrogen receptor and the progesterone receptor and the HER2 receptor. And so, women with that type of breast cancer often have mutations in their p53 gene. And we and many, many other scientists are trying to better understand how mutations in that gene lead to cancer, and perhaps a little bit understand this sort of dual role that this protein plays, both as a protector against cancer, but also, when mutated, as something that helps drive cancers.

Chris Riback: And if I’m understanding correctly, some of your work is to try to determine how to reactivate that protector part, how to reactivate the tumor-suppressing powers. And so, where are you on that? Is a challenge how do you activate the good without also stimulating the bad part of that protein?

Dr. Joshua LaBaer: One of the funny elements of p53, and one of the reasons we believe that it has these sort of dual roles, is that, classically, when a gene prevents cancer, then anything that messes it up, any kind of mutation that messes it up like a deletion or a truncation, meaning they cut it out completely or break it into pieces, that’s typically the kind of mutation pattern you see with genes that prevent cancer, but p53 doesn’t follow that pattern. Most of the mutations found in cancer have very specific point mutations. They have very subtle changes in one or two what are called bases, these little letters that are in our DNA alphabet. One has changed, just one subtle change. And that changes everything. It causes the cancer.

And so, that’s the pattern you see in p53, which would be more typical for the genes we call oncogenes, genes that drive cancer. So, what our group has done is we’ve identified the 10 most commonly mutated changes that occur in breast cancer. And we’ve introduced them into a cell line that doesn’t normally have a mutant p53. And we’ve asked, what does it do there? How is it changing the behavior of those cells in a way that leads to cancer? And do the different mutations behave differently? Which they do. And what other genes are they collaborating with to cause the cancer? And that latter question is an important one because it turns out that cancer is not commonly caused by single gene changes. Most cancers arise because multiple genes have changed over time.

Recall that I mentioned earlier that cancer takes well over a decade often to occur. And during that time period, multiple genes are getting altered. And so, what we’re trying to understand is how do we under… What other genes are participating with the cancer? We’re doing that because, as you mentioned, what we really want to do is replace the good function of p53. Well, it’s hard to give back a function. So, what we’re looking at is, well, maybe these collaborator genes, these other genes that are also helping cancer, maybe we can block those.

Maybe, if we identify what those other genes are that are working together with p53 to cause the cancer, that will be a target that we could inhibit, we could block, and at least prevent part of that cancer causing pathway. So, we’ve actually gathered up a huge amount of information, on these different mutant forms of p53. And the goal, of course, is now to get all that information out there so people can use it to help identify where to target those cancers.

Chris Riback: In listening to you right now, also in reading about you, it was evident. You just talked about we. And reading about you, a word that I came across a lot is “team.”

Dr. Joshua LaBaer: Yes.

Chris Riback: Talk to me about that. Because many of us outside of science, we’ve got this image. There’s a crazy mad scientist, maybe someone who looks a little bit like you, in a white lab coat, working all night in bad lighting. How do you describe a team approach to science research? And why does it matter?

Dr. Joshua LaBaer: The team is everything in science. And I think that’s only becoming more and more the case as science advances further and further. Years ago, when I was a graduate student, it was not uncommon to find what I would call boutique scientific labs. They were small labs, five or 10 people working on a very focused question, using a kind of technology that their lab had developed, and using that approach to solve their problems. But as science has advanced more and more, and we’ve gotten much more technological, now, the kind of science that my lab does involves whole teams of individuals, because we’re using very high technology. So, part of what, frankly, BCRF has been critical for, for us, is enabling us to build a library of genes for humans. So, we’ve built the largest collection of full link genes anywhere on earth.

We now have nearly every human gene assembled, because we want to look at how those genes might participate in causing cancer. Well, to do that, you need a team. You need people who are good at computers to identify those genes and gene sequences and assemble them in a format that allows you to produce the clones. You need people who are good at robots to be able to run the actual devices that can actually run thousands of genes at a time. Because doing something five or 10 times, you can do by hand, but doing something a thousand times, you need help with. And then, of course, we need people who are good at chemistry to set up the assays that those robots will activate. So, you need people with lots of different scientific expertise, people from different disciplines, to come together in a group, in a team, to make this sort of thing happen.

That became critical, for example, when we set up our COVID testing as well. We had to have people from eight or 10 different disciplines come together as a team, working in parallel to make big things happen. And so, the modern science, modern biology, really occurs in a coordinated team approach. And part of the fun of it, frankly, is learning how to speak all those different scientific languages, and sitting at the table when all those different people are talking in their different languages, and bringing them all together so they can all understand each other and work as a group. It’s really a lot of fun.

Chris Riback: Yes. It sounds like it. And it sounds like people like you are part scientist, part conductor, part maybe multi-lingual translator. And it’s a wide range of skills. As we close out the conversation, how did you get into this? I mean, was it always science for you? Were you ever thinking you were going to maybe be an orchestra conductor instead, or did you know from the start you were a science guy?

Dr. Joshua LaBaer: So, it’s interesting. When I went to college, I had in those days, the classic middle-class notion that I was either going to be a lawyer or a doctor and very quickly decided that I didn’t want to be a lawyer. So, I knew I wanted to be a doctor. But then, I took this course in organic chemistry from a very famous organic chemist at Berkeley [named] Henry Rapoport. And that organic chemistry course, it was an honors course. The difference between the honors course and the regular course was rather than doing cookbook experiments, where you basically do the experiment because you know it’s going to work, we did a multi-step long-term synthesis of a molecule that we learned early in the course had never been made before.

Chris Riback: Wow.

Dr. Joshua LaBaer: And when I heard that, something tripped in me. I thought, “That’s pretty cool. We’re doing something that no one’s ever done before?” And the more I looked into research, I realized that’s what research is. It’s about doing things that people have never done before. And it’s about standing on the edge of human knowledge, and looking into the dark, and saying, “I’m going to go out there and I’m going to discover something new.” And when that bug bit me, it bit me hard. I thought, “I got to do that. Whatever I do in my future, it has to be about discovering new things.”

And so, then I decided that if I was going to do… I still like medicine, but I had to do the PhD part, I had to do the research part. And since that time, I’ve always been a physician-scientist. I love medicine, and I love caring for patients, but what I love the most is discovering new things. And so, that sort of set me on that road. And then, as I got further and further into science, I think my passion for learning different disciplines of science and learning how to integrate them only grew. And that’s kind of how I ended up in the role I’m in now.

Chris Riback: Well, we are grateful that you’re in the role that you are in now. How would you describe your role at BCRF?

Dr. Joshua LaBaer: It’s hard to overstate the role that BCRF plays. With our role as scientists, we always have to justify what we do by writing what are called research grants and these applications to get funding for what we do. The funding mechanisms in this country are fantastic, but they are complex. And they are often challenging. These days, it’s gotten so competitive to get some of those grants that you have to have already done the work, to get the funding, to do the work that you’re trying to apply for. And sometimes, when you have a creative idea, like the type of protein microwaves that my lab does, or cloning a large library of human genes, it’s just not something that the government is set up for funding. And they’re just not going to even look at it.

And that’s where BCRF comes in, because BCRF helps fund the investigator, and they say, “Look, you’re a creative person. You’ve done very good work on these other things. Let’s give you funds to do something new, to do something creative, to do something that you might not get funded from an NIH grant, or it might take you years to get funded, and we don’t want to wait that long for you to get that funding. We want you doing that right now.”

And so, it has enabled me to do projects that I just could not easily get funding from NIH. And I’ve been pretty successful at getting funding from NIH, but there are some things I just can’t get from them. And BCRF is sort of willing to fund us to do those things just because of what BCRF does. It’s been phenomenal.

Chris Riback: Well, that’s terrific, and glad that it has been, but more importantly, thank you. Thank you for your time. Thank you for the work that you have done and, in your words, kind of standing on the edge and staring into the darkness, trying to find the light for the rest of us.

Dr. Joshua LaBaer: Thanks very much.

Metastasis, the spread of cancer cells from the breast to other sites in the body, is responsible for nearly all breast cancer deaths. Approximately 150,000 men and women are diagnosed with metastatic breast cancer each year. Today, BCRF is the largest private funder of this critical area of research.

Dr. Martine Piccart is passionate about metastasis research and the vital role that international collaboration plays in her work. A BCRF investigator since 2004, Dr. Piccart’s research aims to better understand the origins of metastatic breast cancer and how it evolves. Through the Breast International Group (BIG), she oversees the AURORA EU study, the Belgium-based arm of the Evelyn H. Lauder Founder’s Fund for Metastatic Breast Cancer Research. Named for BCRF’s founder, the Founder’s Fund is a multi-year, international collaboration. In 2019, AURORA EU presented findings on the molecular differences between metastatic cells and other tumor cells, revealing a new avenue of research including the potential for targeted treatments.

Dr. Piccart is Professor of Oncology at the Université Libre de Bruxelles, Belgium, and Director of Medicine at the Institut Jules Bordet. She is also the co-founder and chair of BIG, which unites 55 academic research groups from around the world, running over 30 trials, and developing numerous research programs.

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Read the transcript below:

Intro: I’m Chris Riback. This is Investigating Breast Cancer, the podcast of the Breast Cancer Research Foundation and conversations with the world’s leading scientists studying breast cancer prevention, diagnosis, treatment, survivorship and metastasis.

We frequently discuss metastasis, which, of course and unfortunately, is directly related to the overwhelming and challenging role it plays in cancer broadly and breast cancer specifically.

Which is only part of what makes the goal that today’s guest has set for herself so audacious: To understand the origins of metastatic breast cancer and how it evolves.

Why would someone set such a standard? As Dr. Martine Piccart explained to me: She’s frustrated. She is grateful for the advances that have been made to date, for sure – the trials, drugs, therapies, approaches. She also wants more. Like everyone else, she wants the metastasis to end, and to get there, she wants a molecular understanding of the disease. In this outstanding conversation, she explains her passion and how she plans to get there.

More about Dr. Piccart: She is Professor of Oncology at the Université Libre de Bruxelles, Belgium, and Director of Medicine at the Institut Jules Bordet.

She also is co-founder and chair of the Breast International Group, which unites some 55 academic research groups from around the world, running over 30 trials, and developing numerous research programs. As you’ll hear, AURORA—a study to better understand metastatic breast cancer – is the most ambitious of these.

Dr. Piccart is President of the European Cancer Organisation, past-president of the European Organisation for Research and Treatment of Cancer, immediate past-president of the European Society for Medical Oncology and has served on the ASCO Board. She is author or co-author of more than 470 peer-reviewed publications, and among her awards includes the Jill Rose Award, William L. McGuire Award, Umberto Veronesi Award for the Future Fight against Cancer, the 2013 David A. Karnofsky Memorial Award, among others.

Chris Riback: Dr. Piccart, thanks for joining me.

Dr. Martine Piccart: Thank you for giving me the opportunity.

Chris Riback: Can we start with your career goal? I read that it is to understand the origins of metastatic breast cancer and how it evolves. Now what really interests me about that is for most of us, but perhaps too many of us, our goals usually center on the end of the journey, rather than trying to understand the beginnings. Your mind or at least your approach seems to work differently, why is that?

Dr. Martine Piccart: Okay. Let me try to explain to you what is behind. I have been treating women with breast cancer now for 30 years, and I am still very frustrated that we are unable to offer cure for women whose disease relapses in distant organs. Clearly I’ve seen progress in the disease with the development of some great medications. These drugs help patients to live longer and live better many times with the disease. But at the end of the day, we don’t cure any of these women. My frustration comes from the fact that we basically understand nothing about metastatic breast cancer. We don’t know why the disease in some patients, for example, comes back in bones and stays there for several years and suddenly one day, it will go to the liver, the lungs and obviously become life-threatening. Then in other patients, the disease will immediately attack different organs at the same time.

These patients will present with disease in the liver, in the lungs, sometimes in the brain and in the bones. Our molecular understanding of this disease is minimal and the clinical trials run today, the most efficient ones, are run by pharma. Pharma is of course, taking metastatic breast cancer as a kind of laboratory to test new drugs. This is good, this is essential because this is also why we’ve better drugs certainly today than the ones available when I started my career 30 years ago. But what I think is clearly missing is the molecular understanding of this disease. We do have fantastic technological tools to try to understand what’s going on, but we have never applied them in a consistent fashion and on very large number of patients. Because what complicates the job is that breast cancer is not one disease but several very different diseases.

We need therefore, to do the study on relatively large subgroups of patients. When I had this idea that it was time to do something better for these women, I was extremely lucky that I could very easily convince the Breast Cancer Research Foundation that this was a very worthwhile research project. But you know when you get money to start something, it helps you to convince other organizations to help you.

Chris Riback: Of course.

Dr. Martine Piccart: The project is the following one. We want to study at least 1000 women presenting with metastatic breast cancer. What we are going to do for these women, and by the way, the program has already entered more than 800 women, so it’s moving very nicely forward. We want to go back and recuperate the primary tumor, the original tumor in the breast. Then we want to collect tissue from a metastatic lesion, in the liver or in the lung.

Chris Riback: So the place to where the cancer has traveled?

Dr. Martine Piccart: Exactly. Then there is this other fantastic opportunity which is to just take blood, isolate plasma and there with these new technologies look for genetic material that the cancer cells are releasing in the circulation. Now we can of course detect this genetic material, distinguish the material from the genetic material that normal cells are also spreading in the blood. We can then study this genetic material in-depth so we can find aberrations in the genetic material like mutations. What the program has, which is really unique because there has been several attempts already to confront the analysis of the primary tumor with the analysis of the metastatic lesion using Next Generation Sequencing, that has been done by several teams. But what all BCRF funded program overall does, which is unique, is to follow these women to all their sequential therapies to collect the information on whether or not these therapies have been helping or have not been helping.

