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HER2-Low Breast Cancer Roundtable: Decoding HER2-Low Expression in Metastatic Breast Cancer
This video discusses HER2 expression in metastatic breast cancer, including the nuances of HER2-low diagnosis, clinicopathologic differences between HER2-low and HER2-positive expression, and the implications for managing the disease.
This video discusses HER2 expression in metastatic breast cancer, including the nuances of HER2-low diagnosis, clinicopathologic differences between HER2-low and HER2-positive expression, and the implications for managing the disease.
This roundtable discussion is sponsored by Daiichi Sankyo.
Dr Adam Brufsky: So, hello, my name is Dr Adam Brufsky. I'm a professor of medicine at the University of Pittsburgh, and welcome today to our Oncology Learning Network Roundtable video program for HER2-low breast cancer education and awareness. The goals, actually the learning objectives of this program are to understand the role of HER2 expression in metastatic breast cancer, including some of the newer data on HER2 IHC 1+ and/or 2+ FISH-negative tumors to review the current clinical guidelines for HER2-low breast cancer and current and future treatment landscape. And then finally, we'll have a talk and some discussion about the current recommendations for HER2 testing and the clinical impact of the timing of the test on various treatment choices for HER2-low breast cancer. So with that, let's introduce everybody. I'll start by myself since I'm the moderator. So I'm Adam Brufsky. I'm professor of medicine at the University of Pittsburgh, co-director of the Breast Cancer Center there. And then we'll go, I guess Dr. Moscol can go next.
Dr Giancarlo Moscol, MD: Yes. My name is Giancarlo Moscol. I'm an assistant professor of breast medical oncology, and I work at the University of Texas MD Anderson Cancer Center in Houston, Texas.
Dr Adam Brufsky: Great. Dr Jhaveri?
Dr Komal Jhaveri: Hi, I am Komal Jhaveri. I'm a breast medical oncologist at Memorial Sloan Kettering Cancer Center in New York. I serve as a section head for our endocrine therapy research portfolio, and I also have a dual appointment within our early drug development service where I serve as a clinical director. Happy to be here.
Dr Adam Brufsky: Great. Dr Lustberg.
Dr Maryam Lustberg: Hello everyone. I'm Maryam Lustberg, chief of breast oncology at Yale Cancer Center.
Dr Adam Brufsky: And last, but definitely not least, Dr Gradishar.
Dr William J. Gradishar: Bill Gradishar, professor of medicine at Northwestern University in Chicago.
Dr Adam Brufsky: Great. Alright, so let's get started. So really, I think we can start with breast cancer in general and HER2 in particular. The big thing that's happened, really, in breast cancer is this whole concept of HER2 low. And I think one of the first questions that people have about HER2 low is, is it a separate disease? I think that was really an important issue. We had a whole thing in San Antonio last year, about an hour and a half, where we discussed about whether HER2 low is a separate syndrome. So let's start off, well let's start with Dr. Moscol. Do you think HER2 low is a separate disease?
Dr Giancarlo Moscol: I think that it may have a prognostic implication. I'm not a hundred percent sure it's a separate disease, because when you follow the natural course of these patients, it's not necessarily that differentiated. It's probably now becoming more important to realize about the true expression of the HER2 receptor because you can now target it with better drugs. But I'm not a hundred percent convinced that it is indeed a fourth category the same way we talk about triple negative and HER2 positive.
Dr Adam Brufsky: Right. Komal, what do you think? Is HER2 low a separate disease?
Dr Komal Jhaveri: Yeah, no, I think this has been certainly a big area of focus and debate given that we've seen now antibody-drug conjugates such as trastuzumab deruxtecan approved for this so-called new entity in breast cancer. But while this is a very prevalent subtype, if you will, with 65% of the tumors with hormone receptor positive that have HER2 low, when we've tried to look at data sets to see if survival differs between, say, HER2 low and HER2 zero, we've really not been able to find that. We've not been able to find differences when we've even looked into intrinsic subtyping to see if there are differences between HER2 low and HER2 zero. I think it turns out to be, it's just a way for these novel antibody-drug conjugates to be able to deliver this very potent cytotoxic payloads to the cells of interest. So, unlike a HER2 overexpression, where we think it's an oncogenic driver, HER2 low really is just a medium by which novel antibody-drug conjugates can deliver their toxic payloads.
