Identifying Risk Factors for Secondary Malignancy in Breast Cancer Survivors
The Cancer Advances podcast is joined by Abhay Singh, MD, MPH, a physician with the Department of Hematology and Medical Oncology at Cleveland Clinic to talk about his study, which aimed to identify risk factors for secondary malignancy in breast cancer survivors. This study was presented at the American Society of Hematology (ASH) 2022 annual meeting. Listen as Dr. Singh explains how he explored the different risk factors, such as G-CSF exposure, how the CHIP Clinic might be able to monitor patients, and the long-term goal to figure out which therapies patients should try to avoid.
Identifying Risk Factors for Secondary Malignancy in Breast Cancer Survivors
Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig phase 1 and sarcoma programs. Today I'm happy to be joined by Dr. Abhay Singh, a member of the department of hematology and medical oncology in the Taussig Cancer Institute. He's here today to talk to us about identifying risk factors for secondary malignancy in breast cancer survivors, specifically work that was presented at the American Society of Hematology meeting. So welcome.
Abhay Singh, MD, MPH: Thank you so much for having me over, Dr. Shepard. Glad to be here today.
Dale Shepard, MD, PhD: Absolutely. So, give us a little bit of an idea, what do you do here at the Cleveland Clinic?
Abhay Singh, MD, MPH: So, I'm fairly new, so I started in August of 2021. I am part of the Leukemia and Myeloid Disorders program here at the clinic. In terms of my clinical focus, I see patients with any acute or chronic leukemias. These are disorders of clonal expansion. So as such, I am interested in precursor states as well. So, focusing on the other side of the spectrum, which is the preventive aspect of it as well. So, from that standpoint, this is this entity, clonal hematopoiesis of indeterminate potential, or we call it CHIP, which is my research focus. So, I had the CHIP Clinic here at the Cleveland Clinic and then focused on my research and clinical time as part of the CHIP Clinic as well.
Dale Shepard, MD, PhD: Excellent. So, we're going to talk a little bit about some research and risk factors and things, and maybe we'll double back and get an update on the CHIP Clinic. We've had a previous episode, where we talked about the CHIP Clinic, so maybe just a little bit of a quick overview at the end. So, to start out, we're going to talk about some research that was presented about determining risks for secondary malignancies. To just a wide range of people that might be listening in, tell us a little bit about this whole concept of secondary malignancies in patients who have been treated for cancer.
Abhay Singh, MD, MPH: So, it's very common. Patients who have a prior solid malignancy or a hematological malignancy can go on to develop a secondary malignancy. Some of it could be because cancer is a diagnosis of the aging population, so they are at risk of secondary cancer diagnosis. There're some germline predispositions. There are other identified risk factors, smoking being one, obesity an emerging one, and then also any exposure to chemotherapy and radiation therapy that increases the risk of secondary malignancies. Most patients end up receiving, with advanced stages, some sort of chemotherapy and radiation therapy, and they go on to this period of survivorship, during which they're at risk of acquiring another malignancy. Not everyone who receives this chemotherapy or radiation therapy goes on to develop this outcome, which has a poor prognosis overall. About 10 percent or less go on to develop therapy-related myeloid neoplasms. So that's kind of where we were thinking that not everyone exposed to chemotherapy or radiation therapy goes on to develop a secondary malignancy. So why is it that some people do develop it and others do not? So that was kind of how the idea started.
Dale Shepard, MD, PhD: All right. We'll talk about that in a second. Just to think about our current state. You looked at breast cancer, and most patients with breast cancer are going to have an initial therapy, that is chemotherapy. But do you think there're going to be changes in the future as we do more targeted therapies, genomic therapies, immunotherapies? Do we think that maybe we'll see less treatment-related toxicities like malignancies in the future?
Abhay Singh, MD, MPH: Yes. So that brings me to some of my work that actually was done during my fellowship, using a large SEER database. So, in that analysis, what we looked at is we did, according to time period, how the risk of secondary malignancies is changing. And surprisingly, what we found was in the era of immunotherapy and targeted therapies, impact has been profound in the last 10 years, like melanoma and renal cell carcinoma. We saw that actually the risk of secondary acute myeloid leukemia is on the down trend. But there was some interesting pattern to the increased risk of MDS, and there are certain investigations that we are re-doing right now to see why that might be. But certainly, the risk of acute myeloid leukemia is going down with the advent of neurotherapies.