Essentially, we followed all these women until the end. At each disease progression, we sample blood once more. We do sequential sampling of plasma to look at the evolution of the genetic material that the cancer cells are spreading. Of course, our hope there is that by studying the longitudinal evolution of the molecular landscape of breast cancer, we might get a better understanding of which changes are driving this metastatic process. Possibly and that’s my dream, we could even design strategies to even prevent the metastatic disease to take place. For sure, we are going to find more intelligent ways to treat women with metastatic breast cancer, I’m confident in this. But we might also go one step further and start thinking about some clever preventive strategies. You know that today to prevent the cancer from coming back, we gave to many women chemotherapy or endocrine treatment, or some targeted treatments.

But here, I’m thinking that we could become even more specific and that’s what is so exciting about this program. I can tell you that when we ask women whether they are willing to participate, they are all enthusiastic. Even though very often they understand that they might not necessarily benefit from the knowledge that you are going to acquire to this program. But they fully understand that it could help possibly their daughters if they get the disease. It’s a very exciting program that was very difficult to initiate because it’s a European-based research program, where we have the analysis centralized and we have currently over 60 hospitals participating across 12 countries. At the beginning of course, it was difficult. The physicians got a little bit discouraged because sometimes when you do a biopsy of a metastatic lesion, well, you don’t do it well and then the tissue you get is not usable.

Dr. Martine Piccart:  Anyway, there were a lot, a lot of barriers. But after two years, finally the program started to run smoothly. Today, we have every month, 20 fully evaluable patients entering the program. We are not even thinking that we might try to go a little bit beyond 1000 women. Again, because breast cancer is complex and is divided in different entities. Of course, we want to get solid knowledge about each of these entities. That’s where we are today. The program is clearly not finished. We have already done an in-depth analysis of the first 381 patients entered in the program, and we are now working on studying the next 300 in-depth because you have to realize that we are not only looking at genetic aberrations. We want to go beyond that, we want to look at the stages of the immune system. So we want to study the microenvironment of the cancer cells in the metastatic lesions. We are also collecting frozen material to do RNA sequencing.

It’s going beyond just DNA and trying to finally, perhaps, I hope understand better what is going on and what we can do these women and to offer them hope. Call the program AURORA, because it refers light in the darkness, a program that will offer hope for the future.

Chris Riback: That is an excellent, excellent overview. I understand why you have the end dream that you have and perhaps you will get there. I understand as well the steps in between that you hope and frankly it sounds like expect to reach. There’s so much that I want to follow up with you on so many of the things that you just discussed. One of them is your use of the word evolution, because that was the image that was coming to my mind as you were discussing the progression and how you are looking at that initial tumor. Then you are looking as well at the lesion, the metastasis that has occurred someplace else in the body. Then you’re continuing to look as the disease progresses hopefully does not progress of course, but as the patient continues to go forward. That sounds like an evolution, and I can imagine that folks may be wondering.

So you can describe in a sense how metastasis works or that it works. You can describe what happens, the cancer travels from one part of the body to another. I think that folks can understand that you don’t have a cure for that yet, obviously, that’s the work that you’re doing. Why is it so challenging scientifically to understand the why? If so many, and you talked about that frustration, if so many people are looking at this and thought about it, and it is such a tremendous challenge, why is the why so hard? Even if we can’t fix the why, scientifically, why is it so hard to get that handle on exactly why the metastasis occurs?

Dr. Martine Piccart: Well, I will give you my personal opinion on this. If you look at the research currently done in metastatic breast cancer at all the hospitals, you will very quickly realize that this research is driven by the pharmaceutical industry. Pharma develop drugs and then they think about what is the clinical situation where my new drug can really show an improvement beyond what is available today. That approach means already in itself that you are not looking at the evolution of the disease from the beginning to the end. You are just studying with your new drug a certain clinical situations. For example, is my drug better than what is available today after patients have failed a first-line treatment for the metastatic disease? All the research is done in this way and it is supported by pharma. So investigators, clinicians of course, are desperate about new drugs. They want to go to participate into these trials and clearly, it’s important, but the result is also that all the other aspects are neglected.

Nobody has been thinking, why are we seeing an evolution that is, at the end, little? Why is this evolution taking two years in some women and 17 years in others? These kind of in-depth thinking has not happened. Then even if it happens, who is going to pay for that? This is exactly the situation where foundations like BCRF, we could simply not do the work even if you are enthusiastic about the work. I think it’s part of what I call academic initiatives without commercial interest, there is no obvious commercial interest, at least in the first place. I imagine that if we find some new things in this program, there could potentially be some commercial exploitation of the findings. But at first glance, this is a very cerebral program and I am not sure that too many commercial enterprises would be interested in supporting it.

I think it’s understandable that we have not seen these kind of effort happening before. I’ve seen that some of my colleagues in the UK are doing a similar program for lung cancer. It’s likely to happen for other cancers, but it just beginning. At least in breast cancer, I have not found a similar program yet in the world

Chris Riback: Well, I’m sure if there were one, you would certainly know about it.  Another area that you discussed that as I have read about you makes total sense that it’s something that you would incorporate into a project such as AURORA. That is the coordination with multiple doctors and hospitals, and countries. Tell me the importance of that. You have a keen interest, it seems to me it’s in fact part of your core philosophy that to make the advances needed in cancer and breast cancer in particular, this is going to be a global… I guess if not global, certainly a Pan-European or a Pan-regional, but it’s going to be a global effort. It’s not going to occur necessarily just with one person. That seems to be core to who you are and how you approach what you do.

Dr. Martine Piccart: Exactly. Well, I have two personal reasons for that. One is that, when I was 27 years old, so I was starting my studies to become an oncologist, my mother got breast cancer and there I suddenly became aware that they were very important questions regarding the optimal treatment of women with breast cancer that had no answers. I became impatient. I thought, “How is it possible that these essential questions have no answers?” Then the second reason is that of course I am based in Brussels, so I’m Belgian and Belgium is a small country. It is a small country, but it’s very open to Europe as you know, because we have the headquarters of the European Union in Brussels. I immediately got interested in international collaboration. I started to work for several years with EORTC, which is a European Organization on the Research and Treatment of Cancer.

I could really feel the power of international collaborations. Of course it’s difficult, you lose time at the beginning because it’s cumbersome, the administration is very heavy to get all the countries aligned. But the time you lose at the beginning, you recover so efficiently after, you can really do things so much faster. I think patients today, they have not a lot of time to wait for us to become efficient in research. I am really enthusiastic about international research and I have indeed been looking for international collaboration during my entire career. You are right.

Chris Riback: Yes. It is evident in your history. I’m curious, when you were 27 and you got the news on your mother, were you already in science, were already a researcher, a scientist, a doctor?

Dr. Martine Piccart: Yes. I was starting, so I was a physician but I was doing my training to become a medical oncologist, and I was working in a lab to do a thesis on resistance to endocrine treatment. Yes, I was already involved. But I can tell you, I got upset because there were very important questions such as; how many cycles of chemotherapy should my mother receive, and this is a very unpleasant and toxic treatment. At that time, it was not known and in fact, my mother got a one-year treatment with chemo, which we never, don’t do anymore today. Because it has been shown in clinical trials that six courses is enough. Then came the question about the duration of endocrine treatment. All these questions that are so important for women because of the burden of the treatment on your daily life, they had no answers. Then I looked and I found clinical trials of a few hundred patients here, a few hundred patients there. All these trials were completely underpowered to answer the question.

Anyway, that gave me the idea that I had to create a very large breast cancer network, which is the Breast International Group.

Chris Riback: Yes. Yeah, it’s an extraordinary network. The last thing that I want to follow up with you on from your opening statement and just terrific description of everything that is happening. You talked about the women’s willingness to participate. I can tell you, I have heard that in so many of these conversations, there’s an all truism almost around the women and the men, the people who participate in these programs, in trials. It is very much a sense, nobody is unaware of the challenges, but it’s very much about doing this for others. What is it about that community, what generates that? Do you believe now that you’ve looked at it for so many years, what generates that sensibility in that sense within that community?

Dr. Martine Piccart: That’s an interesting question. Of course, I am not sure I can give a broad answer because I am only treating women with breast cancer so I don’t know much about other cancers, in particular, cancers happening in men. But for the women, a clear motivation is of course that, if you get breast cancer, well, the risk for your daughter is there. It might not be a huge one if the disease is not genetic, but the risk is there. That to me easily explains that women with this little disease, metastatic breast cancer, have this fairly strong desire to contribute to something that might make things a lot better for their daughters. It’s the explanation that I have out of my experience, let’s say.

Chris Riback: Yeah. Well, I do hear about it quite often. You see it and you see it in the women who participate, and it’s remarkable. Dr. Piccart, to close this conversation, in listening to you, I’m struck by what feels to me to be a paradox within you but maybe there’s a reason or maybe you’ll explain it. On the one hand, you do not seem to be a very patient person. You discussed your frustration, you want action, everyone wants action, you want action and you are frustrated. In fact, I came across, I have to find it here but there was a quote I found of yours from 2015. You said the same thing I heard as a 2015 video of you. Where you said you were disappointed in much of the research output because very few biomarkers have been validated for their predictive value.

It struck me when I heard it there. It’s striking me when I’m hearing it now. At the same time, you are running a project and working on a project, AURORA, that requires incredible patience. You are watching a disease within hundreds, maybe thousands of people over a period of years in order to work your way backwards to the origins of the disease. How do you reconcile those two sides of you that I’m hearing, the frustration? The fact that on some level, you perhaps and we’re all grateful for this, are not very patient. On the other hand, you’re running and working on a project that requires incredible patience.

Dr. Martine Piccart: Ah, that’s another interesting question. Well, what I can tell you about AURORA and what gives me a lot of excitement and probably also helps me to be a little bit more patient is that of course, we are not going to wait until we have accumulated all the data on these 1000+ women. We are analyzing the material and the clinical data in badges. Already with the first analysis we did, I learned things that I didn’t know, and that is what excites me. For example, we found that one in four metastatic breast cancer is displaying alterations in genes that are very important to repair DNA damage. That indicates that probably we are not using, at least for these women; one, four, we are not using the best possible cytotoxic agents that we have to treat them initially. If you look a little bit at guidelines for the treatment of metastatic breast cancer, you will see that the preferred regimen you should start with is a toxin.

Okay, so a general statement, which of course cannot be true because it cannot be the drug that fits the shoes of all the patients, it’s impossible. I’m starting to realize that if we get some better knowledge of what’s really going on in the cancer cells, we might become a lot better at choosing the best drugs. The best drugs if you have alterations in DNA with their genes, could be, for example, all drugs that are not too much excited about anymore, like Cytoxan. Cytoxan is a very good drug if you have these kinds of alteration. Cisplatin is another good drug. Usually, they are no longer part of the first, even not the second line choice of physicians. The way we practice medicine is okay, but I still have the feeling that we could do a lot better. This program will help us become better doctors.

Chris Riback: Well, I’m sure that it will. I’m not sure that … You are a great doctor to begin with and luckily for the rest of us, and impatient one. We appreciate your lack of patience and your drive in your work, thank you. Thank you for the work that you’re doing, thank you for taking the time to talk with me today.

Dr. Martine Piccart: Thank you.

Metastasis, when cancer cells leave the breast and spread to other sites in the body, is the major cause of mortality from breast cancer. The brain is one of the most common organs breast cancer invades, occurring in more than one-third of patients with advanced breast cancer, up to 300,000 patients a year. The prognosis of cancer patients who develop brain metastasis is poor, with only 20 percent of patients surviving at one year.

For Dr. Priscilla Brastianos, a BCRF investigator since 2017, this cause hits close to home. Both her mother and grandmother died of metastatic breast cancer. That’s why she has dedicated her career to better understanding brain metastasis. As the Director of the Central Nervous System Metastasis Program & Assistant Professor of Medicine at Harvard Medical School and Massachusetts General Hospital, her research focuses on understanding the mechanisms driving metastatic disease to the brain. She is currently conducting studies to characterize the genetic and molecular profiles of brain metastasis compared to primary breast cancer with the goal of identifying potential targets for therapy and strategies to improve response to existing therapies.

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Read the transcript below:

Intro: I’m Chris Riback. This is Investigating Breast Cancer, the podcast of the Breast Cancer Research Foundation and conversations with the world’s leading scientists studying breast cancer prevention, diagnosis, treatment, survivorship and metastasis… which just happens to be the topic of today’s conversation.

Metastasis, of course, is the process by which cancer cells move to different parts of the body. In other words, we might beat cancer in one place, only to have it show up – sometimes years later – in another place.

For breast cancer patients, the brain is one of the more common organs it invades. In fact, this occurs in more than a third of patients with advanced breast cancer, up to 300,000 patients year. And the prognosis of cancer patients who develop brain metastasis is poor, with only 20 percent of patients surviving at one year.

Which makes the work that Dr. Priscilla Brastianos leads so significant. Dr. Brastianos is Director of the Central Nervous System Metastasis Program & Assistant Professor of Medicine at Harvard Medical School and Massachusetts General Hospital. Dr. Brasitanos’ research focuses on understanding the mechanisms that drive metastatic disease to the brain, and she is conducting studies to characterize the genetic and molecular profiles of brain metastasis compared to primary breast cancer with the goal of identifying potential targets for therapy and strategies to improve response to existing therapies. She has been a BCRF Investigator since 2017.

But as you’ll hear, Dr. Brastianos’ work is not just urgent, it’s also personal. Her grandmother, as a 23-year-old medical student in Greece, was diagnosed with breast cancer. She passed away six years later from metastatic breast cancer. Then, more recently, Dr. Brastianos’ mother also passed away from metastatic breast cancer. As Dr. Brastianos has said, “We need to find better treatment options for patients with metastatic cancer.”