Dr Adam Brufsky: Fair enough. Maryam, what do you think?
Dr Maryam Lustberg: Yeah, I agree that primarily it's a therapeutic target and because we have these newer antibody-drug conjugates is the reason we're talking about it. So I also do think, as we'll talk about later, that our diagnostics for assessing HER2 low have been in many ways challenging. So looking at these older legacy assays for determining of HER2 and determining who's HER2 low versus not, we know that these have been impaired tests, so in some ways we can't really completely talk about whether this is indeed its unique subtype, because just all over the place in terms of how HER2 low has been assessed using immunohistochemistry. So I think we need a little bit more information with newer quantitative testing to truly answer that question.
Dr Adam Brufsky: Bill?
Dr William Gradishar: Well, I would share the sentiments expressed by others already. I don't have a lot that's unique to say. I think that based on the body of data that we have available, I'm not convinced yet that this is a unique biological subtype, and we'll talk about some of the features. But right now, as Komal said, I think it's not a unique entity. But it is because of the therapeutics we now have, we have a better way of delivering active drugs to this particular low-level HER2 breast cancers, essentially.
Dr Adam Brufsky: Got it. Okay. So I mean we'll kind of talk, so that's the first thing, I mean it seems to me, I think, there's consensus that HER2 low is not a separate entity. But let's go back a little bit and talk, I think that, about really just the treatment in general of metastatic breast cancer and where these drugs at least have a place at this point in time. I mean, I think obviously these drugs are developed in HER2-positive, HER2-3+ breast cancer, and I think most of us are familiar with the data of DB03. And are most of you now using trastuzumab deruxtecan in your practice for second-line therapy? Have you changed your practice completely to T-DXd? Let me start with going backwards. We'll go with Bill first. Are you really now using it for HER2 3+? We'll get to HER2 2+ in the next section, but I'm really just talking about HER2 3+.
Dr William Gradishar: Yeah, so where we've placed it now, and I think it's really based on pretty robust data that's pretty compelling from DB03, is unless there's some really unique situation, and we can talk about what those might be, but T-DXd is my preferred second-line therapy.
Dr Adam Brufsky: Have you had any problems, Maryam, using T-DXd at this point? ILD, anything like that?
Dr Maryam Lustberg: I've had a handful of patients, but I think in general, it's been firmly in my practice as second line of therapy in the metastatic HER2 overexpressing tumors. And certainly, every therapy can have its complications, and so generally I've seen robust responses, with a handful of interstitial lung disease issues that I've dealt with.
Dr Adam Brufsky: Okay. Komal, you guys probably use for all the HER2-positive patients for second line. Do you agree?
Dr Komal Jhaveri: Yes. Yes, absolutely.
Dr Adam Brufsky: And are we going to see, let me ask this. I don't know if Giancarlo knows the answer. Are we going to see DB06 at San Antonio? I don't know. Does anybody know whether we’re going to see that? Because that's really actually first-line chemo, not second.
Dr William J. Gradishar: I don't think so.
Dr Adam Brufsky: We're not. So no DB06. Okay, fair enough. So I guess the question is that, where to place these drugs is important in HER2 3+, and I think most of us would give, I think, trastuzumab deruxtecan for second-line therapy for HER2 3+. And since we have a little bit of time, let's just focus on that a little bit more before we really get into the HER2-low section of this. And I think that the real mystery is what do we do after somebody – now this is for HER2 3+, we’ll talk about HER2 low in a few minutes. But for HER2 3+, so we all now, based on DB03, which is very robust data, as I think we all know, it's like a 28-month progression-free survival, which is really a quadrupling of T-DM1, as we all know.