Dale Shepard, MD, PhD: So maybe a hematologic malignancy, just a different problem.
Abhay Singh, MD, MPH: Yes, yes. Exactly.
Dale Shepard, MD, PhD: So, tell us a little bit about the work with these breast cancer patients. Was it a large population that was examined? Tell us a little bit about what that was.
Abhay Singh, MD, MPH: Yeah. So, therapy-related myeloid neoplasms, about 10 percent of patients, develop after their first diagnosis of primary malignancy. They're exposed to chemotherapy and radiation therapy. Many of them enjoy survivorship without any bad outcomes, with TNM can be one worse outcome. And that was kind of the motivation to do this analysis. Using a large, large database, we looked at around upward of 230,000 patients, female breast cancer patients, and we looked at a variety of risk factors and what might increase their risk of having that transformation, where some of these patients do not develop any secondary malignancy and a subgroup of patients go on to develop these malignancies after exposure to chemo or radiation therapy.
Dale Shepard, MD, PhD: And so, what were some of the things that seemed to be a risk factor?
Abhay Singh, MD, MPH: Yeah. So, we started off looking at a variety of risk factors, some of which are well-established, like we discussed, advancing age, smoking, chemotherapy, radiation therapy. In addition, we looked at some of the risk factors, which are whether associations are less well-defined or there's some ambiguity that exists, those being history of autoimmunity, growth factor or G-CSF exposure, so to speak. And then some other comorbidities that have been associated with therapy-related myeloid neoplasms. These are the clonal hematopoiesis-associated comorbidities. So, these are cardiovascular disease, hypertension, hyperlipidemia, prior organ transplant. So, these were all the risk factors that we looked at in these patients with primary breast cancer.
Dale Shepard, MD, PhD: So, I was a little surprised with the growth factor being a risk. Tell us a little bit about that.
Abhay Singh, MD, MPH: Yes. There's been a lot of back and forth with the growth factor. I think historically, what we've kind of decided upon is that although there might be some increased risk, but overall survival benefit is so much in solid malignancies, that use of G-CSF is supported to use it in a prophylactic manner to prevent prolonged neutropenia and use dose-dense chemotherapy. So, what we saw in this analysis was that if there was G-CSF exposure, there was a threefold increase in risk of therapy-related myeloid neoplasms.
Dale Shepard, MD, PhD: So that's not insignificant, but like you say, if you're going to be using something, you don't want to get neutropenic fever, but at the same time you might have an increased risk.
Abhay Singh, MD, MPH: Increased risk, yes.
Dale Shepard, MD, PhD: Is there a thought, from a mechanistic standpoint, that we should come up with better ways to stimulate bone marrow?
Abhay Singh, MD, MPH: How I am thinking about it is that there're pre-existing clonal mutations or the precursor state or clonal hematopoiesis of independent potential. So, are we in a way stimulating the marrow and more so the CHIP clones to get bigger in size over the course of one's lifetime that they're at increased risk? So that's something that needs to be studied mechanistically and at a molecular level to understand this phenomenon better. We've done a few more analyses. We are seeing a consistent trend, not only across breast cancer, but we've looked at all the five major cancers diagnosed in the US. More than a million people get diagnosed with these cancers in a year in the United States, so breast, lung, bladder, GI cancers, prostate. And this risk is significant all across the board for all these cancers.
Dale Shepard, MD, PhD: And so again, considering the growth factors are primarily associated with chemotherapy, as we move away from chemo, I guess this might kind of solve itself, but it seems like a pretty significant issue.
Abhay Singh, MD, MPH: Yes. Absolutely. So, as we won't be using it as much with targeted therapies or immune-modulating therapies, that risk hopefully will go down.
Dale Shepard, MD, PhD: So, in this particular analysis, you also noticed sort of an increased risk in patients with autoimmune conditions in terms of developing secondary heme malignancies. Tell us a little bit about that.