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

Dr. Priscilla Brastianos: Thank you for the invitation. Delighted to do this.

Chris Riback: So in this podcast, as you would expect, we talk in each episode about breast cancer. We also talk very frequently about metastasis, but people may not realize the brain is one of the more common organs that it invades. In fact, this occurs in more than a third of patients with advanced breast cancer and which I guess calculates to up to 300,000 patients a year. That is such a big number.

Dr. Priscilla Brastianos: Yes, unfortunately, breast cancer that’s spread to the brain as a very common complication of cancer and it does occur, as you mentioned, in about 30 to 40 percent of patients with advanced breast cancer. And unfortunately, while advances in cancer therapies have dramatically improved our ability to control breast cancer outside of the brain, we still have a long way to go to develop better therapies for cancer that has spread to the brain.

Chris Riback: What makes the brain so vulnerable and what makes the brain itself so difficult to address?

Dr. Priscilla Brastianos: That’s a fantastic question. So one reason the brain is so vulnerable is that many drugs that we use to treat breast cancer or other types of cancers don’t get into the brain as well as other parts of the body. And that has to do with what’s called the blood brain barrier, which is actually a protective barrier. It protects the brain from chemicals or other toxins. But that also means that drugs that could work for cancer outside of the brain don’t work as well in the brain. So that’s one reason.

And then the second reason is, and this is, and I’ll touch upon this later in the interview too, the second reason is, and this is a lot of my research that we’re currently doing, is that brain metastases do differ genetically from the primary tumors. So targets that work for the primary tumors may not necessarily work for the brain metastases.

Chris Riback: And that’s-

Dr. Priscilla Brastianos: And I can touch-

Chris Riback: Yes, sorry, I’m sure that you will. No, no, I know you will touch on that because that’s the core of, if not all of your study, a significant area of the study that you’re doing. So, let’s get into that. You’re conducting studies to characterize the genetic and molecular profiles of brain metastasis compared to the primary breast cancer, which you just explained, with the goal of identifying potential targets for therapy and strategies to improve response to existing therapies.

So I take that to mean either to find new therapies, find new strategies and tried to improve the approaches that are currently underway. So, let’s break that down. First, tell me if you would, about the studies themselves, how do they work and how far into them are you?

Dr. Priscilla Brastianos: Yes, so that’s a great question. That’s actually dear to my heart and to what my lab does. So I do want to start by saying that historically a lot of clinical trials have excluded patients with brain metastases. And that has to do with…

Chris Riback: Why?

Dr. Priscilla Brastianos: Yes, it’s a great question. One reason is because patients with brain metastases often do worse than other patients. So unfortunately, drug companies are often hesitant to want to have their drugs investigated in patients with brain metastases, and that is unfortunate and terrible. And so a common exclusion criteria in clinical trials throughout the US has been the presence of brain metastases and us in a number of other investigators are really trying to change that. So we’re really trying to change the attitude that we should be excluding patients, that in fact we should be studying patients with brain metastasis because we need to find better treatment options for patients.

And so that is actually the crux of why we do what we do is we’re trying to find better treatments for patients with brain metastasis. And how we do that is we try to understand the molecular underpinnings of metastatic disease that goes to the brain. So, what does that mean? So, cancer is caused by changes in DNA and often these changes can be targeted. So targeted therapy or personalized medicine has revolutionized how we manage many different types of cancers. Even in breast cancer, for example, overexpression of the marker HER-2 is associated to responses to HER-2 therapy, so anti HER-2 therapy.

So what my lab has focused on in the last few years is trying to understand are the therapeutic targets in the brain the same as the primary tumor? So often what we see, so I’m also a clinician, so I’m a physician scientist. So, I treat patients with brain metastasis, but I also run a lab focusing in this area. And often what we see is that patients with brain metastases will often progress in the brain and not outside of their brain. So that’s not an uncommon clinical scenario.

And so the question is, is it because there’s new genetic changes in the brain that we don’t necessarily see in the primary tumor? And over the last several years, my lab has been focusing on trying to answer that specific question. So we have been collecting and analyzing the genetics of brain metastases and comparing them to the primary tumors and then seeing if these genetic changes are potentially therapeutic targets.

So, in one of our initial studies that we published a few years ago, we had taken patient samples from about a 100 patients and that included not just breast cancer patients but other histologies, meaning other types of cancers such as lung cancer, renal cell cancers, as there are other cancers that go to the brain also. And in that initial study we did find that brain metastases have new genetic changes or new therapeutic targets that are not detected in the original primary sample.

So what does that mean? It means that if we are only targeting what we see in the primary tumor, we might miss potentially clinically significant alterations that are in the brain metastasis.

Chris Riback: In reading about your work and listening to you now, tell me if this is wrong, it’s almost like you’re creating a Google Map of how the cancer moved, of how it metastasized from the initial tumor location to the brain. You’re trying to determine, wait, where did this thing make a wrong turn and not just where did that occur, but what happened to the vehicle to make it make that wrong turn? Is that, obviously hyper basic understanding, but is that something of a description of what you’re after? Are you doing something way beyond Google Maps?

Dr. Priscilla Brastianos: That’s a fantastic description. And in fact, the other way we like to describe it. So are you familiar with the term the Cancer Genome Atlas?

Chris Riback: Yes.

Dr. Priscilla Brastianos: Or TCGA? So TCGA has its genome atlas in all kinds of different cancers, lung cancers, breast cancers, have been studied in TCGA. So it’s an atlas of the genetics of specific tumors. And most of these samples or most of the samples analyzed are primary tumor samples, very few of these are our brain metastatic samples. So essentially we like to say we’re creating an atlas of brain metastases genetics. And I do like the idea of the Google Map, essentially that’s exactly right. We’re trying to pinpoint what are the key alterations that drive metastasis, and can we understand why that cancer metastasized? Why did it go to the brain? And that’s one of the key questions we’re trying to answer.

Chris Riback: And what’s your hypothesis, and I don’t know exactly, you can fill me in, is there initial feedback or insights from which you can extrapolate? What are you learning about the genetic and molecular profiles of brain metastasis compared to the primary breast cancer? Are there connections, and if you’re not fully there yet, the data just aren’t sufficient. What’s your hypothesis?

Dr. Priscilla Brastianos: We’re knee deep in the analysis now. With our initial sequencing data, we are finding that the brain metastases do have new driver mutations that we’re not seeing in the primary tumor. And in fact, we see that there are commonalities across many samples. So there are certain pathways that seemed, or molecular pathways that seem to be common in the brain metastases across many brain metastases.

And there are some pathways that seem to be very common and that’s already led to a clinical trial in patients with brain metastases. So we actually just activated a clinical trial mid-August that is a national clinical trial, where we’re actually going to be treating patients with brain metastases based on the genetic alterations that are found in the brain metastasis. And that’s a different paradigm to how we’ve traditionally been treating patients with brain metastases in the past.

And if I can go a little bit more into how brain metastases patients were commonly treated. In the last several decades, brain metastases patients almost always got whole brain radiation and that was just standard. And now as patients are living longer, we’re seeing that there are a lot of toxicities to whole brain radiation. And there’s still a role to whole brain radiation in a select group of patients.

But we’re trying to now create a more personalized approach to patients with brain metastases, whereby we can try to understand what are the molecular drivers in this particular patient with the brain metastasis and can we target that patient. And that piece is still a work in progress. We’re actively now investigating in this national trial that we’re doing and we’re hoping that this will lead to better clinical outcomes for patients with brain metastases.

Chris Riback: And from my understanding, when you talk about these patients and the folks in the trial for brain metastasis or with brain metastasis, did they all originate from breast cancer or are these, as you mentioned earlier, patients who have gotten cancer and it has metastasized to the brain, but it originated out of multiple forms of cancer?

Dr. Priscilla Brastianos: We’re actually allowing all histologies, so we’re allowing lung cancer patients, renal cell, melanoma to go onto this study because we’re finding some of these same patterns that we’re studying in breast cancer are actually emerging in other cancers also. So we’re hoping that we’ll be able to help not just breast cancer patients, but other cancers also. But we do have breast specific arms of the study, where we’re specifically going to be treating or looking at the breast cancer population, but we are allowing other histology. Then we’ll be analyzing those separately, if that makes sense.

Chris Riback: And it makes total sense and it hits on truly one of the most interesting things that I have learned in these conversations is how leading researchers like you connect work across cancers. I mean, you’re like the ultimate investigators finding clues. Maybe it’s, in some cases, from one part of the body. Certain folks that I’ve talked to or certain types of cancer and then defining how they may or may not be applied to other parts of the body or other types of cancer. I assume that that’s part of your approach as well as trying to understand the similarities, differences across these various types of cancers in terms of how they metastasize to the brain?

Dr. Priscilla Brastianos: That’s exactly right. That’s exactly right. So we’re looking at how breast cancer differs from lung cancer in the brain, but then we’re also looking at the similarities, because one can learn a lot from each of the different cancers.

Chris Riback: Yes, I hear that frequently and it’s a really interesting part of all the study that goes on. Tell me about the brain metastasis tumor bank. I understand that you are in fact working with an international network on this. How do those logistics work?

Dr. Priscilla Brastianos: Yes, so I am so grateful at this group of national international collaborators that we have. So we have established a number of collaborations, both within the US and nationally, and we are receiving samples from, we’ve received samples from Spain, from Poland, from Toronto, from Korea, and then from a number of institutions in the US and a number of others also. And we’re collaborating to try to create the largest resource we can to study brain metastases and one cannot do great science in isolation.

So before, I would say 2010, 2011, the largest study to comprehensively characterize a brain metastasis from breast cancer. And that’s using the genomic tools that we’re using now, had one patient sample. So you can’t do much with one patient sample. So now we have in our bank more than 1500 brain metastases from all histologies. That includes breast cancer, lung cancers, melanoma, renal cell, carcinoma, and we’re now systematically analyzing these samples to try to see, again, what’s unique to each histology and then what’s common across all histologies and how can we take this data to clinical trial. And the beauty of this collaboration is that we share data back to our collaborators and each collaborator can then run with that data and investigate the analysis in their labs too.

Chris Riback: Yes, yes. I don’t know if it’s kind of a combination, it sounds like between democratizing but also exponentially growing the amount of data and the insights that various scientists and researchers can get out of the inputs.

Dr. Priscilla Brastianos: That’s exactly right. And I do have to say that we’ve benefited a lot from philanthropic support, and I am grateful for that. So we’ve received funding from places like Breast Cancer Research Foundation and other foundations to help with a lot of these efforts. And that’s been tremendously rewarding.

Chris Riback: Yes, I am sure. Kind of maybe a final question on this part of what you do, in thinking about the potential outcomes and benefits and therapies and strategy that you hope and others hope might come out. What might an improved strategy to the existing therapies look like? What could that entail?

Dr. Priscilla Brastianos: An improved strategy is personalized medicine for each patient with a brain metastasis. So taking each patient, studying the tumor for each individual patient and finding what the right targets and what the right treatment approach may be. And I’ve talked a lot about precision medicine and targeted therapy. Right now, immunotherapy is also quite hot and is being looked at and has revolutionized many different types of cancers. We’re still trying to figure out what the best roles for it in breast cancer.

However, again, in the future what I hope is that we’ll be able to predict from analyzing a tumor sample what is the best treatment for this patient? Should we give this particular targeted treatment, should we be giving this patient immunotherapy or chemotherapy and individualized treatment will be I think the future for these patients.

Chris Riback: As I am listening to you, I’m also aware of course of all the directions that studying metastasis in the central nervous system can go and you have studied it in a number of areas and of all the connections it might have to other medical conditions. For you personally, it’s not by accident that you’ve been inspired to explore at least in part its connection to breast cancer. Is it?

Dr. Priscilla Brastianos: Yes. I have a very personal connection to breast cancer and yes, my personal story is that my grandmother was diagnosed with breast cancer at the age of 23 and she at that time was one of the only females in her medical school class. And she palpated a breast mass while learning how to perform physical examinations and she diagnosed herself with breast cancer and she went on to graduate from medical school and she unfortunately passed away in her late 20s from metastatic breast cancer. And she left behind my mom who was six at the time.

And I grew up hearing my grandmother’s story and my grandmother for the short life that she had made an impact on her patients even in those few years where she practiced medicine. And I remember hearing her story and knowing I wanted to become a medical doctor like my grandmother, but I knew I wanted to study cancer.

And then unfortunately, 40 years later my mom was diagnosed with breast cancer and at that time I was in medical school and so we started her journey of mastectomy, radiation, chemotherapy. And together we live through the trepidation of awaiting scan results, trips to the ER, side effects of her chemotherapies and it’s these two women and their stories woven into my life that really inspired me to become a medical oncologist and scientist and look for treatments that metastasize.

And unfortunately, my mom passed away just a few years ago from metastatic breast cancer and when she was alive, I felt like I was racing against the clock to try to delve into the research that could potentially help her. I was not able to do so unfortunately. And before she passed away, she made me and my brother promise that we were going to dedicate our lives to this pursuit. And we’re doing that, and I miss my mom every day and that’s what drives me every day. I really want to find better treatments for patients with metastatic cancer. And I made that promise and I hear her every day and I’m determined to do that.

Chris Riback: I’m sure that you are and you are doing it, and obviously, and in learning about your story and thinking about it, there were two aspects of it that really hit me. One is you must connect so directly with what I assume is one of the main concerns of anybody with an illness like that, which is the pressure of time, the stress of time, the limitation of time. How does that affect either your work or maybe your connection to the mentality, mindset, that’s really the word I’m looking for, the mindset of patients. How does the question of time play into what you do?

