William J. Gradishar, MD: There are many reasons why we would consider using neoadjuvant therapy, or preoperative chemotherapy, for patients with early stage breast cancer. Part of the rationale is dependent on the subtype of breast cancer that’s present, even though hormone receptor—positive breast cancer could be subjected to or considered for preoperative chemotherapy. At least in the United States, that’s relatively uncommon. It is perhaps used less than it should be. Whereas for triple negative breast cancer and HER2-positive breast cancer, we’re much more inclined to use preoperative therapy. The rationale for using preoperative therapy very broadly is 2-fold.

One instance is with patients who have operability that’s plus-minus, meaning that you’re considering doing breast conservation therapy but the tumor size to the breast size is such that the cosmetic outcome may be suboptimal. In those situations, giving preoperative chemotherapy with or without other agents may put a patient in a position where the cosmetic outcome would be much better by shrinking the tumor prior to surgery. Otherwise, that patient may end up getting a mastectomy, or the outcome following a lumpectomy may not be optimal.

Of course, the other rationale for giving preoperative therapy is that it not only accomplishes that, but you start the systemic therapy early. We do know that patients who receive preoperative therapy and are rendered with a PCR, or pathologic complete response—particularly if they’re HER2 positive or triple negative—tend to have a better overall long-term outcome. Understanding what the biology of the disease is based on and how it responds to therapy may give us some insight to how that patient may do over the long term.

Specifically with respect to HER2-positive disease, we generally consider giving preoperative therapy for patients who have tumors that are 2 cm or greater or positive lymph nodes. There are perhaps some patients, although there are relatively few, who have much smaller tumors where preoperative therapy would be considered. In other words, stage I disease.

What we do know, as I mentioned earlier, is that of patients who receive preoperative therapy—even with HER2-positive disease, where we’re combining that with HER2-targeted agents—those who are rendered with a PCR, with no evidence of disease at the time of surgery, tend to have a very good outcome. We’re much more inclined, and that’s evolved over the last few years, to be using more and more preoperative therapy. We’ve even come to the point where we recognize that if you do receive preoperative therapy and have residual disease present, we have strategies to try to treat those patients differently from how we did in the past.

If a patient receives preoperative HER2-directed therapy, it’s typically with chemotherapy, trastuzumab [Herceptin], and pertuzumab, and there’s a very high pathologic complete response rate, probably in the 50%-or-greater range. But that also implies that there is a fraction of patients obviously who do not have all disease resolved at the time of surgery. Based on the KATHERINE trial, we know that in those patients who have residual disease, rather than continuing the full year of Herceptin and pertuzumab, switching the patient to trastuzumab emtansine may result in a much better outcome. So we’ve evolved our strategies for taking care of patients with HER2-positive disease, not only in the front end preoperatively but also in those patients who have residual disease following surgery.

Most women who have stage II or III disease are going to get a recommendation for preoperative therapy. I suppose the only situation in which we would not do it is where the patient was very nervous about having her surgery done. But that has to be balanced against what the cosmetic outcome might be. If a patient is very clear that she wants a mastectomy, no 2 ways about it, in that situation shrinking the tumor may not be as relevant for a cosmetic outcome, because we know what the surgery is going to be. But as I mentioned earlier, if they have a stage II or III tumor, we would try to shrink it to optimize the cosmetic outcome, so that breast conservation would look good. You’re much more likely to achieve that goal if you do preoperative therapy.

Transcript Edited for Clarity