Abhay Singh, MD, MPH: With patients who had autoimmune conditions prior, they were at increased risk of developing therapy-related myeloid neoplasms. So smaller studies have looked at it before, but we looked at a very large population, and this result has stayed consistent throughout other cancer types as well. And this holds strong and true even without chemotherapy exposure. So, there's baseline risk with autoimmunity, but when we add chemotherapy and radiation therapy on top of that, that risk goes, for example, from threefold to eightfold. So that's something that is going to be very important to learn and understand how molecular events happen in autoimmunity and how they lead to this progression to therapy-related myeloid neoplasm.
Dale Shepard, MD, PhD: And is there a thought that this is related to immune surveillance? Or is it too early to know?
Abhay Singh, MD, MPH: So again, these are specific mutations that are thought to be immune-provoked or inflammatory clones, so to speak. So DNMT3A and TET2 mutations are the two mutations that have been associated with inflammation, and then they increase the risk of cardiovascular disease. So certainly, there's some connection there. There's some connection between T-cell activity and those clones. So, a lot needs to be unraveled. A lot needs to be learned, but that's something that's really intriguing and interesting that we are trying to figure out.
Dale Shepard, MD, PhD: You've mentioned the CHIP clones and things. Are there any particular abnormalities that sort of seem to fall in line with that increased risk of? Have we gotten to the point where we could say, well, these are the ones that are the bad actors? And then I guess does that translate into are we managing those patients differently from a monitoring screening standpoint?
Abhay Singh, MD, MPH: Yes. Yes. So that actually is the eventual goal. It's steps towards that direction, but we haven't reached there yet, so certainly the bad actors being the TP53 mutations and another one, which was another of our work, which we did in relation to this novel therapy, PRRT, not novel anymore, peptide receptor radionuclide therapy that's used in neuroendocrine tumors. So, there's this clone, a PPM1D mutation, so it's X in the same pathway as the TP53 mutation. And if there is presence of those mutations, there seems to be an increase of therapy-related myeloid neoplasms down the line, so certainly a lot of room for prevention screening and to devise those strategies once we have a better molecular understanding of these processes.
Dale Shepard, MD, PhD: And I guess if we get to the point where we understand what some of those quote-unquote bad actor clones are, is that maybe going to be a trigger for what types of therapies patients get to try to avoid sort of stimulating that response downstream? Is that a goal as well?
Abhay Singh, MD, MPH: Yes. A lot needs to be figured out from that standpoint. But a particular example that I can think of is someone with early-stage breast cancer, who has had a lumpectomy and a plan for radiation therapy. And then when we plug in numbers into some sort of risk calculator to see how much adjuvant chemotherapy might add to the overall survival benefit and if that survival benefit is marginal and we have screening strategies that are set up to look for any CHIP mutations, so to speak, so if there's a TP53 clone, maybe that'll be a reason to forgo chemotherapy in that patient and prevent something bad from happening down the line. So that's how I foresee.
Dale Shepard, MD, PhD: So, we think about the Oncotype testing and things, incorporating more of what we learn about CHIP technology into those sorts of screenings. So, this particular analysis looked at breast cancer, are there any other cancers, and you mentioned a growth factor with other major cancers, any other big surprises when you look at other tumor types? I mean, breast cancer, this is 230,000 patients. Any surprises from the other types of cancers?
Abhay Singh, MD, MPH: So yeah. So, of all cancers, there seems to be an increased risk and it's pretty significant. So, the smallest cohort that we looked at was the cohort for indolent and aggressive lymphomas. G-CSF is also used as well. And it seems there is also a pretty significant increase in therapy-related myeloid neoplasms. Similarly, in bladder cancer as well, any G-CSF exposure increases the risk three to fourfold in that patient population as well.
Dale Shepard, MD, PhD: And so, I guess the question people that may have been treated with breast cancer find out about this risk and there, of course, going to be concerned, what should they be thinking about? Like if an oncologist might be listening and says, what should I be doing to monitor my patients, what recommendations can you make?
Abhay Singh, MD, MPH: So, I think we're still in a stage where we're learning a lot of things. I think we need to understand this better at a molecular level. There's certainly a population level signal for this. If there is an opportunity to avoid G-CSF exposure, that might be the strategy to go. But as of now, we haven't gathered enough data to say for sure that this needs to stop right now or anything like that. Because there's certainly benefit that has been shown in other larger studies with the use of G-CSF, and there's survival benefit there as well. So certainly, we haven't gathered it. I think how it can be used in a more precise manner in the era of precision medicine is that if we have identified those clones prior to the chemo in that setting, there may be opportunity to forego certain therapies and then just go from there. But I think there're still things to be figured out at this point.