Dr. Priscilla Brastianos: So my experience with my mom has made me a better doctor. I can understand the patient and family and the anxiety that goes with a diagnosis of metastatic breast cancer because you don’t know how much time you have. And we lived through that. So, and that inspires me in my work because I’m constantly trying to find better treatments so that we can give patients more time. Median survival is still not great for patients that have brain metastases and I want to try to extend that.

Chris Riback: The other part that struck me is your role. I mean, my belief is that you are still on the young side as well. Your grandmother was very young and made incredible impact, it sounds like, and from what I’ve read, I don’t know what your mother did, but obviously in a very young as well, how do you think about that part of your role specifically engaging with or encouraging young women to take on such enormous challenge? I mean, you personally have met great success and maybe more importantly or as importantly, incredible responsibility at a relatively young age. How do you think about this? Do you think about this in terms of engaging with or encouraging young women to take on challenges like you’ve taken on?

Dr. Priscilla Brastianos: What I tell young women is that if they have a passion, they should absolutely pursue it. And in my role as a physician scientist, I take great joy in mentoring young women. So I have young women in my lab and also I work with residents and fellows and I try to guide them, and I try to inspire them in some ways so that they’re not afraid to take on big challenges and ask big questions and then pursue their goals.

Chris Riback: And you indicated earlier that you kind of decided at a very young age that for you it would be science. Was that the case? Was there ever a second option or was it just, it was always science and it was always math and becoming a fiction novelist just was never really going to be in the cards?

Dr. Priscilla Brastianos: Yes. I enjoy writing and I actually write poetry on the side, but I-

Chris Riback: So, maybe that is where this is going to go.

Dr. Priscilla Brastianos: Oh, I enjoy the humanity of medicine too. So there’s an art of medicine too, so I love that, the artistic side of medicine. So, obviously I knew from a young age I wanted to pursue medicine and help people in some way, and I loved science. But I do love writing and I do creative writing on the side.

Chris Riback: Well, excellent. We’ll have to check out the… Find if there’s a website out there, even if you haven’t done it yet, maybe you’ve got a nom de plume that’ll have to be… Anything you want to talk about? Anything you want to reveal right now?

Dr. Priscilla Brastianos: Not yet.

Chris Riback: Okay, well-

Dr. Priscilla Brastianos: Not yet. Maybe if I decide to retire at the age of 80 or 85, I can start publishing poetry.

Chris Riback: Well, the world isn’t going to wait until then for your poetry. So you’re going to have to come up with another plan. Dr. Brastianos, just to close up, two questions. One, you mentioned earlier the incredible role that organizations play in funding work and helping create opportunity, I guess, and there are a number of them, the Breast Cancer Research Foundation, what role have they been able to play in your research?

Dr. Priscilla Brastianos: I am so grateful for the support that Breast Cancer Research Foundation has provided. So they have provided support for us to be able to create this tumor bank of samples and to genomically characterize the breast cancer-brain metastases samples and the work has already leading to clinical trials. So I’m incredibly grateful for their support.

Chris Riback: And of course not to appear ungrateful in any way, but people, of course are going to want to know what’s next? Is it really focusing on finishing these clinical trials and the current study? How do you define what’s next in terms of the science?

Dr. Priscilla Brastianos: Well, we still have a long way to go to understand the genomics of brain metastases. So our goal is to identify the genetic drivers that are specific to the development of brain metastases and we’re still not there yet. And so that’s one goal.

And then the second is to take this work to more clinical trials. So we need to find more effective targeted treatments. Not just target treatments, but treatments for brain metastases patients, and that’s going to be my life goal. We need to find better treatments for patients with brain metastases.

Chris Riback: We certainly do. Dr. Brastianos, thank you. Thank you for your time, and thank you, obviously, for the work that you do.

Dr. Priscilla Brastianos: Thank you very much.

The immune system plays a critical role in tumor growth by attacking cancer cells with white blood cells. Cancer cells that survive this immune attack can become invasive and metastatic (a process called immune escape).

Dr. Kornelia Polyak’s groundbreaking and interdisciplinary breast cancer research has worked to address this. Her work has ranged from studying new prevention techniques to exploring metastasis to better understanding treatment resistance. Her goal is to understand the role the immune system plays in the evolution of breast tumors. And that’s why her lab is dedicated to the molecular analysis of human breast cancer.

Dr. Polyak, a BCRF investigator since 2008, is an internationally recognized leader in the breast cancer research field. She is a professor of medicine at Harvard Medical School, principal faculty at the Harvard Stem Cell Institute, and co-leader of Dana-Farber/Harvard Cancer Center’s Cancer Cell Biology Program.

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Read the transcript below:

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

Dr. Kornelia Polyak: Thanks for having me, and thanks to everyone for joining us today.

Chris Riback: Yes, I’m grateful to the listeners as well. Let’s start at what must be the very basic for somebody who wants to understand you and the work that you do and have done. What does it mean to be dedicated to the molecular analysis of human breast cancer?

Dr. Kornelia Polyak: What it means, very simplistically, we basically want to understand why women get breast cancer, why some progress to advanced and treatment-resistant disease, and what can we do about it. I’ve always been a very rational person, and I want to understand what’s causing the problem, because I feel like that’s the way we can solve it. So, I really want to know the molecular basis. So, how cancer starts, how does it progress? Why are they not responding to treatment, and then how can we prevent the process and also treat patients better?

Chris Riback: And that last part of what you just said is one of the areas that I wanted to ask you about. How do you think about preventing breast cancer as opposed to treating breast cancer?

Dr. Kornelia Polyak: Well, we all know that the biggest impact of any disease to reduce mortality and morbidity would be to prevent the disease. I mean, we’re always advocating that, for if it can become prevented. So, in a way, we all know that it ideally would be best not to have breast cancer, and when people tell me that way, I would not have a job, I tell them I’m very happy to do something else with my life.

Anyway, prevention has the biggest impact because then if we don’t have breast cancer, then we don’t have to worry about progressing and treating, and we would save a lot of people’s lives, and also we would reduce the morbidity associated with it.

That would be the ideal goal with breast cancer. But of course, it’s not so easy to achieve that goal. It’s a very challenging area from the scientific point of view, but also from the medical point of view to try to apply any prevention strategies because it has to be very safe. It has to be applied to the right person at the right time. And we know that for example, breast cancer risk may be determined in your young adulthood, maybe even during puberty. So it’s not easy to decide when would be the best to apply that treatment or prevention strategy and how. And then also how we can identify people who are related to high risk of breast cancer.

The second-best option for having an impact on morbidity and mortality is early detection. Because the earlier we are diagnosed with cancer, the more likely we have it in a stage when it hasn’t spread and more likely to respond, to treatment. So breast cancer, I would say, is actually one of the cancer types where we know, we have examples for prevention. I mean, we know that for example, the high-risk women can have mastectomy, which is not ideal, but at least we know that that can reduce the risk.

And then also we have screening strategies for the mammograms, as much as they are imperfect, but it’s still a screening strategy. And, we diagnose people at early-stage disease and that has the biggest impact on improving mortality. So I think those are the two areas that I’m really passionate about, but it doesn’t mean that we don’t care about people who already have advanced-stage cancer, but ideally we would like to reduce the number of those patients, by having prevention and earlier diagnosis at larger numbers.

Chris Riback: So let’s talk about molecules. What is immune escape?

Dr. Kornelia Polyak: Immune escape basically means that we have our immune system that’s working to protect us from many diseases, a lot of infectious diseases, but at the same time also ensuring that we don’t get cancer. So if you think about it, despite the fact that breast cancer, other cancers are, fairly common, it’s still pretty rare if you think about how many cells in our body we have, and also how long we live.

It’s very rare for somebody to have multiple different cancers in a lifetime. So in our immune system is one of the most effective, defense against infectious diseases, but at the same time also against cancer. And we think that many early cancers that actually, eliminated by the immune system or they don’t become symptomatic.

But then cancers escape from what we call immune surveillance, which is basically like the immune system tries to recognize what doesn’t belong to your body. What is looks abnormal and eliminated, and then cancers as they, grow or progress, they figured out a way how to overcome this immune defense. And that’s what we call immune escape.

So we and others have shown that, as the tumors progress, we see a progressive decline in the active immune cells in the tissue, suggesting that somehow, either the cancer cells kind of not recognized properly, or they figured out a way how to suppress the immune cells in a way that they cannot be attacked and eliminated. So that’s what the immune escape is.

Chris Riback: Am I understanding you to say that, in a sense, are there two questions? One is, is it that the white blood cells, or the immune system, is not able to sufficiently address the underlying cancer or precancerous cells? Or is it that somehow those underlying precancerous cells, and please you’ll correct me that the parts that I’m getting wrong on this.

But that somehow those cells are able to evade or avoid the white blood cells and the immune system. Is that one of the questions that you are seeking to address is which side is the problem on? Is it on the immune system, or is it on the precancerous cells’ system?

Dr. Kornelia Polyak: Yes. So actually, it can, both sides can happen and both sides are happening. Because for example, one way the cancer can avoid the immune cells or a white blood cell swarm eliminating it, is that it grows in a shielded environment. For example, early-stage breast cancer grows within the duct.

For some reason, immune cells cannot enter the ducts. So the question is, it’s kind of almost like a physical barrier that forms around some of the cancers that makes the tissue too stiff and too kind of, dense for the immune cells to infiltrate. So that’s one thing that can be happening and we know it’s happening in some cases.

At the same time, the cancer cells can themselves produce suppressors of immune cells. For example, this immune checkpoint that probably many of you heard PDL-1 is one of those immune checkpoint proteins.

They can be produced by the cancer cells. They can be also produced by some kind of, white blood cells that are actually promoting cancer. So then the cancer cells can do it directly or indirectly by recruiting more suppressive cells. For example, there are, different types of macrophages, which are some of those cells that phagocytes, eat like other tissues. So some of those can produce immune-suppressive, molecules, and also a lot of these traumas, tissues that some cancers recruit again, they can produce a lot of those.

We think both of those can happen. It can even vary in one patient at different stages of progression or treatment, and also could vary depending on the different regions of the same tumor or different lesions in the same patient. So, that’s why it’s kind of so complicated and could be very unique at the particular stage to a particular person.

Chris Riback: How important is it to be able to research the cells? In the area, in the place where they originally are? Which I know is a core part of your research?

Dr. Kornelia Polyak: I think it’s very important, because spatial location, like where are the cells in the tissue. It’s incredible information. So there is a good analogy that I’ve seen somebody present in a talk that I really like, because, if you think about it, like you eat a meal and somebody gives you a shake and, you don’t know what’s in the shake. You try to figure out that you’re like mixed up apples, oranges, and so on. So you can, there are some molecular tests that could tell you that.

Nowadays we have molecular tests that would tell you every single cell in a tissue. What they are. There are the single cells, just profiling of the tissues, but you need to be so shaded for that. And then there are the set of technologies, one that we have been using and really, believe it’s important is that not just the composition of their shake or, like the tissue, but you also know which cell is where.

Where is the cancer cell? Is the cancer cell next to the immune cell or the white blood cells? Or what of cancer cells are next to each other? And what are they doing?

Why do you see a particular pattern? So, this is a very fascinating area because we have an explosion in technologies. Like I’ve been in, breast cancer research for 20 years. And I always feel like every five, 10 years, we have such a technological advance that just makes you like, “Wow, now we can really understand things.” So that’s happening now. We see so many of these very detailed, single-cell methods, including insight to technologies like we can do sections tenets, see every single cell we can get full transcriptome.

Meaning like hundreds of genes expressed in a particular cell. And we know where they are, what is the location? What do they express? And even more, we also, testing technologies that would give you preserved the horse 3D architecture of the tissue. And see you, the cells in a three-dimension that are these technologies now core, the clear sheet microscopy.

So there are advances just at the molecular front and also the imaging front and the competition. Because, we are using machine learning and artificial intelligence to have the computer look at these images, because honestly, even a very experienced pathologist or people in the lab, we can be biased.

We are all human, we can be very well trained humans, but we’re still human. We have a certain error rate. And we also don’t recognize patterns. If you have to think about recognizing a pattern that you have thousands of different variables, we’re not good at that. You know, we can recognize a couple of colors, but not that, but the computer, we can train them and say like, “This pattern comes from a patient that doesn’t respond to treatment. Can you recognize it in another patient? And tell us, is this person likely to respond or not?”

I think the combination of the experimental methods, the computational methods and the microscopy imaging, it’s all coming together to really allow us to dissect tumors and even how CT shoes at the depth that we never been able to do before.

Chris Riback: And tell me what study, what research do you have going on right now that we should know about, around this area or in a new area that you may be, pushing forward on?

Dr. Kornelia Polyak: Our lab studies the progression of breast tumors. Like starting from the very early stages and even some prevention studies. I can just give you a snippet of what we’re doing, but at the same time, we also studying the late metastatic tissues, because I feel like we’re studying the evolution of the tumor with which goes from start to late-stage treatment-resistant cases, because we want to help everybody.

For example, in our prevention study is one thing that we’re very excited about is we able to eliminate, the progenitors, the cells from which cancer would start and eliminate it, and then we can prevent cancer from ever forming. So that’s one of the areas we’re very excited because I feel like if we would do that in woman, then we don’t have to have a mastectomy, because we just eliminating the cells from which the cancer would start out and we have the same effect as having good compete mastectomy.

That’s one of the areas we’re very excited. The other area that we’re very excited about is the role of the immune system and the immune escape and when does it happen? And we think that it really happens at an early stage, what we call this Dr. Carcinoma insight two. For the reasons that I already kind of highlighted that at that stage, the tumor is still within the duct, so it hasn’t started spreading and it. In a way it’s shifted, but once it starts spreading in a body, then if it would not have the immune escape, then it would be likely to be destroyed by the immune cells.

