Refining Neoadjuvant Chemotherapy for HER2+ Breast Cancer


Adam M. Brufsky, MD, PhD, FACP: Now we’re going to change gears and talk about HER2-positive breast cancer. I think there were some interesting abstracts at San Antonio, both in the early and late stages of HER2-positive disease. I think the first one is that neoadjuvant therapy for HER2-positive breast cancer has been a tremendous success. I think what we’re trying to do now is refine it, and there were some data that were presented on the optimal chemotherapy backbone for the use of trastuzumab/pertuzumab. Francisco, do you know anything about that trial?

Francisco Esteva, MD, PhD: There was a retrospective study from MD Anderson looking at the different combinations with THP, taxane/Herceptin/pertuzumab, compared with the same plus carboplatin, TCHP, or THP followed by an anthracycline. This was a retrospective study but they had a decent number of patients, more than 200 patients. The pathologic complete response rate was higher in patients treated with THP, which was a little bit interesting because you would think TCHP or THP followed by AC would give you a higher pathologic complete response. So, that was reassuring.

How those patients were selected, and why, is the question, because of course you select the patients well. You’re a smart doctor. Maybe that’s all they need. But it’s something to keep in mind that some patients may do very well with THP, like they did in the NeoSphere trial, which was the FDA registration trial for pertuzumab. After surgery in that trial, the patients got FAC chemotherapy. But maybe they don’t need FAC chemotherapy if they achieve a pathologic complete response. So, I thought it was interesting.

Hope S. Rugo, MD: It’s interesting, because if you look at the data from APHINITY and NeoSphere, etc, the grade 3 diarrhea rate when you add carboplatin and use docetaxel is around 18%.

Francisco Esteva, MD, PhD: It’s very high.

Hope S. Rugo, MD: You have it, more or less, just by using the weekly paclitaxel/trastuzumab/pertuzumab regimen. You still see diarrhea, that’s the thing, and you still see some at grade 3. But it’s just so much better tolerated. So, I love the idea that less is more. You do some kind of induction, look at response—as you’re talking about—and then you could actually parse patients, based on their tumor characteristics and, of course, tolerance, into different therapies. We had a woman who was in her 70s who really had terrible scoliosis and bad medical care over time. She just got THP and had a pCR, which is great because then she dropped her ejection fraction.

Adam M. Brufsky, MD, PhD, FACP: So, do you use THP with paclitaxel or with docetaxel?

Hope S. Rugo, MD: With weekly paclitaxel, because I don’t give docetaxel to old ladies.

Lee Schwartzberg, MD, FACP: I actually have a patient I’m treating right now who is in her mid-70s and has T2, N1 HER2-positive cancer, and I actually like docetaxel and I’ve gotten comfortable with it. Although weekly paclitaxel I certainly like for low-risk patients, too, but it’s a little bit easier every 3 weeks. Obviously, the diarrhea is an issue. I thought I’d give her the first cycle and see if we could add the carboplatin because she was at high risk, and she couldn’t. I saw her this week and we got cycle 3 in, and we’ll do cycle 4. As you say, Francisco, the results are very good with single-agent taxane, Perjeta [pertuzumab], and Herceptin.

Adam M. Brufsky, MD, PhD, FACP: So, when you give the THP, when you give weekly paclitaxel in that regimen, do you do it continuously or do you give them a week break? Do you want to do it like in the metastatic setting?

Lee Schwartzberg, MD, FACP: No, no, no, 12 weeks.

Hope S. Rugo, MD: Continuous.

Francisco Esteva, MD, PhD: We’re doing it continuously. At New York University, we generally give weekly Taxol [paclitaxel], trastuzumab, and pertuzumab for 12 weeks and then dose-dense AC before surgery. But it’s true that some patients may not need it. It’s hard to tell.

Hope S. Rugo, MD: And now, we’re just starting to explore that. It’s really been a relatively recent change. We do the same, but we always give the paclitaxel first.

Adam M. Brufsky, MD, PhD, FACP: Do you give the pertuzumab?

Hope S. Rugo, MD: Then we give the pertuzumab, 4 doses, and then we give dose-dense AC, right? But if somebody has a pCR essentially by examination and imaging after their THP, it’s hard to give them AC, especially for older patients.

Adam M. Brufsky, MD, PhD, FACP: Why give AC at all?

Hope S. Rugo, MD: Well, that’s the big issue.

Adam M. Brufsky, MD, PhD, FACP: Should we be giving AC?

