Case 1: Adjuvant Therapy for Residual Disease in HER2+ Breast Cancer

Hope Rugo, MD, FASCO: I think we all are using, as you mentioned, T-DM1 [trastuzumab emtansine] in patients who’ve failed to have a pathologic complete response [pCR]. This patient had a pathologic complete response. I think it’s really easy to decide what to do when a patient has positive nodes or a big tumor left. But as was seen in KATHERINE much more frequently in patients with ER [estrogen receptor]–positive disease—which represented 70% of the patients in KATHERINE—and is as we expected from prior trials but something I have faced in clinic that’s an issue is patients who have 0.3 centimeters of disease left, a T1a tumor. What do you do with those patients? Adam?

Adam Brufsky, MD, PhD: That is the question right now, and I think it’s a tough question to answer. My thought process is right around T1a, but I think that we are even starting to think about extending it to T1b tumors. As we know from KATHERINE, even patients with T1a, T1b residual disease appear to benefit from T-DM1.

It’s a great question, and it really depends on what you think of the biology. Are you really thinking it’s a resistant disease? Or do you think maybe if you gave 1 more cycle of TCHP [docetaxel, carboplatin, trastuzumab, and pertuzumab]—maybe 7 instead of 6 cycles—whether they had a pCR? That’s the debate. There is no right answer to this. Right now, for T1a tumors I’m probably not. But after that, I think I probably would give it.

Hope Rugo, MD, FASCO: How about you, Ian?

Ian Krop, MD, PhD: I agree that it philosophically feels like there probably should be some lower limit. But if you look at the KATHERINE subgroup data—although they didn’t break it down quite as precisely as I think we would like—if you look at the group that’s node-negative and T1a or T1b, the difference in absolute IDFS [invasive disease-free survival] was something like 4% or 5%. So they weren’t able to identify a group that didn’t seem to benefit from T-DM1. I think one would just assume, intuitively, that the benefit’s going to be smaller in the patients with less disease.

Adam Brufsky, MD, PhD: That’s the mystery. For T1a, is it really a 4 or 5, or is it like a 1 or a 2? And is 1 or 2 worth it for a year of this? That’s the whole problem.

Ian Krop, MD, PhD: Right. I guess my feeling is that given the data we have, we weren’t able to identify a group that didn’t seem to benefit. And in truth, with the added toxicity of 14 cycles of T-DM1 compared to 14 cycles of HP [trastuzumab and pertuzumab]—and we can get into whether we should be using HP in that setting—it’s really not that different. And if you get 6 or 8 cycles of T-DM1 in and the patient stops because they’re one of the 18% or 20% who can’t do the whole 14 cycles, and you have to switch to trastuzumab or HP at that point, it’s not the end of the world. So I typically am still using T-DM1 for virtually all patients who have more than isolated tumor cells left over.

Hope Rugo, MD, FASCO: We have been, too. I think it seems like a small tradeoff for us now. The cost is not as big of an issue for us as it might be in other countries, but it’s still an ongoing issue.

I’m going to close up this particular case with a question to each of you, and I just want a very short response. Adam, is there a patient whom you would give neratinib after 12 months of adjuvant therapy? And if so, which type of patient?

Adam Brufsky, MD, PhD: Yes. ER-positive with substantial residual disease. We know 50% of the patients who are ER-positive will not have a pCR. Now, the real question becomes, “How much residual disease do they have?” If it’s substantial, I will offer them adjuvant neratinib. When it comes down to it, that is maybe 15%, 20% of the patients I take care of. I think the big problem in doing it is the diarrhea, but we’re kind of getting there. I think with the dose escalation and with the other antidiarrheals, we’re really getting to a point where we can manage this. But I think what’s happened is a lot of women, after a year of doing their therapy, are tired and want a break. So it has been a tougher sell, to be honest with you, than anything else. That’s the biggest issue. But from a medical standpoint, the data are pretty clear.

It’s not clear with pertuzumab. I have to agree. But I'll tell you, in the right patient, it’s offering a substantial disease-free survival benefit—probably 4% or 5% in the limited subset of patients who had neoadjuvant therapy next to that. There’s something there that I think can be offered.

Hope Rugo, MD, FASCO: I think that’s really interesting, and I think there is a group of patients for whom we still feel like we’re not really meeting our goals and providing the best, like a curative setting, where they have this residual disease. But what about the other end of things? Ian, in a very quick response, if somebody has a past CR, do you always continue a year of H and P?

Ian Krop, MD, PhD: To me, that’s actually the bigger controversy. It affects more and more of our patients. My thinking is if they were a high enough risk patient at the beginning to give them neoadjuvant therapy with the addition of pertuzumab to your regimen, meaning that they were either node positive or largely clinically node negative, then I think it makes sense to continue the pertuzumab even after a pathologic complete response. That’s based on 2 reasons. One reason is because the only good long-term data we have on the benefits of pertuzumab are from APHINITY, and that used a year. Whether you’re getting it as neoadjuvant or adjuvant doesn’t really matter.

And this is the patient population who clearly has shown sensitivity to their dual HER2 therapy. So for those 2 reasons, I think it makes sense to continue the pertuzumab. But if you start out with a low-risk patient, maybe you shouldn’t give pertuzumab in the neoadjuvant setting. Or if you do, then that would be a patient for whom it would make sense to stop it and just give trastuzumab for the rest of the period.

Hope Rugo, MD, FASCO: Thanks very much. This is a fascinating discussion. It’s going to also be very interesting to see the new studies that are looking to de-escalate responders and looking at oral TKIs [tyrosine kinase inhibitors] to try and reduce CNS [central nervous system] recurrence, which—although occurring in a small number of patients—appears to still be occurring at about the same percent. It’s going to be interesting to continue to see the progression of treatment options for early-stage HER2-positive breast cancer.

Transcript edited for clarity.