And one thing that we have been, studying that when a tumor starts to develop in the tissue, even when it’s a localized tumor, it can have some systemic effect. For example, you can have a breast tumor growing, but your bone marrow cells, or your lung stromal cells, supportive tissue cells, somehow getting signals from that cancer that makes them behave differently to be more permissive for cancer growth.

So we innovate with saying that metastatic process and metastatic development starts much before we can actually see metastatic lesions. And part of it is these factors that are secreted by the tumor cells, in the tumor. And many of those seems to educate the immune system in a way that don’t recognize the cancer cells or allow them to grow at sites, they would not be growing. So we’re trying to figure out when can be detected. Can we really detect it very early?

And can we recognize these women at early, even before they have metastatic lesions? And somehow interfere with this process in a way that they would never have metastatic lesions that would be clinically symptomatic.

Those are the areas. And then the third one is we are focusing on, treatment-resistant disease. Breast cancer, many women are fortunately responding well to treatment, like particularly, hormone receptor positive and her two positive disease. And even in triple-negative disease, you know?

Chris Riback: Yes.

Dr. Kornelia Polyak: More than half of patients respond well, but then we still have a large number who don’t. And we’re trying to understand why, why are they all resistant? Is it because of the tumor is very diverse, meaning like many different types of cancer cells very early on? Or we studying the tumors as kind of an equal system? Because tumor is not just the cancer cells, it’s a community of cancer cells that form their little environment. And again, I already mentioned that there are these systemic changes occurring in patients, that or seem to be supportive of cancer.

We want to understand that. And of course, we also want to have better therapeutic strategies, and we all know that combination therapy is the best. Because when you have a combination of therapy, then you have the lowest likelihood that you have a subpopulation of cancer cells that resist that therapy. But it’s not easy to develop these combination therapies because of course I could tell you like five, six different drugs that you combine, and then you’re likely to kill all the cancer cells, but unfortunately you likely to harm the patient also.

Because the more drugs we mix, the side effects and the interactions of the drugs can be more serious. So it’s very challenging to develop these combination therapies. So we using the computational and mathematical modeling approaches. And again, studying tumors as an ecosystem to develop these combination therapies and also figure out what time is the best to apply those early on.

Many times, I feel like many of our clinical trials for early agents are done in metastatic disease, which is very late. Many therapies may work better if you’re doing it earlier. And I know that is a push for example, immunotherapy to apply earlier because you know, it may be more effective. So those are the three major areas that we’re focusing on prevention, why do you get cancer? How they progress, how they escape the immune system. And then lastly, the therapies. Like how can we have better, more effective and less toxic therapies.

Chris Riback: You are active and the whole spectrum really from the beginning pre beginning stages, it sounds like, through to the therapies that you just discussed. And as you think about your work in those three stages, what frustrates you? What keeps you hopeful?

Dr. Kornelia Polyak: What frustrates me? Well, one of them now we have a fear about losing the young, talented people. That kind of not just frustrates me, it’s kind of scares me because we need young, talented, smart people in science and medicine to make progress because as much as what we can do, we need the next generation. We need to train them.

Especially now, it’s very challenging, the COVID makes everything is even more challenging. It’s not easy to do academic research. It’s the funding. It’s not easy, it’s many of the studies we do are long term. We’re not talking about a year, but many of our projects that we working on and finally publish a paper, it takes like four or five years.

So training for the people is several years. The number of jobs for academic faculty is right now, very difficult to get. So I’m worried about having the young generation discouraged, from getting into science and, and not to mention that for example, many of our trainees are from other countries. The U.S has been, really taking advantage of providing an outstanding training environment for many students and even postgraduate trainees from different countries, who come here and then many of them go back to their country.

And that seems to be now jeopardized somewhat by the political climate of the U.S and the world also in general. And of course, COVID right now. So that’s one of the challenges, the training and the next year generation. Then COVID now puts a challenge on us, on how do we interact and funding.

I know many, foundations and everybody’s losing money. So that’s going to be the next few years, not going to be easy to continue and support research. Which kind of in a part. Even the NCI director said that, “We just had such a positive impact on cancer. Mortality has been going down and we all fear that this kind of challenging time now because of the COVID situation and the economic turnaround, and then people not going for screening and all that, that will, change that.”

Meaning we may actually see an increase or gain in cancer mortality. So that is the funding and not losing the faith in science. I think we really need to have people realize that science is our future in a way that that’s how we solve problems.

We really need leadership at every level that supports science and research because we know, but we need data. You know, anybody who tells me they have an idea and they make a conclusion without data is not a real scientist. So we have to have people who recognize and support science and know how science works.

We can’t do magic, as much as I wish I could, but that’s not how we do. We need data. We need to, have conclusive data, which means that not everything like anecdotal evidence is not real science. So that’s a big challenge, I think for the whole world, in terms of like, we need to be supporting science at every level and making sure to be making progress. And, I would say that those attitudes are the two biggest challenges to funding, the training and also for the general public to be supportive of science.

Chris Riback: Yes. It certainly is a current topic across a whole number of scientific areas. What about on the hopeful side? What are you seeing from your research that keeps you hopeful?

Dr. Kornelia Polyak: We have such a convergence of technological advances, computational advances. And very enthusiastic committed group of people who working together as teams. We don’t have individuals now, we have teams that includes mathematicians, clinicians, pathologist, research lab-

Chris Riback: Interdisciplinary.

Dr. Kornelia Polyak: Interdisciplinary, I’m just working on one DOD grant. But our whole research, if you look up our papers, we always have been working with, pathologists clinicians, computational biologist and epidemiologist. We really have a teamwork and we are working together with talking to each other.

First of all, nobody can do everything. And second that’s our strengths that we have. People with different expertise that also comes with a different view of, seeing the problem and asking questions. So I think that the technology is the integrated nature of science. Those together, I think gives me hope that we will figure this out.

Chris Riback: And as we close the conversation, you mentioned a moment ago, the allure that the U.S education system has had over the years for students, who have come here internationally. I happen to be talking to one of them. Growing up in Hungary––was it always science for you? Was there a different interest? Did you always know, maybe you didn’t know it was going to be coming to the U.S but did you always know it was going to be science?

Dr. Kornelia Polyak: Yes. I have to say I was an unusual child. I just loved science from very early stage. And my mom could tell you that I just loved like dissecting things. And I always wanted to understand things. And I loved reading books and I love doing, experiments. Some experiments, even at young age. And my family, and also growing up in Hungary, they were very supportive of science and allowing me to do extracurricular activities to, do more than the regular curriculum and, I’d be very thankful for the teachers who always sometimes are frustrating because they said, “Oh, you know, like you don’t deserve an A, because you could have done more.”

Which as a child, you don’t always appreciate, but in reality, you need people who kind of push you and challenge you to see the most, what the most you can get out of yourself. I always kind of, was of course enthusiastic about science and math. I think in high school is when I really knew I want to do molecular cancer research. And this was in the 80s, when I was in high school, and I started reading books about molecular genetics. And, we had a very supportive high school.

It’s somewhat kind of almost like college here. Like I could take major subjects. I finished the biologic curriculum early. My teacher arranged me to go to the clinic, actually the pathology and learn about the tissues and diseases at very early age. And then I kind of felt like this is what I want to do. And then as you know, in European system, we go to medical school straight from high school it’s different way of training.

So when I, when I went to medical school I was 18, but I kind of wanted to do research, and experience what research is like. So as a medical student, I started working in a research lab. And again, this was in the 80s, so it was still molecular biology, which very not that developed in late 80s. But I happened to be lucky to work in a Hungarian National Academy lab. There’s only one. Hungary is a small country. So there’s only one institute and it happened to be right next to my medical school. So they let me work there as a medical student. And that was the time where PCR was discovered, the genes were discovered and all these very basic things in the late 80s. And I just, I was fascinated by that.

And then I knew that I want to pursue cancer research at the level that, very few places could do it in Europe. I’m in Hungary. Again, it’s a very small country. It’s like New York city when you think about it. The whole country is the size of that.

I could not do that kind of cancer research. So I applied for graduate school and I actually, I was at Cornell/Memorial Sloan Kettering, so close to you in New York. And, I happened to have a fascinating and amazing, graduate training that you can only imagine. For a student, because I worked with Joan Massagué at Sloan Kettering and discovered P-27, which is an inhibitor of cell.

It was a major discovery. We were in The New York Times. And also I felt like I can have an impact. I can actually discover things that will have an impact. So that kind of hooked me staying in research because after medical school training, I did do the exams to think about doing residency and fellowship training. And then I just felt like after being in a lab that this is what I want to do.

But in a way that I work with the clinical people and we work together, but the only step I don’t do is I’m not treating the patients. And then the other major impact on my career was training with Bert Vogelstein as a post doc at Hopkins. Who I call the real, the father of cancer genetics. He’s a translational research. So he really kind of taught me that when you start doing cancer research, you’re not … we have a famous quote from him is that, “The ultimate goal of cancer research is figuring out why people get cancer and how we can treat them better,” very loose like that.

That’s what he always made us focus. Yes, you can spend many other things doing things, but cancer research at the end, you have to solve problems and apply them and make a difference in a clinic. So those training, both in, Joan’s lab and Bert Vogelstein was really influential in terms of setting up my career and doing what I’m doing.

I’m incredibly thankful for the opportunity. I just got a distinguished alumni award from Cornell. This May, which unfortunately we could not celebrate, but I’m just incredibly thankful for the opportunity, to allow me to train here and allowed me to pursue a career and do what I always dreamt like doing. And I think what I see that I see many of the young people now, that we don’t want to deprive them of that opportunity.

And I think it’s just such a shortsighted, you that I really feel like the problems that affect mankind need to be solved by mankind, meaning like we need to work together, not just as a team in the science, but also as a team, as an international level, and I think it’s really just gaining a lot more by working together worldwide, than excluding people from pursuing and contributing to society the best way they can.

Chris Riback: No doubt that is true. And what a terrific story and an acknowledgment of some of those, folks earlier in your career that really opened your eyes to what that feels like. And I can only imagine I’m feeling it in listening to you, what that feels like to have that realization, “Wait a minute, I can have an impact here. I can, I can help human life and help individuals lives.”

And it sounds like that was something that, you really came across early through some opportunities in your studies. I just want to make sure to clarify one very important point, which I imagine every listener’s going to want to know which is. To be clear, when your mom said, “Kornelia, would you like to go, play tennis this afternoon? Or should we go, would you like to go ski?”

Your response was, “No, mom I’d really like to go dissect something.” Am I understanding you correctly?

Dr. Kornelia Polyak: Yes. And I went to summer camps in solving math problems. I know my daughter always thinks that I was crazy, but no, I was like that. I was very much into discovering things and just challenging my mind then solving problems. And I feel like I’m still doing it.
 

Chris Riback: I’m sure that you are, and if your child thinks that you’re crazy, then that says to me that only that you’re doing, you’re doing parenting, right. Because if the children don’t think we’re crazy, I think we must be doing something wrong.

Dr. Polyak thank you. Thank you for being just a little bit crazy. Thank you for your dedication to science and, to the molecular level, and for the work that you do.

Dr. Kornelia Polyak: Thank you so much. And thanks for listening.

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It was among the biggest cancer news stories of the year: A new study – the largest breast cancer treatment trial ever conducted – showed no benefit from chemotherapy for 70 percent of women with the most common type of breast cancer. As the Washington Post described, that means: “most patients who have an intermediate risk of a cancer recurrence — a group that numbers 65,000 women a year in the United States — can avoid chemotherapy and its often debilitating side effects.”

The TAILORx trial, as it is known, is helping change everyday procedures in the everyday lives of patients around the world. And the lead author is our guest today.

Dr. Joseph Sparano is Professor at Albert Einstein College of Medicine. He is Vice-Chair, ECOG-ACRIN Cancer Research Group and has been a BCRF Investigator since 2012.

Read the transcript of the conversation below:

Chris Riback: I’m Chris Riback. This is Investigating Breast Cancer, the podcast of the Breast Cancer Research Foundation and conversations with the world’s leading scientists studying breast cancer prevention, diagnosis, treatment, survivorship and metastasis.

It was among the biggest cancer news stories of the year: a new study – the largest breast cancer treatment trial ever conducted – showed no benefit from chemotherapy for 70 percent of women with the most common type of breast cancer. As the Washington Post described, that means: “most patients who have an intermediate risk of a cancer recurrence — a group that numbers 65,000 women a year in the United States — can avoid chemotherapy and its often debilitating side effects.”

The TAILORx trial, as it is known, is helping change everyday procedures in the everyday lives of patients around the world. And the lead author is our guest today.

Dr. Joseph Sparano is Professor at Albert Einstein College of Medicine. He is Vice-Chair, ECOG-ACRIN Cancer Research Group and has been a BCRF Investigator since 2012.

I asked Dr. Sparano about the TAILORx study and how it feels to have been part of such landmark work. But I also asked Dr. Sparano about what’s next – about new work he’s doing around breast cancer recurrence – specifically relapses that occur many years after original diagnosis. 

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

Dr. Joseph Sparano:  My pleasure. Thank you for the invitation.

Chris Riback: So you’ve had quite a last six months, to say the least. Any big news or studies that maybe you’ve been associated with that you’d like to discuss? Anything in the New York Times for example?

Dr. Joseph Sparano: Sure. I guess my mention in the Times has been for good reasons and that surrounded the release of the results of the long awaited TAILORx Trial and this was really the first precision medicine trial and the largest precision medicine trial that’s ever been coordinated and supported by the National Cancer Institute, probably will be the largest one ever conducted. Where we screened about 10,000 women who had estrogen receptor-positive, HER-2 negative lymph node-negative breast cancer which accounts for about half of all breast cancers in the US and about 9% of all cancers in the US.