The question is, what do we give after? That's the real mystery. I think that, are we simply just trading, because we now know from DB02 and HER2-positive disease that we get, I don't know, I think it's 17-month progression-free survival, 18-month progression-free survival, and an overall survival benefit. Are we simply just trading one thing for the other? So, question was asked to me yesterday, actually. I'm really curious. I'm sure this was a big topic at ESMO as well, and I'll start with Komal. I mean, what do you think, we just, should we save T-DXd in triple net, HER2-positive disease for third-line instead of second? And just give the T-DM1 first because T-DM1 after T-DXd may have no activity? What do you think? I'm going to ask you guys these questions. I'll come up with some questions here for this section before you get into HER2 low. What do you think, Komal?
Dr Komal Jhaveri: Yeah, no, I think it's such an interesting question, especially because we have the data for T-DXd, both in the head-to-head comparison with T-DM1, but also data for T-DXd after T-DM1. Having said that, I feel like I'm a believer of utilizing good drugs upfront, and given the unprecedented, as you pointed out, 28-month immediate progression-free survival, the response rates that we saw in that study, 21% complete responses, right? Which is really, really unprecedented even in the first-line setting. When we think about Cleopatra, the complete response rate in Cleopatra is 5%. So this is four times the amount of patients that are getting complete responses in the second-line setting. So my practice has been, or my thought process has been, something really works very well, it works really well when it's used up early, I would use it early. So I am utilizing it in the second line and I'm not holding off utilizing it later unless there is a concern for me to give T-DXd to a patient. So I'm thinking ADC, I'm doing T-DXd.
Dr Adam Brufsky: So the question for all of you then is what do you give after? Maryam? What do you give after, and do you see responses after T-DXd in HER2-positive disease? We, does anything work afterwards, in your clinical experience, right now?
Dr Maryam Lustberg: Yeah, so whether they have brain mets or not, I've been using the tucatinib-based therapy, tucatinib, capecitabine, and trastuzumab typically in this third-line setting. And yes, seeing some responses for sure. And it has further bumped down T-DM1 on my list of drugs that I'm using. So tucatinib has been my next go-to drug outside of a clinical trial.
Dr Adam Brufsky: Would that be the consensus from everybody, that we probably would use the HER2CLIMB regimen next?
Dr Komal Jhaveri: Yes.
Dr Adam Brufsky: Shaking their heads, no one would not. And are we seeing responses? I know there's been some data, there was an ASCO, some just limited observational data. I don't know if it was, was it actually using tucatinib-based regimens after T-DXd? I forget, remember that?
Dr Komal Jhaveri: Yeah, I think, I think it was at ASCO where we looked at that data and certainly the median progression-free survival was slightly lower than what we had seen in the HER2CLIMB study. But we did see that data in a small cohort of patients when that approach was done.
Dr Adam Brufsky: Okay, fair enough. So again, I mean that's the big mystery. I think that's just an uncharted area now, what we do after T-DXd because it works so well. But most of us would use the tucatinib or the HER2CLIMB-based regimen. What about fourth line? What would you do after that? Does anybody see any activity of T-DM1 in fourth line in HER2-positive disease?
Dr William Gradishar: Well, I think one of the things that's probably true of these drugs, just like any other subset of breast cancer, is the farther you get downstream, the probability of responding is going to diminish. So I think we probably have all seen responses. Some may be anecdotal, we see here and there, but there's diminishing returns when you start getting third, fourth, fifth line. But it doesn't preclude the possibility that someone will respond to any of these things. So we always try to leverage HER2-directed therapies somewhat indefinitely, even with progression.
Dr Komal Jhaveri: Sometimes in my triple-positive metastatic breast cancer patients with ER-positive, HER2-positive disease, I'll probably intervene at some point with monarch, HER-like regimen as well with trastuzumab, fulvestrant, and abemaciclib as a way of trying to have another way of approaching the tumors. And that could be one thing that I would do, but the thought is that we just don't know what's the most optimal way of sequencing these agents after patients have progressed on T-DXd. And I think all of us will recommend all of these regimens at some point. And as Dr Gradishar pointed out, I think the responses could be diminished, but we would only have to try to find out how exactly an individual patient would respond.