Lee Schwartzberg, MD, FACP: I’m still an anthracycline adherent in general, but I think if you look at BCRG-06, there’s a 2% numerical benefit. It wasn’t compared. It’s hard to say a nonanthracycline regimen is better, but they’re probably comparable. The thing that I worry about is actually tumor heterogeneity and whether we should be giving AC for those patient populations that have variable HER2 in their tumor, particularly larger tumors where there’s more likelihood.

Hope S. Rugo, MD: That’s a different case. In triple-negative disease, I’m a big anthracycline fan.

Adam M. Brufsky, MD, PhD, FACP: But for HER2-positive treatment in NeoSphere, and I think the other one was TRYPHAENA, if you were ER-negative/HER2-positive, you got either THP or TCHP. You had a pCR rate of around 70% to 80%.

Lee Schwartzberg, MD, FACP: 70%, right.

Adam M. Brufsky, MD, PhD, FACP: Without an anthracycline. Remember, they got all the anthracycline afterwards.

Francisco Esteva, MD, PhD: That was in the TRYPHAENA study, but the primary endpoint was not pCR, it was cardiac safety.

Hope S. Rugo, MD: TRYPHAENA was small.

Francisco Esteva, MD, PhD: It was a very small study.

Lee Schwartzberg, MD, FACP: 70 patients.

Hope S. Rugo, MD: Yes, 70 patients in each arm.

Francisco Esteva, MD, PhD: The problem with NeoSphere is that they got THP, then surgery, and then FAC, so we don’t know what would be the pCR. In a way we have to extrapolate a little bit, but I don’t like Taxotere [docetaxel anhydrous] and carboplatin in general.

Hope S. Rugo, MD: Because of toxicity.

Francisco Esteva, MD, PhD: Because of the toxicity. So, the weekly Taxol/trastuzumab/pertuzumab and AC, we find, is relatively easier.

Komal Jhaveri, MD, FACP: It’s gentler, I agree. I think I agree with Lee. I’m still an anthracycline adherent, and I think the follow-up analyses of the event-free survival from the NeoSphere data—despite giving THP, surgery, and FAC—still did not meet the EFS endpoint at the follow-up time point.

Adam M. Brufsky, MD, PhD, FACP: But they were numerically superior.

Komal Jhaveri, MD, FACP: They were, and I’m not saying that we should not de-escalate. I definitely think that there is room for de-escalation, and that’s where we should be focusing our biomarker work on. But as it stands now, I do think that I’m adherent to the anthracycline. The problem with docetaxel, just a last point about that, is not only the diarrhea, but as we have seen in the metastatic as well, the febrile neutropenia is also a definite PI.

Adam M. Brufsky, MD, PhD, FACP: At least in my practice with THP, we give growth factor to everybody.

Lee Schwartzberg, MD, FACP: I agree, we give growth factor to everybody, TCHP.

Adam M. Brufsky, MD, PhD, FACP: So, what you’re saying is if someone has a pCR, they need more therapy? You’re still giving anthracycline? Why?

Lee Schwartzberg, MD, FACP: But do they need anything? Do they need maintenance trastuzumab?

Komal Jhaveri, MD, FACP: We continue to give all therapy up front, so I haven’t really changed my practice yet to break it down.

Hope S. Rugo, MD: The studies now are looking at a parsing out, a triage. We have to make a change. We don’t want to do everything for everybody and just add more. So, what we could do is say, “OK, we’re going to start with something and then we’re going to triage based on your response.” For the really good responders, OK, we’re done. For the patients who have an intermediate response, we’re going to do this. For the patients who have no response, we’re going to look for alternative therapies and try and overcome resistance. I actually think that’s an incredibly important step for us to take now.

Adam M. Brufsky, MD, PhD, FACP: I agree.

Lee Schwartzberg, MD, FACP: pCR is such a good biomarker in HER2-positive disease, so why not use it to either escalate or de-escalate?

Adam M. Brufsky, MD, PhD, FACP: That’s what I’m asking. Speaking of de-escalation—before we go to that, because we’re going to go to the adjuvant setting in a minute—is there any role for HER2 TKIs, at this point in time, for neoadjuvant therapy? Are either neratinib or lapatinib used, at this point in time, as neoadjuvant therapy? Not adjuvant but neoadjuvant?

Hope S. Rugo, MD: I don’t think so right now.

Komal Jhaveri, MD, FACP: Right.

Lee Schwartzberg, MD, FACP: I would agree.

Adam M. Brufsky, MD, PhD, FACP: So, no one would use it off trial? No.

Francisco Esteva, MD, PhD: No.

Komal Jhaveri, MD, FACP: No.

Adam M. Brufsky, MD, PhD, FACP: We agree. There are not a lot of data. There are a lot of data showing a slightly increased pCR rate, but not survival benefit. I think we’re all in agreement.

Transcript Edited for Clarity

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