Dr. Joseph Sparano: A cancer where we typically recommend chemotherapy, adjuvant chemotherapy after potentially curative surgery to help reduce the risk of recurrence. But on average only about 3% to 5% of patients treated actually derived benefit. And our approach for the last probably 20 or so years has been to treat patients as a precaution in order to prevent the possibility of recurrence even though we really couldn’t identify who was more or less likely to have benefit from therapy.

So what we did was we took a new diagnostic test that became available around 2004, 2005 called the Oncotype DX 21-gene recurrent score. It’s a test that could be done on routinely processed and collected tumor tissue that’s typically stored in the pathology lab after it’s removed and where it’s sent to a lab and the RNA is extracted from the tumor in a panel of 21 genes evaluated. It’s computed into what’s called a recurrence score that provides prognostic information, it provides information that identifies who’s at greater or lesser risk of occurrence if treated with endocrine therapy alone.

But also more importantly, it identifies about 15% to 20% of patients who are the ones who are deriving the benefit from chemotherapy and it sort of takes the guesswork out of identifying and selecting the patients who are most likely to benefit. So what we did in TAILORx was we took patients who had, as I said, ER positive, HER-2 negative breast cancer who met standard clinical criteria for recommending or at least considering chemotherapy and then we assigned their chemotherapy treatment based on the score so that the score was low, very low.

Dr. Joseph Sparano: We advised only endocrine therapy alone because we knew those patients had a very good prognosis for the endocrine therapy alone they were unlikely to benefit from chemo. And for the patients who score was very high we recommended chemotherapy and endocrine therapy for those patients because we know those patients had a 3% to 4% benefit, more like a 25% benefit from chemo. And for the remaining two thirds of patients who score was in the mid range, we randomize those patients by chance to receive chemo endocrine therapy which we consider the standard arm versus endocrine therapy alone.

Dr. Joseph Sparano: And what we found is that the two-thirds of patients who fell into this group who had a mid range score, who had a risk of recurrence that was high enough to consider chemotherapy that we found that they actually were not benefiting from chemotherapy and that was a major finding that we reported at the 2018 ESCO meeting and published in the New England Journal of Medicine. So the bottom line is that it’s turned this test which previously provided a clear direction to only about a third of patients who had a very high or very low score into a binary test. The test I can tell you, yes, you benefit from chemotherapy, you’re in the 15%, maybe 20% who benefit from chemotherapy or know you’re in the 80% to 85% of patients who definitely don’t benefit from chemotherapy.

Chris Riback: It’s just remarkable. I mean, it’s difficult to overstate, I would think, how massive of a change that is and kind of more specifically how big of a change that is not just, of course in the approach and the care for patients, of course, we can talk about that, but also the very practical and immediate effect that that has on people’s lives on not other the folks who otherwise would have been undergoing chemotherapy. And now because of this, because I guess previously everyone, as you said, as a preventative measure, everyone was kind of assigned chemotherapy and now that’s no longer the case and just to be part of something that’s just such a massive change in immediate life enjoyment, life style, that’s just got to feel remarkable.

Dr. Joseph Sparano: It does, and it’s a very gratifying experience. I’m particularly thankful to the 10,273 woman who volunteered for the study because none of this would have been possible without them. And I think many of them actually who participated who were in the mid range group, at least half of those women benefited because they would have otherwise received chemotherapy and they didn’t. We found out now that they did just as well. So there are actually a large number of those patients directly benefited from participating the trial number one.

Number two, they move the field forward and of now by virtue of the trial we now have a higher level of evidence to make treatment recommendations with a greater degree of precision than we’ve ever had. And thirdly, they’ve pushed the field even forward beyond the clinical scenario that the trial was designed for that is no negative disease because now people have a much higher comfort level with the using this test and maybe even other tests to spare the use of chemotherapy and women who were at higher risk of recurrence because of positive axillary lymph nodes.

And in fact, at the recent San Antonio breast cancer symposium there was an entire session that was devoted to this, there was a counterpoint type of debate between two prominent breast medical oncologists about what they would do in patients with no positive disease on the basis of information regarding not only the clinical pathologic features but also the information provided by the recurrent score test to 21-gene. So it’s moved the field I think forward and it’s happening at a good time because we actually now have other treatments available that may help prevent recurrence that are not chemotherapy.

Dr. Joseph Sparano: We’ve completed very large trials testing those agents, at least one very large trial called the Palace Trial, which is testing one of those agents called Power The Cycle of an early stage breast cancer and we have other new drugs that we’re now able to move into this space and test determine whether or not they can help reduce the risk of recurrence in a way that chemotherapy has not been able to do.

Chris Riback: Silly question. You said it was common practice commonly understood and I believe, please correct me if I’m wrong, it was around 2000 that the guidance came out for preventative measure to use chemotherapy. Do I have that date right? Around 2000?

Dr. Joseph Sparano: Yes, there was an expert panel convened by the National Institute of Health that recommended that all women, regardless of lymph nodes status, hormonal status or age be considered for adjuvant chemotherapy.

Chris Riback: So you’ve got an NIH sponsored group and that comes out with that type of finding, very very strong finding. What made you or others and the folks that you work with think, wait a second, maybe we ought to do a study and not just to study but you know, the biggest of all time and really look at that and question whether that recommendation is what we actually should be recommending? What was your hypothesis? What kind of drove you towards this?

Dr. Joseph Sparano: Well, first of all, we knew at the time that probably 60% or more of patients who fell into this category were receiving adjuvant chemotherapy. Why wasn’t a larger proportion of patients receiving? Well, probably because women who were older than 70 or who had significant medical problems or patients who just declining therapy because of the uncertainty of its potential benefit. So even with those patients who were not receiving therapy for whatever reason there was still a very large portion of patients who fell in this group of receiving chemotherapy, possibly up to 80,000 women a year.

So that was point number one. Point number two was we never really had the tools to be able to evaluate gene expression profiling or other types of molecular profiling and breast cancer and those tools allowed us to develop assays that could do that. And then thirdly, we actually had the results of studies that showed that this assay, this test was not only prognostic but it was predictive of benefit from chemotherapy if the score was above a certain level. And we haven’t information based not on the results of prospective clinical trials that were designed to test that, because those trials take years to do.

What we had was we had tumor tissue stored from trials that had been completed years ago where we have long term follow up in which patients are randomized to chemotherapy or not and we were able to go back and study those samples and prospectively apply this new test. And when we did that, we were able to determine in a relatively short period of time that the test provided not only prognostic information but also predictive information for chemotherapy benefit. But then we were stuck with the fact that yes, the test provided useful information for maybe up to 30 patients who had a very high or very low score.

But we really weren’t sure about the majority of patients who had a score that was in the mid range. That was a key. And I guess the other important point is, when these tests are developed they’re sort of developed in a way that we study the entire study population, the entire cohort of patients who were on that clinical trial, but that’s not how clinicians use the test in practice. So they will selectively use the test. So for example, for patient who has a larger tumor maybe more than a three centimeter tumor and someone who’s younger maybe under the age of 50 was a high grade despite being estrogen and progesterone receptor positive that clinician may not order that test.

Or if someone is older and has a tumor that’s less than a centimeter low grade, that clinician may not order the test. They make a clinical decision without that. The test is ordered mainly in situations where the clinician is uncertain where they have a woman who is in maybe the early 50s, who has a tumor between one and two centimeters and intermediate grade. And this was the most common scenario, this was the most common clinical scenario in TAILORx and is one of the most common clinical scenarios in clinical practice. And this is the population of patients from whom we have a very clear and convincing answer that the trial addressed.

Chris Riback: Did you work in translational medicine you’re talking about a little bit I guess in terms of the actual tests that are being ordered for patients. But that aspect of connecting research and actual medical practice with patients. First of all, I just want to confirm that I have that right that you do both and then if so what role did that play and if you don’t practice translational medicine, what role did feedback from the field, from patients play in how you approached the research?

Dr. Joseph Sparano: Yes translational medicine is defined as translating information, techniques, technology from the laboratory to the clinic and certainly the development of the 21-gene recurrence score leveraged technological advances that allowed one to extract RNA from routinely processed formal and fixed paraffin embedded tumor tissue. So that was really a huge technological advancement. The other advancement was the discovery based research that identified the genes that were associated with recurrence through what’s called supervised analyses.

Meaning that the researchers tested the association of specific patterns of gene expression with a recurrence versus no recurrence and looked at the differences in gene expression between the two and then developed an algorithm that integrated the information from these multiple genes. So yes, that’s an example of the translational research. In terms of the input of patients and advocates that was very important. In the design of the trial there were patient advocates involved in the ECOG-ACRIN research group and other groups. One in particular Mary Lou Smith lead an effort to solicit feedback from patient advocates regarding the trial, it’s design, the question it was addressing.

The methods by which it was trying to address it. And in addition she organized and solicited feedback from patients, ordinary patients who are not professional advocates. And that feedback was really very important in not only helping to design the trial and affirming what our design was, but it also helps in terms of developing patient education materials that can help explain to patients why we were doing the trial and why it was important to them to volunteer for it.

Chris Riback: Yeah, the feedback and the communication back and forth between research and actual work with actual patients that occurs in a clinic is always interesting to me and I can’t tell you the number of researchers that I’ve spoken with who just highlight that component as important in terms of their understanding what they learn along the way, seeing it and getting that immediate human patient level feedback. It never ceases to amaze are impressed me how important that is. I want to ask you about another objective to the study which was to create a bio repository of tissue and blood, and you’ve mentioned this a bit, so that researchers can learn more about the patients in the low risk groups who had a recurrence and in the high risk groups who recurred despite added chemotherapy. And in fact, you’ve ended up with quite a repository, haven’t you?

Dr. Joseph Sparano: Yes, we have and actually this is where the funding from the BCRF was critical in terms of providing additional resources that needed to establish this bio repository. And it’s been money well spent because of the fact that we have a really long term follow up on a very large number of patients who are uniformly treated and we have plans to do more advanced molecular sequencing on selected tumor specimens from patients, including patients who relapsed and those who didn’t relapse so that we can get to another level of information that may not be provided by the recurrence score that may provide further insights with regard to prognosis, prediction and also identifying potential therapeutic targets. In other words, identifying non chemotherapy approaches that might help reduce the risk of recurrence or even treat patients with more advanced disease. So that that work is currently in process.

Chris Riback: Question about you. How did you kind of get started in all of this in the first place? I mean, going way back and growing up, was it always science and math for you? Did you think about ever becoming a playwright or poet or anything like that, or were you always math and science?

Dr. Joseph Sparano: I was pretty much math and science with sort of a touch of humanity and in terms of the fact that I was influenced very early on by a family member, my maternal grandmother who lived with us in a typical first second generation Italian-American home who developed breast cancer when I was very young and died of the disease. My recollection of the events although I was very young is that she had neglected breast cancer and presented with a very locally advanced stage of disease. And I do have the vivid memories of the priests coming into our home and giving last rites in a couple of occasions and her dealing with her illness.

So that sort of sparked my interest in medicine and in general and in breast cancer in particular. And what also interested me in oncology was a second aspect of it was kind of the mystery behind it. That at the time that I got into the field or certainly when I was growing up and learning about science and medicine, a lot of it was very very mysterious. We had very little insight into what caused cancer, what drove cancer or even how to treat cancer. So that was the second critical point that that drew me to this field. And the third critical point was that for many types of human illnesses you can treat it, you can manage it, but you can’t necessarily cure it, such as hypertension or diabetes or heart disease.

But cancer is actually a disease that in many forms of cancer you can cure with either a combination of local therapy like surgery, radiation, and sometimes with systemic therapies added or entirely with systemic therapy with certain blood disorders, blood cancers, for example. So those are the three things that kind of drew me to it. The stakes associated with a diagnosis and the human toll it can take the mystery that surrounded a lot of it and the challenge in sort of uncovering those mysteries and deciphering how to better treat cancer and then the opportunity to actually cure people of an illness that’s potentially life threatening.

Chris Riback: How old were you when you were experiencing that with your grandmother?

Dr. Joseph Sparano: I was about the age of five but it left a very big impression on me, let’s say. But I also was sort of gravitated and inclined and interested in science. Again, what intrigued me about science was the mystery of a lot of science back then, especially the life sciences.

Chris Riback: That’s a remarkable mix of the personal but also I guess it just sounds like part of your DNA where you were just talking about the curiosity, about the life sciences and the mystery, very interesting and always interesting how different aspects of one’s own personality and external events frequently can come together to set a live course. So the last item that I kind of have for you and what I think most of us, many of us, maybe all of us could really learn from you is time management. So I did a quick review of your work and you’re involved and have been involved in so many different types of major research and major efforts.

I mean biomarkers of recurrence in early stage breast cancer, improving treatment outcomes in breast cancer, developing invalidating gene expression signatures in breast cancer, evaluating interaction between breast cancer and the micro environment. There are others including developing more effective therapies for HIV associated cancers. So first, how do you find all the time, and secondly, do these all connect in some way that is easily understood by the rest of us?

Dr. Joseph Sparano: Well, I guess the point of connection is the fact that at the end of the day or the beginning of the day, or between the beginning of the end of the day, for the most part I’m a clinician who tweets patients and most of the work that I do or really all of the work that I do I’m motivated and become interested involved with because it directly impacts the care of the patients that I care for. And so that really sort of guides me or directs me to become interested in certain areas. The second important point is that I certainly don’t do this work alone, I surround myself with and interact with many, many, many talented people and I try and learn as much as I can from them and also look for opportunities to apply what I think is the best work to the care of my patients.

