Welcome to The Breast Cancer Sessions brought to you by the Video Journal of Oncology (VJOncology).
This exclusive discussion features leading experts, Lisa A. Carey (UNC Lineberger, Chapel Hill, NC) and Aleix Prat (Hospital Clínic Barcelona, Barcelona, Spain) who discuss the latest advances in breast cancer presented at the San Antonio Breast Cancer Symposium (SABCS) 2021 and what the latest research means for the clinic.
The topics of discussion include their highlights from the meeting, including recent updates from the MONALEESA studies, as well as the findings of a subgroup analyses.
LISA CAREY: Hi, I’m Lisa Carey from the University of North Carolina. And I’m here with-
ALEIX PRAT: I’m Aleix Prat. Medical Oncologist from Hospital Clinic in Barcelona, Spain.
LISA CAREY: And we are here doing a VJ session, for VJOncology here at San Antonio, 2021. And it’s going to be a lot of fun. We are here on the first day and Aleix, I’m very excited about tomorrow’s presentation. About the overall survival data from the pooled analysis of the MONALEESA-2, 3, and 7 trials. Aleix, why don’t you tell the story about the PFS analysis and then we’ll catch everybody up on what’s going to be presented tomorrow.
ALEIX PRAT: Sure Lisa. And this, as you pointed out, another work presented tomorrow by you is a prior work. That we would reported last year. Which is basically the first analysis of intrinsics of typing in hormone receptor positive HER2-negative advanced disease. And in the context of three large phase three trials, which are the MONALEESA-2, MONALEESA-3 and MONALEESA-7. In that study, we showed that intrinsic subtyping might be important in the sense that first, you identify all the subtypes within hormone receptor positive HER2-negative, with different distributions. Luminal A’s where the vast majority, 50% approximately. Followed by luminal B’s, around 28%. And then you have these non-luminals, which I think are interesting and we can, we can discuss now. The HER2-enriched around 13% and then 3% of basals. And what we show in that first report is that subtypes are prognostic on one hand, strongly prognostic from a PFS perspective, but also potentially predictive. What we observe is that ribociclib is effective in luminal A’s, luminal B’s, and HER2-enriched, which was kind, to me, unexpected and we can discuss that, and it was not effective in basals, no? So this was the work presented, and I think now we have the opportunity, and maybe Lisa can point it out what we’ve done now.
LISA CAREY: Yeah, you know, I think the PFS had differences and the, and the heterogeneity of breast cancer, particularly hormone receptor positive breast cancer. The fact that it’s molecularly so heterogeneous, that plays out in ways that are, prognostically, really important. And as you point out, the PFS data suggested that it was going to play out in a therapeutically meaningful way, particularly for the HER2-enriched, which I think people were surprised at those data. But the survival data that’s going to be presented tomorrow, you know, it holds up. I mean, prognostically, it makes a big difference. It’s even more striking the differences in prognosis between the luminal subtypes and the non-luminal subtypes. Which, you know, this is more than 20% of the population. So this is actually, clinically, an important subset. And it does look like, from a survival standpoint, you start to compensate in the HER2-enriched group, which was doing very poorly within a good, less than 30 month overall survival. And they move up into the, you know, almost to the luminal B group. So I think, you know, as we’re heading down this, this road of trying to get away from ERPR and HER2 as being the defining characteristics of breast cancer. We’re now seeing, in the metastatic setting, as we know, in the early setting, the underlying biology is crucial for how these tumors behave. Do you want to talk about what your next steps are going to be?
ALEIX PRAT: Well, I think, plenty of ideas, right? And I think now, based on this data, many different potential prospective trials should be done, in my view. One thing we were very happy about is the collaboration between SOLTI and AFT, Alliance Foundation, together with with Novartis to to be able to run a prospective phase three trial. Pre-selecting patients based on intrinsic subtyping, no? Using tumor biopsies, metastatic tumor biopsies. We’re talking about more than 2,600 patients screened in Spain, Portugal, and the US. So, huge effort. And focus on the HER2-enriched, which is a group that, no doubt, Ribociclib is effective from a PFS and an OS perspective. But this is a group that needs attention. At the end of the day, they don’t have an outstanding overall survival. So, I think studying that group is going to be very crucial. And in particular, in HARMONIA, testing if difference in the case, might have different activity in HER2-enriched. I think it’s an important, because it’s in a group that the first three months is important. Actually when you look at the overall survival curves, they separate very fast in the HER2-enriched with, with ribociclib, suggesting that it’s very important that you choose the right drugs in this population that you might lose if you don’t treat them right. So at the same time, HARMONIA will have an opportunity to focus on the basals, which, again, is 3%, but in other contexts, like our lung cancer colleagues, 3% is still a population of patients we see in the clinic. Definitely these patients don’t benefit from endocrine based treatments, including CDK forensics inhibitors. So in HARMONIA we are planning to treat these patients with chemo, a chemo based treatment. Which is gonna allow us to see if chemo in these patients makes more sense than just starting with a CDK, and waiting for an early progression. So, yeah, these are the types of studies I think, you know, Lisa, that we should be thinking about, no? Selecting patients based on sub typing. I think just using, as you pointed out, the HER+/HER2- it’s not enough.