Dr Adam Brufsky: Yeah, I think that as we'll talk in the HER2-low setting in a minute, it's a little bit easier because I think most of us, at least with the ER-positive, HER2 low will give, go through the usual kind of targeted agents in endocrine therapy. But it's an interesting question in these triple-positive patients. The way I've always looked at it is, and in fact there are patients that are what we call quadruple positive, and I'm not sure I really like that, when you add BRCA 1 or 2 into it. So you have someone who's HER2-amplified, ER-positive, BRCA-mutated, which do you choose and when? It sounds like most of us would give trastuzumab deruxtecan second line, maybe the HER2CLIMB third line, and then we get to the fourth. And it's crazy. I mean, Bill and I are old enough, the rest of you probably younger than us or, to remember we had nothing. Now we're talking, we're debating fifth, sixth-line therapy 30 years later, 20 years later. And the question is, would someone just, I mean, Komal, you hinted that a little bit, but would you go down those different pathways, and how do you choose after you've done through T-DXd maybe HER2CLIMB regimen and then you have someone who could potentially get an ER-positive targeted regimen, right? Like with abema or olaparib or talazoparib. I mean, how do you choose? How do you guys choose? I'm really curious before we move on.
Dr Komal Jhaveri: To be honest, I think for good or bad, I think the BRCA carriers with HER2-positive disease is a very, very rare phenomenon. We see that more commonly with triple-negative and ER-positive tumors. So not sure if I've faced that more than once or twice, where I do have a situation where the patient might also be a germline carrier. And there was a clinical trial through the TBCRC that was trying to address that question with niraparib and trastuzumab, but I don't even know how the tumor biology in such tumors is driven predominantly by the germline mutation versus HER2-driven as an oncogenic driver by HER2. And which one? Targeting which one is more and more important. So fortunately, I've not come across that scenario a whole lot. If there was a clinical trial, I would offer that patient, that clinical trial that might address that question for me. I have been using HER2-based therapies more, but I would be open to a PARP inhibitor should that situation arise.
Dr Adam Brufsky: But you would use HER2-based therapies with abemaciclib though?
Dr Komal Jhaveri: Yes, absolutely. I have definitely used trastuzumab along with abemaciclib and fulvestrant.
Dr Adam Brufsky: Is everybody the same way? Does everybody have the same thing? Have we all used abemaciclib in a triple-positive or abema or palbo or ribo in a HER2-positive patient? Have we used CDK4-6 inhibitors?
Dr Maryam Lustberg: Especially in the presence of brain metastases, since we do have some data in terms of better CNS penetration with abemaciclib. I think the issue that I face in my practice, and I'm sure others as well, is that it's not as much systemic control of disease that becomes challenging as these patients go further down the line. I think CNS metastasis become quite troubling, or radiation necrosis. So I think trying to select therapies that may have some known CNS activity is what is driving my decision-making there.
Dr Adam Brufsky: Is that a general consensus from every, Giancarlo, would you do the same thing? I mean if someone, I would agree with you, and we have data that goes back, we have registry data that's probably 10 years old already, where that tends to happen that by the time you get to the third line in HER2-positive disease, you already start to, 50% of the patients will have brain metastasis at that point. So Giancarlo, do you tend to think about more brain-focused things the further along you get?
Dr Giancarlo Moscol: Yeah, correct. I know that my third line, at least tucatinib with Xeloda, the HER2CLIMB is giving you some coverage after that. I would also say I've used Margenza, margetuximab with eribulin. I like that it allows you to use a innate chemotherapy to get better control of the burden of the disease. I know that the data is not that appealing, but I've seen a couple of good responses and mostly stable disease. And when I use a CDK4-6, I usually tend to use it in probably third or fourth line. No pass beyond that. Mostly because the cytopenias become very challenging, especially when you have marrow involvement.
Dr Adam Brufsky: Yeah.
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