HER2-Targeted Therapy in Early Stage HER2+ Breast Cancer

Transcript:Adam M. Brufsky, MD, PhD: So, let’s move on to HER2-positive breast cancer. And I think that the questions that have been asked in the last couple of months to years with this is, what do we do with the triple-positive, the HER2-positive, and ER-positive group of patients in the early stage? There was a neoadjuvant study that was presented, B-52, at the San Antonio Breast Cancer Symposium, and it was a chemotherapy, TCHP (docetaxel/carboplatin/trastuzumab/pertuzumab). And in the ER-positive subgroup, they did either tamoxifen with an LHRH (luteinizing hormone-releasing hormone) agonist or with an aromatase inhibitor. And so, what do you guys think about that trial? I’ll tell you what the result was. There was no difference in pCR. It was kind of a negative study. Did that surprise anybody?

Kimberly L. Blackwell, MD: Again, it was an equivalent setting. I’ll go back to the days when the bone marrow trials came out. They said transplant trials, they were equivalent, so it wasn’t like we were harming women by depleting their estrogen levels. But I think this remains one of the biggest black boxes in breast cancer biology. The number of lectures I go to in any given month about how ER has cross-talked with the HER2 pathway, you can almost come up with any story. And this is going to be relevant not only in the metastatic setting, but also in the early stage setting. We saw this from B-52. And then we have the ExteNET study coming down the path, which is the addition of neratinib really benefitting in the extended HER2 blockade setting, really benefitting the ER-positive patients the most. So, is there some interface? Yes. Do we understand it? I don’t think we do, and you can model it in oophorectomized mice all day long. That was the basis of B-52, which is take out the ovaries, add some lapatinib, add some trastuzumab, and you always see some synergy and anti-tumor effects. The B-52 study failed to show us a benefit in that. I guess the reason I was picking on the equivalence is at least for some women where preservation of ovarian function is important, some of us would feel comfortable utilizing an LHRH agonist. And at least what we didn’t see was a huge detriment in the pCR rate. They were equivalent. It really had no effect. That’s disappointing, but at the same time not surprising, given how little we know about the interaction between ER signaling and HER2 signaling.

Adam M. Brufsky, MD, PhD: With ER-positive disease, is pCR even an endpoint that we should be using, Mark?

Mark E. Robson, MD: I think in ER-positive, HER2-negative, probably not. In triple-positives, I think that’s an open question. I think the challenge is that triple-positive disease is very heterogeneous, and that’s what the PAMELA study is talking about.

Adam M. Brufsky, MD, PhD: Can you tell us about PAMELA, the design?

Mark E. Robson, MD: It’s single-agent HP (trastuzumab/pertuzumab) and looking at whether or not PAM50 is predictive of pCR. In just the group of patients that were truly HER2-enriched in the triple-positive subset, those were the ones who appeared to benefit from the therapy, whereas those who are not don’t. And I think, over the years, we’ve expanded our definition of HER2 positivity from the pathology standpoint to avoid missing people who could potentially benefit from anti-HER2 therapy or HER2-directed therapies. But in doing so, we may well have cast a net to include people who aren’t going to benefit because their tumors aren’t really HER2-driven. In this triple-positive subset, you probably enrich for folks who are not going to necessarily have HER2-driven disease.

Adam M. Brufsky, MD, PhD: Well, it was overall. It was interesting. Only about 57% to 60% of the people who were in PAM50, which was a phase II trial of HP in the neoadjuvant setting, I think for 6 cycles, were looking at pCR as an endpoint. And in PAMELA, it was interesting that only 60% of the people were HER2-enriched, and they were really the only ones that had a pathologic CR. Some people will ask, “Should we be using PAM50 now? Should we be intrinsic subtyping everybody now?” What do you think? A patient walks in with an HER2-positive tumor, triple-positive. Should we intrinsically subtype them?