Dale Shepard, MD, PhD: And I guess the things to be figured out can be partially through things like the CHIP Clinic. Right? So that's how we might be able to learn more about the molecular basis. So, give us a little bit of an overview about what CHIP Clinic is and really back to patients that might be out there in the community somewhere saying, hey, what is my risk? How likely is it I'm going to get heme malignancy. Tell us a little bit about how the CHIP Clinic might be able to monitor patients.
Abhay Singh, MD, MPH: Yes. So, CHIP Clinic is a large effort that is being started at several major cancer centers, and it's up and running at numerous cancer centers around the United States. We are lucky to have CHIP Clinic here at the Cleveland Clinic. We have up to 180 patients, who have been enrolled onto this protocol. And we are focusing currently on patients who are breast cancer survivors. They're not on any chemotherapy or radiation therapy currently. And also head and neck survivors. These patients get next generation sequencing testing to look for any clonal mutations at the time of enrollment. And they're followed each year for 10 years to see how these clonal trajectories evolve over time in response to various therapies. Some of these patients have had surgery alone. Some of these patients have had only radiation, and some of these patients have had chemotherapy or a combination of all. And there are patients that we are now identifying, after this population level data, that have been exposed to G-CSF as well.
So, there's a lot to learn from all these treatments and how molecular signatures may differ when differentiating between patients who've just received surgery versus chemotherapy or a combination of a few drugs. So that's something that we are learning through the CHIP Clinic. Some of the findings we are excited about are going to be presented at ASCO this year by our CHIP Clinic. The Cleveland Clinic experience, as a discussion session, certain things that have come out in terms of putative molecular mutations that are associated with low blood counts, we'll be presenting at ASCO this year.
Dale Shepard, MD, PhD: Excellent. And then you mentioned sequencing, getting clinical information, but it's really a yearly follow up. So, if somebody wants to get involved, it's a relatively little outlay of effort. Right? So, it sounds like it's a pretty easy thing for people to get a check-in, contribute to science, and learn a little bit about what the risks might be.
Abhay Singh, MD, MPH: Risks might be, yes, absolutely. So, we have a wonderful team that works here for the CHIP Clinic. They make it really easy for our patients. The first effort is the enrollment. They get the blood test done, and then we just try to coordinate their visits when they're actually coming here for their visits. So, there're no extra visits. There're no extra drawings. So that's how it's very streamlined for them for this. So, it is not burdensome or onerous for the patients at all.
Dale Shepard, MD, PhD: Excellent. What else do you find most exciting on the horizon? Where do you think this is all going to take us in the end?
Abhay Singh, MD, MPH: So, I think science has advanced so much in the last decade or, so we are moved away. We are trying to find newer therapies, targeted therapies, immunotherapies. And we are doing great in terms of improving survival and quality of life for our patients. But I think where we might have a little more room to expand and grow is the preventive side of things. So, my passion is blood cancer prevention. I'm an internal medicine and preventive medicine trained. So, this CHIP Clinic is an important thing for us here at the clinic to be at the forefront of preventive medicine and preventing things from happening so we can help our patients enjoy a better quality of life and then improve survival outcomes.
Dale Shepard, MD, PhD: And as you mentioned previously, a lot of this focus is sort of on survivorship, but we may learn more and actually be moving this upstream so that we actually can tailor therapies accordingly.
Abhay Singh, MD, MPH: Absolutely. That is the goal. So, we're trying to enter into this phase of expansion, where it will be exactly how you mentioned. We will try to go to the upfront setting, so we are able to capture mutations prior to any exposure and then monitor clonal evolution over time in this multi-year study. And also, we are trying to be cognizant of the fact that we have a lot of patients who go to our region as well. So, we're trying to expand to all our regional sites as well so that our patients can benefit from our regional sites as well.
Dale Shepard, MD, PhD: Wow. That's great. So that's some outstanding work. I appreciate all you're doing in this area. Thanks for giving us some great insights today.
Abhay Singh, MD, MPH: Thank you so much, Dr. Shepard, for your kind words and for having me over. This was wonderful.
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