And then thirdly, some of the eclectic nature of the work that I’m involved with such as the HIV associated cancers dates back to things that I was interested in because I commonly saw them in practice in the 1990s in the institution that I practice in and in the area of New York City that I practice in, HIV associated cancers were very common and rapidly lethal. And the prognosis associated with them has improved very much in part because of improved therapies directed against HIV but also improved anti cancer therapies. So that’s sort of I think may explain some of the eclectic nature of some of the stuff that I’ve been involved with.

Chris Riback: And Dr. Sparano there’s work that you are currently doing funded by BCRF, tell me about that.

Dr. Joseph Sparano: Yeah this is really important work that I’m really excited about. It actually started about five years ago when it became more and more recognized that half of all recurrences have estrogen receptor positive HER-2 negative breast cancer, the most common breast cancer subtype occurs not within the first five years of diagnosis but after five years. And this is a major problem and I became more aware of it as I became a more experienced clinician and had patients in my practice for long periods of time. And seeing women have a recurrence of their disease, 5, 10, 15, 20 and even 30 years after their diagnosis.

And we really had no clue as to why these women were relapsing this late and what we can do to prevent these relapses. So I saw an opportunity to study this by evaluating women and offering women the opportunity to donate blood specimens who a woman who had already participated in other clinical trials were different treatments were tested and asked them would they participate another clinical trial because we were following them anyway, we knew what treatment they had, we already had their tumor specimens and their blood specimens at the time of their diagnosis and we asked them to provide additional blood specimens.

And we created what we call the lake relapse bio specimen bank. So right now we have over, it may be close to 20,000 blood specimens in that bank so that we can study and apply some of the newest technologies like the ability to detect to our DNA in the blood. The ability to detect circulating tumor cells in the blood so we can evaluate tumor associated factors associated with recurrence and also host associated factors because we do know that there are factors in the patient that may be assisting and driving the risk of recurrence.

So one of the first results that we had from that effort was a study where we looked for the presence of circulating tumor cells in women who were between four and a half and seven and a half years after diagnosis, clinically cancer free no evidence of recurrence by history and physical. And we found that about 5% of those women who had estrogen receptor positive, HER-2 negative disease actually had tumor cells circulating in their blood and we found that those women who had detectable, what we call seats and fees had about a 13 fold higher risk of occurrence.

And that for the 5% of those who are CTC positive they had about a 30% risk of having a recurrence by two years whereas they were CTC negative they had a 97% chance of being cancer free at two years. So what we’re doing now is we’re in the process of designing a very large trial, a TAILORx like trial really where we will evaluate women who are five or more years after diagnosis, perform a CTC type test on them and then to select those women and then test a newer treatment like a CDK 4/6 inhibitor to see if we can prevent a recurrence from ever happening. The timing is actually right for this because the FDA has recently now recognized what’s called metastasis free survival as an end point that can support the approval of drugs for the syndication.

And the FDA just approved two drugs in men with prostate cancer in a very similar situation. Men who had local treatment for prostate cancer, local treatment meaning either surgery and or radiation who have a rising PSA but who have no evidence of cancer recurrence by standard imaging, CAT scans or bone scans. There have been two randomized trial showing that men who were treated with anti angiogenic therapy that can prevent the development of recurrence. So we think we can apply the same model in breast cancer and the NCI will be hosting a meeting in the Spring of 2019 to discuss and plan a trial that will have this as the foundation, that will have this as a framework for trying to prevent late recurrence.

So I think this is the next frontier of trying to prevent recurrence of breast cancer. And the future that I see is that we’ll be able to use these more sophisticated markers to detect what’s called minimal residual disease, MRD, and identify who’s really at risk of recurrence and then tailor treatments to prevent that risk. Because right now there’s really no surveillance that’s recommended in this setting. Conventional blood tests or tumor markers are not recommended scans, they’re not recommended and we need better ways to monitor people who are at the highest risk of recurrence and intervene before that recurrence actually occurs.

Chris Riback: And I assume this will help identify which patients are most likely to benefit then from specific therapies, is that right?

Dr. Joseph Sparano: That’s the hope. For example, there are tests for circulating tumor DNA that can detect mutations and what’s called the ESR-1 or the estrogen receptor gene and those mutations identify tumors that are more sensitive to specific drugs. So yes, some of the technology that’s evolving will allow us to identify not only who’s at high risk but what drugs they may be more or less likely to respond to.

Chris Riback: Dr. Sparano, thank you. Thank you for the conversation and thank you for work that you do.

Dr. Joseph Sparano: Thank you. It’s been my pleasure speaking with you.

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

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As you’ll hear, Dr. Merajver – who has been a BCRF Investigator since 2004 – discusses her unique, collaborative and extraordinarily human approach to one of the most significant science questions of our time: How to find new strategies for the prevention and treatment of metastatic breast cancer.

Why “unique approach?” Well, it’s not just her science and the way she connects seemingly disparate disciplines to all focus on a single goal. It’s also about the way she views her life’s calling – and applies that view to medicine. As she says in the conversation: “A tumor doesn’t walk into my office; a whole person walks into my office.”

Read the transcript below:

Chris Riback:  I’m Chris Riback. This is Investigating Breast Cancer, the podcast of the Breast Cancer Research Foundation and conversations with the world’s leading scientists studying breast cancer prevention, diagnosis, treatment, survivorship and metastasis.

And that’s what we’re discussing today – in a way and tone that, frankly, I didn’t fully see coming.

Dr. Sofia Merajver is a professor of Internal Medicine and Epidemiology at the University of Michigan, where she is also Scientific Director of the Merajver Breast Cancer Research Program and Director of the Breast and Ovarian Cancer Risk Evaluation Program.

As you’ll hear, Dr. Merajver – who has been a BCRF Investigator since 2004 – discusses her unique, collaborative and extraordinarily human approach to one of the most significant science questions of our time: How to find new strategies for the prevention and treatment of metastatic breast cancer.

Why “unique approach?” Well, it’s not just her science and the way she connects seemingly disparate disciplines to all focus on a single goal. It’s also about the way she views her life’s calling – and applies that view to medicine. As she says in the conversation: “A tumor doesn’t walk into my office; a whole person walks into my office.”

This is a view Dr. Merajver clearly held even before going through breast cancer treatment and care herself, an experience, she explains, helped change the vocabulary she uses – the way she talks – with her own patients.

And a heads up: You’ll want to hear the very, very end of this podcast and the inspirational way Dr. Merajver ends every conversation with her patients. It’s exactly what breast cancer research – and medical care generally – is about.

Dr. Merajver, thank you for your time.

Dr. Merajver:  You’re welcome. It’s a pleasure to be here.

Chris Riback:  I didn’t have to spend very much time researching about you to get what I think must be a clear sense about the type of scientist and physician you are. In fact, there’s one line on your research program webpage that I believe, gives it away, where you write and I’m quoting “We do not turn anyone away, nor do we think any case is hopeless before we start.” Does that sum up your core philosophy?

Dr. Merajver:  Yes, this is definitely operationally how we run it … how I run it and that is I like to think of a patient as a whole person. A tumor doesn’t walk into my office, a whole person walks into my office with everything she or he has experienced in his or her whole life.

And they have specific concerns. They have specific goals. They have dreams and aspirations. They’ve had tragedies. Everything bears into what’s going to happen, and we know very little about how to tailor therapies from a biological perspective, to how stressed or how happy or how relaxed somebody is.

We don’t know how to do that, but we can understand a person. And discuss things with that person about what is likely to happen with different therapies. And how they are likely to cope with it, and who is home with them and bring them to the treatments. And, what are their goals?

Is there a special trip they want to take for six months or is there a wedding coming up. These little things are very important to us in our lives and I think to be a good doctor, or at least to try to be as good a doctor as one can be. You need to really give everyone a chance.

First of all you can’t give up on anybody without knowing about their tumor more or about their biology and also about what’s happened to them before. Yes, it has served me well for quite a few years, so I continue to do that.

Chris Riback:  It certainly has for a number of years and the impact that you’ve been making. How do patients react to that approach and your level of humanity? Does it surprise them? I’m sure they appreciate it but from what we all have positively and negatively experienced in life. That might not be what they expect immediately from somebody who specializes in internal medicine and epidemiology.

Dr. Merajver:  Well, I think I try to give the care that I would like for my family members, for myself. When you do it that way, it becomes … When your job is so close to life or death, then you have a responsibility to give it everything you’ve got.

And not just that part of your brain that remembers facts and figures and names of drugs, and lists of side effects and the shape of cancer cells. But the other part of the brain that puts it all together and tries to predict what’s likely to happen to this person, given his or her circumstances today.

And that requires knowing the person. Practicing medicine has been nothing but an incredible privilege and pleasure for me and I’m very lucky to have been able to have a career I have and combining a passion for science and to bring it to the patients.

It’s just an unbelievable privilege and sure, it took some sacrifices, but I don’t see them as sacrifices. I see them as just basically what it takes.

Chris Riback:  That’s a wonderful characterization, and I’m sure that your patients feel like … people who benefit from your research, feel like they are the ones who have gotten the benefit and for whom the privilege is.

Let me ask you, if I could about the science because that’s the areas in where you are clearly just, and listening to you where you are putting both your heart and your mind … the science is … those are the discoveries that you’re making. And to understand your work, it’s first imperative I believe, to understand metastasis.

Before we get into a little bit of the nitty gritty around your studies and the research. How do you explain to people, not only what metastasis is, but why it happens? And why that, in some cases, cancer cells in one part of the body travel to other parts, yet in many other cases this never happens at all?

Dr. Merajver: Indeed. Cancer, basically all cancers have with possibly just one exception, a savvy capability of eventually going to distant organs. Some cancers do that more easily than others, and some cancers prefer distant organs over others.

The science of metastasis has exploded over the last 40 – 50 years. And we know an awful lot about the individual steps that a cancer cell has to cope with. And it isn’t an easy trip. Let me assure you.

The amazing thing about cancer is how hard it is for the cell to really make it. And how powerful the adaptions … how the cancer cell has to constantly change or recruit other cells to help it, cope with a different parts of the body, has to travel through.

A tiny cell that is lodged in the breast tissue and it wakes up, saying it was left behind, or it evolved in the breast tissue, because we focus a lot on breast cancer. Not exclusively, but certainly most of our work is on breast cancer, a huge public health problem around the world. We figure we want to tackle, and we want to tackle the most aggressive cancers.

The ones that kill proportionately the most women. And a tiny cell is in the breast minding its own business and then there is a constellation of things that need to happen, for it to even begin to move in that little place that it is logged. And then to find the blood vessel … to get inside the blood vessel.

The blood is not good for cancer cells unless this is a leukemia that is a blood cancer. Cancer that arise in organs like prostate and breast and pancreas … Once they’re in the blood, it’s a very hostile environment. It’s not easy for them to survive.

Most of them die there. Lucky for all of us and then our immune system also is able to recognize them more easily once they’re in the blood, because a lot of immune cells also circulates through the blood. There is a real war that is being waged every single day in everyone of us.

Most of us feel that we have the potential to be developing little tiny cancers throughout our lives pretty much. Most of which don’t seem to come and cause us any trouble. Now once the cancer is diagnosed in some organ … even if it removed and then sometimes chemotherapy or hormonal therapies are given, there may be, even from the beginning, just a small … we call them clones because they are all very similar to each other.

Clone of cells, group of cells that already have the potential to spread. And why do they in some cases and why don’t they in some other cases? That is the really holy grail of oncology, in a sense that we all have theories, and we all have very detailed experimental models like I have in my lab and many other scientists … the BCRF scientists have in their labs.

But we don’t what I would call from the physics world a unified theory of a cancer cell. We don’t have that. We are working towards that to really understand at a very broad … what we call systemic level. If you take everything into account.

The cancer cell then the normal tissue where the cancer cell is right now, and then what else is happening in the body. Is this a patient who also has diabetes? Is this a patient who is also obese? Is this a patient who is eating vegetables? Is this a patient who is smoking?

Is he or she drinking too much? Are they seventy? Are they exercising? Are they stressed? Are they poor? Are they constantly concerned about where the next meal comes from? I think if the government shut down goes on for any longer, I think we should take … we should do. We are missing on opportunity to do a research study on government workers because they are under tremendous stress right now.

The prediction would be that they would be some consequences. They may be related to cancer or to other diseases. People under stress don’t do well in multiple chronic diseases and cancer is a chronic disease.

Chris Riback:  It’s so interesting to hear you talk about this holistic approach and all the different angles and aspects in which you need to look at it. First of all, it for me, goes back to the beginning of this conversation and how you even just described in your role … you need to think about all aspects of what’s going on with a patient. It also, from what I’ve read, seems to be how you run your research lab. When your process … One of the things that you’re doing is, you’re using devices to study which breast cancer cells can migrate to different tissues.

Dr. Merajver:  Yes indeed.

Chris Riback:  Your process … you combine this theoretical view what do the models predict will happen with the actual experiments themselves. And to do this, you bring together Physicists, Electrical Engineers, Biological Chemists, Cell Biologists, Oncologists, more. How do you conduct that kind of orchestra?

Dr. Merajver:  That’s what I love the most. I just have to tell you one minute why, and that is, I decided to be a scientist when I was five years old. This is what I announced to my parents. That’s what I was going to be.

And, when you’re five, what do you know what science is and what do you know about this specialty or that specialty? But I understood that what I was happiest at, is and asking questions and find answers. And if I didn’t know the answers to … research the answers.

And that time, of course, you couldn’t Google everything. You actually had to go to the library and read something and think about that and then go again the next day, and so on. Anyway-

Chris Riback:  … I remember reading-

Dr. Merajver:  … Exactly. Holding something in your hand [inaudible 00:15:20]. It is through that process of wanting to be a scientist from such an early age, where the disciplines mattered very little to me.

