Comprehensive insight on the neoadjuvant treatment armamentarium for early-stage HER2+ breast cancer and the appropriate selection of specific agents.
Sara A. Hurvitz, MD: To finish up this pushing the edge of the envelope, how far will you go? Are you, Sara, using your APT regimen, paclitaxel, and trastuzumab in the neoadjuvant setting for tumors that appear to be node negative but close to 2 cm? Are you trying to de-escalate, see how far you can get that response to be to give you the opportunity to use T-DM1 [trastuzumab emtansine] after surgery if they don't have a full response?
Sara M. Tolaney, MD, MPH: Generally, not for the clinical stage 1 patients. Our group has instead been doing more like the Compass-pCR design. If you take someone who you would give preoperative therapy to—let's say someone with a 1.5 cm or larger tumor or has nodal involvement—that we're instead using THP [docetaxel, trastuzumab, and pertuzumab] and for 12 weeks and then taking them to surgery. Then if they have residual disease, giving TDM1 for many of those early stage 2 patients, for example, or giving HP [trastuzumab and pertuzumab] out back and if they achieved PCR. This is based on a little bit of preliminary data now we have from the ADAPT trial, as well as from DAPHNE which had shown us that in fact with THP, in generally early-stage HER2-positive cancers outcomes are fabulous rates of pCR are high. DAPHNE was about 60% in the overall population but almost 80% in the hormone receptor-negative patients—very similar to ADAPT. Then in ADAPT, the long-term outcomes look outstanding. We need further data. I do want to see data from Compass-pCR and DECRESCENDO to show that this approach is reasonable. In general, we're doing it not in the big stage 3 tumor patient, but more someone who falls into this early stage 2 or larger stage 1 patient group, and I think it's a really nice approach. One could argue, is pertuzumab really needed? At your point, why not just give them T [trastuzumab]? Especially if they end up being node negative, where we know that pertuzumab probably isn’t adding. I think the problem is you just don’t know in the preoperative setting what their nodal status really is. For the most part, we're just throwing on the pertuzumab because we don't know, and we just want to make sure we've covered ourselves there. This may be the movement of the future, at which case we may be changing our threshold for who gets preoperative therapy. Maybe we're willing to come down a little bit smaller if we're giving less therapy, but again, I'd love to see long-term data from Compass-pCR to know that this is really a validated approach, and so many of our patients enroll into that trial at this time.
Sara A. Hurvitz, MD: We have a lot of very exciting studies in this setting that I think in the next 3 to 4 years, we'll have so much more to talk about in terms of which regimen for which patient. Bill, can you take us through what your neoadjuvant regimen of choice is for a patient whom you'll treat in that setting?
William J. Gradishar, MD: It might still be viewed as the standard for most patients as TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab]. The last minute or so where Sara was describing the circumstances where she would use a THP-like regimen preoperatively, there are patients where we're a little bit concerned about the addition of adding the C [carboplatin] to the TCHP regimen, and maybe having more toxicity than a given patient can tolerate. Of course, we're looking for the results of those same trials to validate the thought that you can de-escalate the chemotherapy part of neoadjuvant therapy. But, I would still say that for the majority of patients, we’re giving TCHP, and we’re enrolling a lot of patients on the COMPASS trial. I like that regimen and patients are doing well on it. Over time, I would predict that we're probably going to migrate towards that if the data from that trial is supportive.
Sara A. Hurvitz, MD: It is interesting. They look at the small but maybe practice-changing data from TRYPHAENA indicating the TCHP regimen for ER/PR-negative like this patient. HER2-positive was on the order of 80%, so we are seeing high past CRS [cytokine release syndrome] without the use of an anthracycline, which can have uncommon but significant cardiac toxicity. Are you ever using an anthracycline for your patients in the neoadjuvant setting, Sara? Have you moved away from this practice now? What are your thoughts?
Sara M. Tolaney, MD, MPH: Even us on the East Coast have gotten rid of anthracycline. It took us a while—a lot longer than those of you on the West Coast—but we have stopped using it. Now, having more data has made us feel a little more comfortable. Initially, we saw data from BCIRG006 at least comparing TCH [docetaxel, carboplatin, trastuzumab] to ACTH [doxorubicin, cyclophosphamide, paclitaxel, trastuzumab] and at that time, we did see that the anthracycline was associated with more cardiac toxicity, but certainly not unnecessarily improved and disease-free survival. Now in a more modern treatment regimen with TRAIN-2, you see even in people getting dual HER- directed there being a preoperative setting comparing a taxane-based therapy to anthracycline-based therapy. You see identical long-term outcomes with much less toxicity. In fact, there was less febrile neutropenia, there was less cardiac toxicity with the non-anthracycline regimen. I think seeing this data is really important. We can also reduce secondary leukemias by omitting and recycling. Without seeing an improvement in outcome, and I don't think there's any reason to think about anthracyclines anymore for almost all our HER2-positive patients. There are some who continue to argue that maybe for an inflammatory breast cancer they may consider anthracycline therapy but, I'd argue we don't really have data for that necessarily, and our group has done some work with non-anthracycline therapy. NIBC [noninflammatory breast cancer] is also showing very high PCR rates, so I think we've come to an end of an era for anthracyclines and HER2-positive disease.
William J. Gradishar, MD: I would echo that, in the middle of the country between the 2 opposing forces, I can't remember in this setting where we used an anthracycline as part of neoadjuvant therapy. It's been several years now. As Sara said, that's gone away; with it, we've maintained the efficacy and potentially decreased some of the toxicities that were most worried about.
Sara A. Hurvitz, MD: Bill, are you using pertuzumab or dual HER2-targeted therapy for all your patients in the neoadjuvant setting, even those with node-negative disease?
William J. Gradishar, MD: As a general statement, I would say yes. Of course, there are individual patients where we're worried about tolerance for some reason, where it either gets dropped or we try something like a TH [docetaxel, trastuzumab] regimen. No, I don't do that frequently; there has to be some circumstances that would justify that decision-making. For most patients, I do use dual HER2 targeting in the preoperative setting.
Sara A. Hurvitz, MD: We do know that it improves CR [complete response] rates, maybe a little more febrile neutropenia with the chemotherapy, but I would agree with that. I think I saw Sara nodding her head as well.
Transcript edited for clarity.