LISA CAREY: No, it’s not. I think we’re super excited, I mean, this was your brain child, HARMONIA, which is really a unique opportunity to do an umbrella trial in metastatic hormone receptor positive HER2- breast cancer. An umbrella trial defined by, you know, a transcriptomic feature that we know is important. We know it’s important from early breast cancer and these data in MONALEESA suggests it’s equally important in the metastatic setting. And now to build a trial prospectively, to demonstrate that you should be parsing out the biology, according to it’s, you know, where the Achilles heels are. And, you know, I think you point out the basal-like group, you know, you can’t salvage a non-hormonally driven tumor with hormone therapy, even with the CDK4/6 inhibitor. And then the other ones, I think, you know, this is also an opportunity for us to learn more about the biology and some of these, some of the things that you’ve been working on so hard, as well as, as many others. You know, integrating ways to identify the biology and, which only helps if we can therapeutically target it. So we’re very excited about this.
ALEIX PRAT: I agree, and I think, I mean, doing retrospective analysis is great and we need to keep doing retrospective analysis in metastatic, no? The AURORA projects in Europe and the US are perfect examples, but we also need to do these prospective trials with, you know, well annotated cohort, with homogeneous treatments. So we can learn, not only the biological features, but also how those biological features are linked to particular outcomes, no? I think that’s going to inform us, really how to move forward. Because, I mean, the TCGA data has been very important for the community. But at the end of the day, it’s just a description of what’s out there, no? What you can find in, in early disease in this particular setting. But we need to link this to outcomes to be able to, to design trials.
LISA CAREY: Well, and you raise an incredibly important point, which is, you know, the evolution of cancers, as they go from the primary setting to the metastatic setting, itself, you know, ignoring the biologic shifts that also happened there. I mean, you know, we’ve seen that, you see subtype shifting, you know, there are acquisition of therapeutically germane, other aberrations. So I, one of the things that you built into HARMONIA, and I’ll admit that I was skeptical at first, was that it’s really done off of the biology in the metastatic disease, which is, of course, the relevant biology that you’re treating at that time. And I think it’s the right thing to do.
ALEIX PRAT: Yeah, and it’s going to be a great opportunity to study the archival tumors and be able to know, have a large data set that we can compare primary versus metastatic. Really study these changes that occur, and we already know, in this report, but we need to link again, those two outcomes, no? A luminal A that becomes HER2-enriched, no? What’s going on? Versus maybe, a luminal B, and they’re choosing just to luminal A in the metastatic that, you see these cases, but, probably in the future, we can, based on that, we can design trials that could change clinical practice in different ways.
LISA CAREY: Maybe you should begin anti-HER2 therapy to the HER2-enriched. Maybe we can, we can get them even better. That’s not part of HARMONIA.
ALEIX PRAT: No that’s not part of HARMONIA. But these are the type of things that we need to think about, because it’s still breast cancer compared to long, single DNA, somatic mutations are not really getting us much anywhere, no? In general-
LISA CAREY: Not in breast cancer.
ALEIX PRAT: Not in breast cancer. So probably we need to go to the RNA, to the proteins, to really characterize these tumors, and develop different different strategies. It is true, no, that there is a lot of confusion regarding HER2 positivity and HER2-enriched. I always get this question, no? Because people use subtyping sometimes, especially in Europe that we can know, some actually report that. And the question is if they can treat these patients with anti HER2 therapy despite being HER2-negative by ASCO cap guidelines no? And I think, always say, I don’t think so. We don’t have the evidence today to do that. If it’s HER2-negative its HER2-negative. But it’s true, I mean, I think we need to, to evaluate if HER2- pathway is activated somehow and we can target it with antibodies or with TKIs. But I think the studies need, they need to be, need to be done. But again, we’re looking at different things because when we talk about HER2-enriched, we’re not really talking about HER2-positivity. We’re talking just about a particular phenotype of the cell, that resembles the classical HER2+/HER2-enriched tumors, but HER2 is not over expressed. So something else is going on-
LISA CAREY: Right, but the HER2 pathway is turned on, right? And some of the data from HER2 activating mutations would suggest that, in fact, maybe not with every anti-HER2 drug, but you can turn that off, and that may be therapeutically relevant.
ALEIX PRAT: Exactly.
LISA CAREY: It’s something people are looking at.
ALEIX PRAT: So regarding HER2 mutations, I’ll be, we’re going to present tomorrow of course the discussion, CT DNA based analysis across the MONALEESA program. So we linked intrinsics of typings and the features of the CT DNA level. And this is interesting because in, in the MONALEESA program, subtyping was done modeling primary tumors, you know? 70% approximately, only 30% were metastatic. Whereas now, in these analyses, we have plasma CT DNA obtained right before starting therapy. And what’s interesting is that when we compare the two, they are similar, or expected, in the sense that what we see in plasma is what we would expect to see in luminal A’s, luminal B’s, HER2-enriched, and basals. If this was done in primary disease, so, for example, when in the MONALEESA program, we say it’s a luminal A at the DNA level in plasma, before starting therapy you see not many copy number alterations, PTC mutation, highly enriched, no, not much PTC mutations, you see the classical features, no? So definitely despite 70% of the tumors in the MONALEESA were primary tumors, they still, you know, helped identifying the right biology. There is subtype switching going on, but it’s probably not going to be for everybody. And that’s why we see this is consistent.