I was just as interested as knowing what happened to Neanderthals, as I was interested in how to cure cancer. Although I had a very significance with cancer when I was 15 and my father came down with just about the worst kind of lung cancer a person can have.

I felt obliged to study a lot about that to see how I could contribute to his treatment. It’s crazy for a 15 year old to have those aspirations. But I had already been thinking about science for 10 years by then, so was considering myself as semi expert, which of course pretty ridiculous.

But non the less, that is something that has carried me and even though I’m no longer 15, fortunately, I am able to talk to a large number of types of scientists. And just respecting their skills and getting them excited about cancer. Cancer needs all these scientists.

And BCRF is basically the only research organization that respects that importance of bringing engineers and quantitative scientists in really multi-disciplinary, constantly experiencing the cancer phenomenon. Take example artificial intelligence. For example, we are using artificial intelligence in our lab and to figure out which cancer cells are going to go into the brain.

That’s a question that’s never been tackled. If you had a small tumor. Nobody thinks of brain metastasis, but I do because I know a certain number of those little tumors will show up in the brain and they will carry the day for that patient.

The brain metastasis is a very serious metastatic event and people can survive it. A certain number of weeks to months, even sometimes years. But it is rare. The years is very rare, whereas metastasis is other sites, people can survive many years, especially from breast or prostate cancer and so on. But brain metastasis have a certain way of attacking who we are because obviously our personality and our feelings and our identity resides in our brain.

Brain metastasis are especially something I really have a specific penchant for trying to beat and this is something that worried me before I was a hysician. And once I was able to invent a way to take a small tumor and then see if there is some physical phenomenon about the cells because the blood brain barrier is a true barrier.

The whole country now is involved in a barrier question, right? And we have barrier. Until I started studying biology, we know a lot about barriers. And there are leaky barriers, there are semi leaky barriers and there are real impossible barriers.

The blood brain barrier can become a leaky barrier especially for certain cancer cells. But the question was never asked. And I just can’t stand questions that are never asked, and I built this whole system, funded by VCRF to try to see how the cells go through, but then once I had the system going, which of course the Engineers building it with me … They will realize that “Hey, in order to understand this, the cells are so different one from the other, even though they come from the same person … we need artificial intelligence to try to figure out that they are too big.”

If we look at 200,000 cells and each one is a separate experiment, then you need different methodologies in mathematics to really try to predict how do you really separate the ones that will go through from the ones that won’t.

We had to use machine learning like the same thing that’s used to predict the weather and so on, which are incredibly large data set and the motion of stars and planets in the distant galaxies. That’s the kind of mathematics we’re using to predict what’s going to go in the brain.

But I’m not scared by any of this. I know math is good, and I have a PHD in Physics, but I am not the one doing all the machine learning. I couldn’t do it either … I’m not trained in that, but I can talk to other scientists and so we do have now, the capability for the first time in being able to predict by the shape and the behaviors of certain cells, whether they are likely to go into the brain.

And that’s … starting with a paper that’s being reviewed right now, and it took about four years. You have to be willing to have a bit of a dry spell for that question so other things in your laboratory have to be producing papers and results because in most scientific laboratories you can’t four years without a publication, or they’ll think you are a complete failure.

Of course in the olden days, very famous scientists sometimes did go several years but that’s not the pace of biology research today. When you talk about managing the orchestra, a lot of what I do is to steer the projects and manage the funding so that we don’t run out of money for any of the projects, and that they are all producing results are a fast clip to keep up with the pace of science today.

Chris Riback:  That makes a ton of sense, and it also makes me think “Well in the old days we all used to read documents longer than a 140 characters in length.” Whatever you can bring back from the past would be terrific.

I keep listening to you and the journey and the difficulty, and to use your word, the barriers around the movement of cancer cells from one location to another. You talked about the trouble of traveling through the blood except leukemia, cancer, and the challenges of metastasis in a cancer cell moving into the brain and yet we know it happens.

The predictive nature and that’s at the heart of so much of what you do. Where would you say you are … where would you say we are … what do you day to patients around “Here is what I’m looking at as I think about predicting.” I’m not in the predicting business.” You might also say, but when I think about what might happen around metastasis. What do you know about predicting when and how metastasis can occur?

Dr. Merajver:  For an individual patient who doesn’t have metastasis yet, the tools we use in the clinic are not quite obviously as complete and extensive as the tools we use in the laboratory. That’s going to take a while to have a trajectory from the lab to the clinic, in a formal way.

We have a trajectory from the clinic to the lab in that we collect tissues from patients, and we do all this research, and then we refine these predictors and then we test them in the real world.

We’re in the process of doing that next step, which is to test them in the real world in terms of over a broad range of patients, can we predict what their likely metastatic trajectory is going to be.

But I tell you something … we are really exciting, which is really getting very close to the clinic. A few years ago I decided that I was very satisfied with the idea, that when we take a biopsy from a patient … if the biopsy is sequenced that means the DNA is studied, and we find out the gene changes that that tumor has undergone. A large number of labs including a very well known lab here at the University of Michigan has been doing that, and they recommend then drugs for patients.

That was very unsatisfying to me in the sense that I thought this is a great first step, but in my mind I predicted that there would often be lists of drugs and how would the patient underactive, would choose what drug to actually give the patient.

We set out, also with help from BCRF … we set out to build a whole platform, where we can take biopsies from the patients and test them for drugs in the laboratory in a manner that is consistent, rigorous reproducible.

All these important things that need to happen in a scientifically rigorous laboratory because this hasn’t been attempted before, and the oncology has a very bad taste about drug testing of tumors because there were many companies that were reporting to be doing that.

They were not doing it correctly partly because they didn’t know but then they shouldn’t have been going commercial with that, but non the less that happened and some of my teachers in oncology would tell me it would never be possible.

But I never believed that because we are very advanced ways to culture cells directly from the patient. We are very excited that now we can actually test 20, 30, 40 drugs in a matter of days after a patient has a biopsy.

Then in addition to the drugs suggested by those studies that sequenced the DNA, which are incredibly useful, we are then able to perhaps in the near future be able to produce priorities. Patient is now going to take 20 drugs in succession and the question is “What about combining two drugs?” Which two should you combine and why?

We have the capability of testing combinations, testing single drugs and I believe that what I’m going to put the most effort in my lab in the next five years, to get to the point that we can work alongside those tests that are called genomic tests and be able to really help Doctors and patients.

Say “OK, your tumor can be killed by these five different drugs and these are the spectrum of side effects of these five drugs.” And then they have something to discuss in the examining room. They have something to discuss about choices, because right now we are pretty much guessing or they are opportunistic matches.

If somebody has a mutation in a given gene and there happens to be a clinical trial open to a drug that may be related to that gene, then the patient gets put on that trial. There’s nothing wrong with that because that’s the best we can do now. But think we can do better.

We need to do better because we are only benefiting about two to five percent of the patients who are sequenced right now. And that’s too low. We need to get to 80%. I want to get to 80, 90% in the next five to 10 years. I think we can be there.

Then in that landscape, working with many other Centers, I think we are looking at a horizon where in about 10 years, I think 80% of patients with metastasis can look forward to living years. I think that’s the goal that is achievable. If we put funding into this and if we work together. It’s a combination of things. It’s not going to be just one lab doing everything.

Chris Riback:  Well, that certainly would be remarkable and no surprise that your mind is working in ways to bring together an orchestra of research labs, as opposed to just thinking that one instrument could do it all.

Dr. Merajver:  No.

Chris Riback:  I want to ask about you a little more as well. You spoke about this publicly. You are not just a breast cancer scientist and physician. You’re also a patient.

Dr. Merajver:  Yes.

Chris Riback:  Does clinical and scientific experience and how does clinical and scientific experience apply to one’s personal life when the one of the diseases that you’ve studied your whole life, you end up getting as well?

Dr. Merajver:  Yes, that’s a bit of a detour on the road isn’t it? I’m shopping for shoes on Michigan Avenue, Chicago visiting one of my daughters and from the time I chose the shoes until the time I paid for the shoes, I had cancer in both breasts.

That was just really not right. Anyway, that was a very unusual day and I’m incredibly fortunate. I have an incredibly supportive family and the hardest thing for me, was to tell my daughter who was right there. There was no way to fake it and then tell it under other circumstances. It was right there at their store on Michigan Avenue.

I’ll never forget it but so she started crying, and it was very sad for me to see her so sad but it’s an early stage and like all early stages, some have better biology than others. This is what I’ve done all my life. I know my biology, and it is what it is, and I have the best care here are the University of Michigan. Just unbelievable care.

For me, the experience as a patient has been extraordinary, and I hope every single patient we see here, has exactly the same experience. I also need to point out that I absolutely forbid my friends for doing anything out of the ordinary for me.

They were offering this and that and I said “No, I want to see you when you have clinic.” “Oh, I’ll see you on Saturday.” “No, no, I want to come on the regular clinic day.” I don’t want to tall through the cracks because you are doing things out of the ordinary. Even though I’m a Doctor here and I’ve been here for many decades, I’ve got the same care anyone gets because I like that idea. I like the system. I like to get the care that every patient gets.

That’s just a bit of advice to any listeners out there who are thinking “Well I can’t get good care because I’m not a VIP.” Don’t try to be a VIP. Just make sure your Doctor cares about you and that you’re connected to the clinic. You know the office number. You have a nurse or a scheduler at the clinic who’s navigating your case and you keep all your appointments.

And bring a family member of a friend to take notes with you and so on. Just do … just take care of yourself and the systems in America are good to cure patients who are aware more or less of the steps.

I went through all the steps for treatment and I really missed a week of work because I just tele-conferenced from my lazy-boy and I won’t let cancer define my life. It’s something that happened to me, but on everyday I am happening to cancer. I’m beating back cancer in all of my patients and I’m helping my colleagues do the same. I figure cancer got a week out of my life so far and made a bunch of the people I love the most very unhappy and I don’t get that a lot, but other that I recovered that week.

Chris Riback:  That’s terrific and yes, you’ve recovered that week. You’ve given it on to others. Interesting to hear. Anything about your experience of going through that care as a patient? Did you change or alter anything about the care that you give or did it instead maybe validate to yourself “Okay, you know what I’m doing this okay. I’m giving exactly the type of care that I would expect to have gotten myself.” Was there anything that you learned by going through it, that altered the way you approach patients?

Dr. Merajver:  Yes. All of medicine in a way are conversations that we have with our patients and their family. Right? We practice medicine through conversations. People think that we practice medicine with the electronic medical records. Forget that. That’s just an accent of history.

What we do is, use our brain to help people. It’s what medicine is all about. And to conversations … to pro’s and con’s and to reasoning things and to helping people find their path.

What my experience gave me and I’ve always taken pride as a physician in thinking when I’m not in front of a patient. When I’m by myself thinking of a life and what I do, I like to think of ways to say things to people.

What words should I use, and I have trained myself to use certain words or certain comparisons to explain cancer and cancer therapy to people. In general, in the community and when I teach to my students … when I teach at the website and then to my patients when I treat them.

What it did for me, is it added to my vocabulary. When I experienced bilateral mastectomies as a patient, it incredibly added to my vocabulary. When I describe bilateral mastectomies to my patients and I do that very often.

A lot of my patients undergo bilateral mastectomies. Now that I have been a patient in that situation, I do have different words, different things I say. When I treat them with a drugs I’m taking, then I’m able to say other things.

Some patients, they’re close enough and I’ve known them long enough. But they know that I don’t necessarily bring up. They don’t know why I’m describing things in great detail. Some of them know but most of them don’t.

But I feel that it does help me get closer in those parts of the treatment that I have experienced.

Chris Riback:  Dr. Merajver just to close out and what an interesting point about vocabulary and conversation and change-

Dr. Merajver:  … It’s so important-

Chris Riback:  Yes –

Dr. Merajver:  … So important.

Chris Riback:  Yes –

Dr. Merajver:  … What you say can not be unsaid. To think about the words is super important I think.

Chris Riback:  To close out this conversation and words that I could keep listening to from you for a very long time. It’s a terrific and the way that you approach everything, just all comes together. You can really feel it. You’ve touched on this already. The BCRF and the role that they’ve played in your research. How would you characterize that?

Dr. Merajver:  Well, life’s changing. I would still be doing research if I didn’t have a BCRF funding but all of the great breakthroughs that I’ve hoped for in my career, were accelerated and in some cases, completely made possible. It sounds so tremendously.

My contributions to humanity which is the whole point of the work I do. I don’t know what else to say, but to say it’s transformational. A transformation I respect because not just the dollars. The dollars are certainly an important part of it. For the listeners out there, the funding is unbelievably important.

But the other part is the collaborations. It’s the whole group of scientists from around the world thinking in different ways and comparing ideas. It’s just an amazing community and I have learned so much from them.

Chris Riback:  Around the world really matters to you doesn’t it.

Dr. Merajver:  Oh for sure.

Chris Riback:  Very quickly, you’re doing remarkable work not just in the United States, but truly all over the world including Africa.

Yes, we are definitely very interested in continuing our work in Africa and we are studying African samples in our lab, and we have trained African Researchers in our lab, who are practicing in different countries. I am very committed to global cancer cells and I will continue to do the best I can.

I think we need to enhance, take care of women around the world and there are not a lot of us in the United States working on this and if we continue, it’s difficult with the funding. It’s expensive. Things cost a lot more if you have to spend twenty thousand dollars traveling back and forth, and sending samples and buying equipment in another country and things like that.

But we manage to make at least some progress. So, yes we are here to create cures for everyone.

Chris Riback:  Dr. Merajver, thank you. Thank you for your time and of course, most importantly for the work and care that you’ve given to people all over the world.

Dr. Merajver:  My pleasure. I always end my conversations with my patients: “To life!”

Chris Riback:  “To life!” Thank you.

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