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Investigating Breast Cancer: The Underlying Biology of Drug Resistance

Dr. Sarat Chandarlapaty talks about strategies to prevent cancer cells from evading the drugs designed to kill them

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

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

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Read the transcript below:

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

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

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

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

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

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

Chris Riback: Yes.

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

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

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

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

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

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

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

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

Chris Riback: To therapies at that point?

Dr. Sarat Chandarlapaty: To therapy, right.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Chris Riback: Yes.

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

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

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

Chris Riback: Yes.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


Dr. Sarat Chandarlapaty: Yes.


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

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

 

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