LISA CAREY: Well, the subtype switching on the basis of RNA expression may be different than what you’re seeing at the, at gene level, right? It may all be, you know, something that happens post genetic. And I think that’s, that is one of the things we’re going to learn over time. We don’t really know how to kind of align the DNA, the RNA, proteins, the proteogenomics, the, you know, as we, as we get more sophisticated, I think it’s going to be super important.
ALEIX PRAT: Yeah.
LISA CAREY: Yeah, I’m looking forward to tomorrow. There’s a bunch of these CT DNA-
ALEIX PRAT: Yes, exactly.
LISA CAREY: Trials and- and sort of trying to figure out how to fit, circulating liquid, liquid biopsies into the, into how we approach breast cancer. It’s going to have to be done on a trial basis though. Cause at the moment none of us know what the right thing to do is.
ALEIX PRAT: Exactly, and the issue we have in the metastatic is, you know, biopsying patients on treatment progression this is something that, unfortunately, we should be doing if we could, but it’s challenging in daily practice, no? So if we have a trial that has a unique opportunity to do that, I think we need to do it because it’s going to be very informative and then we’ll see how much value we gain by re-biopsying them. But if we don’t, we don’t show it, it’s hard to do it in daily practice. Another aspect is the hypothesis behind what Ribociclib is doing to really improve PFS. Especially in this highly proliferative luminal B’s and in the HER2-enriched. But not only PFS now, OS, no?
LISA CAREY: OS, yeah.
ALEIX PRAT: I don’t know. I mean, this, this hypothesis, we don’t have the right answer. HARMONIA might be able to help us a little bit more regarding that, but I don’t know what you think about really what’s happening now. These tumors are not anywhere sensitive and then they become, and you extend OS. And you think this is through subtype switching that even remains, this biology, stable at progression, for example, and these patients are responding more after progression. That’s why OS is improved or what do you think?
LISA CAREY: Well, you know, I think you’re, you’re hitting on a really important feature, which is the, you know, the RNA expression, the heterogeneity you see there doesn’t change the fact that, I mean, these tumors all were hormone receptor positive and HER2-negative coming in. We’ve been using clinical features and just as you see HER2+ breast cancers, very heterogeneous. That doesn’t mean anti-HER2 drugs don’t work. So it’s also true that anti estrogen approaches in these tumors, I think, are also appropriate. And it may well be that, you know, I always think of ribociclib and the other CDK4/6 inhibiting primarily helper drugs. They’re assisting the endocrine therapy to be more effective. So these are all still endocrine, you know, for the, except for the basals. We’ll stipulate the basals, we’re probably not, not there yet.
ALEIX PRAT: They’re out of the equation.
LISA CAREY: But it does suggest that the HER2-enriched are still, you know, they are still being driven by similar pathways as you would expect them to be. They’re just more proliferative and more, you know, the, and arguably, you were seeing a little bit more of an effect of the CDK 4/6 inhibitors.
ALEIX PRAT: Exactly.
LISA CAREY: And there may be some differences amongst those drugs, which at the moment, none of us really have a reason to think of them as being particularly different from one another, but these are the kinds of data. And, you know, today, we saw, you know, further analysis of PALLAS, right? Which, you know, the, the monarchE study, in the early setting, with abemaciclib is now holding up as being a positive study, whereas PALLAS, which looks very similar, you know, but using a different CDK4/6 inhibitor, in the adjuvant setting, is a negative study. Where, in the metastatic setting, they both seem to behave the same. So, I think we are starting to see some sunlight between, between and among the CDK4/6 inhibitors that may be helpful for us to choose amongst them in the future.
ALEIX PRAT: Yeah. And also we’re waiting for non-metastatic data, still the OS data from ribociclib, abemaciclib, you know, the first line. So, that, I think, is going to tell us, you know, there are differences in that setting, that you start seeing some differences, no? Palbo potentially being less effective in the endocrine resistant context. Abema, ribo, maybe, super analysis I know, but there might be these things now, the adjuvant data, we’ll see that future OS data for, for the first line in palbo and abema. But, anyway, I do think that this concept is there and this drug, at the end of the day, have different toxicities, no? And the dose is different, despite the chemical formula is looking quite similar. So maybe we’ll, we’ll be able to show.
LISA CAREY: We’ll have more sophistication in the future.
ALEIX PRAT: Yes, more sophistication in this regard using biology potentially to selecting patients. I think that’s what, that’s something that we need to explore.
LISA CAREY: Definitely, definitely. Well, thank you, Aleix.