Expert Emphasizes Importance of Neoadjuvant Therapy in HER2+ Breast Cancer

Patrick I. Borgen, MD

Neoadjuvant strategies are underutilized in the treatment of HER2-positive breast cancer, says Patrick Borgen, MD.

Recent data have suggested that pathologic complete response (pCR) may be a reliable intermediate biomarker. Both the NeoSphere and TRYPHAENA trials showed that there was a high pCR rate in patients with HER2-positive breast cancer receiving a neoadjuvant pertuzumab (Perjeta) regimen.

OncLive: If a patient undergoes testing and it comes back that they have HER2 expression, what are some of the first things that you are thinking about?

In an interview with OncLive, Borgen, chair, Department of Surgery, director, Breast Center, Maimonides Medical Center, discussed the importance of neoadjuvant therapy in the treatment of patients with HER2-positive breast cancer.Borgen: What has been amazing over the last 20 years of my career is how much the view of HER2-positive [disease] has changed. In the pre-HER2 blockade or pre-trastuzumab (Herceptin) era, HER2-postiivty was the worst possible thing that you could get on a biopsy result. One of the first papers that I ever added to my CV was about how bad it was to have HER2-positivity in the absence of treatment. Now…both single- and double-targeting of HER2 have really revolutionized the outcomes.

Can you discuss some of the data in the neoadjuvant space that have come out this year?

In the eighth revision of the staging system, going live this January, HER2-positivity is a good factor—not a negative factor. So, as soon as I get a biopsy result back where we have confirmed that HER2 is IHC3+ or FISH-positive, we begin to look at how we are going to capitalize on that. When we look at clinical trials for breast cancer, and we look back at some of the earliest NASPB trials, or MILAN trials, or EORTC, we had to wait 5 or 10 years to get an answer. Our patients do not have the time to wait that long. So, one of things that we are looking at is the possibility of pathologic complete response being a reliable intermediate biomarker in clinical trials. There is some data suggesting, “Yes.”

In 2 landmark trials called TRYPHAENA and NeoSphere, we looked at women with a wide range of cancer, all of which was HER2-positive, ranging from stage 2 all the way through inflammatory. These women got a variety of systemic agents, and then either single or double targeting with HER2. The double targeting group got trastuzumab (Herceptin) and pertuzumab (Perjeta).

Are there any interesting trials currently ongoing?

What we saw in both of those trials was a shockingly high rate of pathologic complete response. In fact, in one of the trials in women with ER-negative, PR-negative, HER2-positive breast cancer, the pCR rate exceeded 70%. So, this is really becoming the new standard, and I think that we should be thinking about neoadjuvant treatment for all HER2-positive tumors.One of the questions that comes up with HER2-positive breast cancers, is at what size in the node-negative setting do we think about HER2 blockade? Would you do it for a 1mm invasive cancer? Probably not. 5 mm? Maybe. 7mm or 8mm? Yes, absolutely.

For small tumors that are otherwise favorable, there is a trial called APT, which was in very small, early-stage breast cancers that were HER2-positive. In APT, women got [paclitaxel] and trastuzumab, that was it. The survival rates from this trial are among the best we have ever seen. These are patients who are probably not going to need multimodal cytotoxic therapy, and they are not going to need double targeting of HER2. That also bears watching.

As a surgeon, what are your thoughts on chemotherapy in this setting?

This spring at the 2017 ASCO Annual Meeting, a trial called APHINITY was unblinded. This was a trial that asked the question of [whether there is a] benefit of double targeting HER2 in ER-positive, node negative, earlier stage breast cancers. The trial met its endpoints, it showed that across the board there was a benefit in double targeting. But, in subsets, the benefit was quite minimal. So now, there are a lot of questions being asked about where the line in the sand is—when am I going to recommend double targeting? I don’t think we know the answers to that yet, it might be the tumor size, where larger tumors will benefit from double targeting. I think that bears watching now in the HER2-positive space.I think that we do not use neoadjuvant strategies in this country as much as we should. And I am including everything from cytotoxic chemotherapy, to HER2 blockade, to estrogen blockade. We don't think about it upfront, but as surgeons we must. If we start the process with surgery every time, then we lose the ability and the benefits of neoadjuvant therapy. And the benefits are very clear. First there is an in vivo response so you can see that the agents are working, and then the surgery becomes smaller with a decreased tumor burden. So, for a lot of reasons I think that neoadjuvant treatment should be the future, and frankly it should be the present.