Kimberly L. Blackwell, MD: In the United States, I think one of the problems with expanding what defines HER2-positive is that we are now obligated, unfortunately. I see one patient a week with a node-negative, ER-positive breast cancer. I saw one yesterday; grade 1, but HER2, ratio 2.1, 2+ equivocal on IHC. And so, the discussion has to be that the standard of care is to utilize trastuzumab for the treatment of your early stage breast cancer. Until we have a real validation study, it’s what we all kind of see. We have the patients that are ER-positive, HER2-positive. You either give them TCHP or your favorite neoadjuvant, and then that thing melts away. And then there’s the other patient who you restain the residual tumor and guess what, the HER2 FISH comes back negative and you’re stuck giving them an anthracycline because, really, they’re more either triple-negative in that case. So, I thought PAMELA mirrored what we’re seeing in the clinic anyway.

Adam M. Brufsky, MD, PhD: I hate to bring this in. What about MammaPrint, the 70-gene assay? I’m going to come back to this. I’m focusing on it, and I’m focusing on it for this reason. In that study, I think there were 500 or 600 patients who were HER2-positive—and most of them were ER-positives, as well as triple-positive—23% of those were low genomic risk, which is similar to the retrospective studies they’ve done with the 70-gene assay in the past. So, those are people you wouldn’t give chemotherapy to, right? Would you give chemotherapy to someone like that who comes in that door with a grade 1, 1 or 1.5-cm T1c tumor that’s HER2-positive?

Kimberly L. Blackwell, MD: Yes, I would.

Adam M. Brufsky, MD, PhD: Even if low genomic risk?

Kimberly L. Blackwell, MD: Yes, I’d follow the ASCO guidelines on this subject, Adam Brufsky.

Adam M. Brufsky, MD, PhD: But if they’re low genomic risk, you still would do that? At the risk of over treating them.

Kimberly L. Blackwell, MD: Yes, I would because I don’t think we have a differentiating assay at this point.

Adam M. Brufsky, MD, PhD: So, the MammaPrint isn’t differentiating?

Kimberly L. Blackwell, MD: To be quite honest, there are doctors out there that are getting sued because they did not offer trastuzumab for an early stage, like a T1c, N0, and the cancer comes back. And those patients, you just don’t know. So, very practically, yes, I would.

Mark E. Robson, MD: And I certainly don’t think, given what we talked about with the limitations of the predictive ability of the assay for chemotherapy benefit, trying to hone down…

Adam M. Brufsky, MD, PhD: Admittedly, there are a few that are retrospective. There are a couple retrospective trials that do the same thing, and now you have a prospective trial. You’ve got 3 independent studies. I don’t know. I’m not going to do it for someone with a lot of nodes, but if someone comes in, like the patient Kim talked about…

Kimberly L. Blackwell, MD: But those are the patients that were enrolled on the weekly paclitaxel/TRAS study, right? They did extremely well. Who knows if they did well because they got trastuzumab or because they were less than 3 cm, ER-positive.

Adam M. Brufsky, MD, PhD: And 67% of those patients were triple-positive.

Kimberly L. Blackwell, MD: We don’t know.

Mark E. Robson, MD: I think many of us, in our heart of hearts, think you’re probably right. But given the data as they exist right now…

Adam M. Brufsky, MD, PhD: Correct. We’re a conservative bunch, I agree.

Mark E. Robson, MD: Well, the thing is when you have a success, it’s hard to back away.

Adam M. Brufsky, MD, PhD: Right, I agree. I totally agree with you.

Aditya Bardia, MD, MPH: And especially if you have an agent like trastuzumab, which has relatively no toxicity, I think you need to have a very strong reason not to give it.

Mark E. Robson, MD: And 12 weeks of Taxol and trastuzumab is really pretty well tolerated.

Adam M. Brufsky, MD, PhD: It is, I agree. Just hair loss, that’s about it.

Transcript Edited for Clarity