Ian E. Krop, MD, PhD: Based on the KATHERINE data, in which knowing the results of neoadjuvant therapy allow us to decide whether patients should or should not receive adjuvant trastuzumab emtansine [T-DM1], we really should be treating virtually all patients with stage II or higher HER2-positive breast cancer in the neoadjuvant setting. Because without that result of whether patients receive a pathologic complete response [path CR] or not, you can’t tell who would benefit from adjuvant T-DM1. I do think that the standard of care now for patients with stage II or higher HER2-positive breast cancer is to treat in the neoadjuvant setting. That brings up the question, what is the optimal therapy to use in the neoadjuvant setting? I don’t think there’s 1 right answer to this case. In general, any of the regimens that people are comfortable with in the adjuvant setting can be used in the neoadjuvant setting. That typically means either an anthracycline regimen or a nonanthracycline regimen.

In the United States, the 2 standards would be an anthracycline regimen such as doxorubicin and cyclophosphamide, followed by paclitaxel and trastuzumab with pertuzumab, or a nonanthracycline regimen, which is typically TCHP, or docetaxel, carboplatin, trastuzumab, and pertuzumab. Both of those regimens have been showing very good pathologic response rates. The toxicity profiles are slightly different between the 2 regimens, but it’s hard to make a strong recommendation that 1 regimen is better than another. Certainly, in a patient who is at higher risk for cardiac toxicity from anthracycline would be better served by using a nonanthracycline regimen such as TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab].

Sara A. Hurvitz, MD: A number of regimens have been evaluated in the neoadjuvant setting for HER-positive breast cancer. We have anthracycline-based regimens, such as 5-fluorouracil, epidoxorubicin and cyclophosphamide, followed by a taxane, trastuzumab, and pertuzumab. We have the TCHP regimen, which is anthracycline sparing of docetaxel, carboplatin, trastuzumab, and pertuzumab for 6 cycles. A number of other regimens have been looked at, including AC [doxorubicin, cyclophosphamide] followed by taxane, trastuzumab, and pertuzumab. I think clinicians would universally agree that a HER2 doublet remains the standard of care in the neoadjuvant setting because of the improved path CR rates. Of choice, and the 1 that’s recommended, is trastuzumab and pertuzumab.

But in terms of the chemotherapy backbone, there’s wide variation in what clinicians will ultimately choose. My preference is the nonanthracycline taxane-based regimen TCHP, because the therapeutic index is better. It has a lower risk of cardiac toxicity and a lower risk of leukemia and myelodysplasia. And we don’t have evidence that addition of the anthracycline provides an incremental benefit to these patients in terms of path CR rate. Case in point, if you look at the randomized studies that have compared anthracycline with nonanthracycline—the TRAIN study and the TRYPHAENA study—these weren’t enormous studies, but the path CR rates were neck and neck with one another in these clinical trials. And then the large adjuvant study of anthracycline-based therapy versus nonanthracycline docetaxel, carboplatin, and trastuzumab provides support that we’re going to get very similar efficacy.

The neoadjuvant setting is unique because we can follow a patient’s response to therapy. If we have a rare patient whose tumor is not shrinking appropriately on TCHP, certainly transitioning the chemotherapy to an anthracycline-based chemotherapy would be appropriate. We have the luxury of being able to watch the in vivo response as it’s happening, and that makes us smarter clinicians when we’re recommending a therapy.

Ian E. Krop, MD, PhD: Clearly in patients receiving neoadjuvant chemotherapy and trastuzumab and pertuzumab, there are potential toxicities. We have the toxicities of chemotherapy, which we’re all familiar with. And there the question is whether we have a risk of anthracycline-induced cardiac toxicity or the toxicities that go along with taxanes. The question we’ve been working with lately is now that we’re incorporating pertuzumab into regimens, that adds its own set of toxicities, including higher rates of diarrhea and rash.

In general, the toxicities of pertuzumab seem most pronounced in combination with chemotherapy. Once pertuzumab and trastuzumab are being used in the adjuvant setting, it becomes much less of an issue. In my practice we typically use Imodium [loperamide] to manage the diarrhea of pertuzumab, and that’s quite effective. It’s quite rare these days to have patients who have diarrhea that’s intractable and requires holding or discontinuing the pertuzumab. I do think now that we’ve all become familiar with these regimens, they’re quite manageable. I do make sure patients have access to Imodium and that they know how to use it effectively, and that seems to be adequate for most patients.

Overall, there’s certainly a movement within our field to try to de-escalate therapy, because patients with HER2-positive disease are doing quite well, and many of them have a pathologic complete response with 1 of these 2 standard adjuvant regimens. It brings up the question, do they all need so much chemotherapy? I think that there’s an interest in cutting back on the amount of chemotherapy. There is a trial that’s getting under way in the United States that’s looking at just 12 weeks of paclitaxel with trastuzumab and pertuzumab, and for those patients who have a pathologic complete response, the trial is asking whether they don’t need additional chemotherapy in the adjuvant setting as a way to potentially identify patients who can get by with a limited amount of chemotherapy. Those are cancers that are very sensitive to drugs like trastuzumab and pertuzumab. These de-escalation strategies hopefully will allow us to cut down the toxicity without sacrificing efficacy. I think we’re all hoping to get to that type of standard of care in the near future.

Transcript Edited for Clarity