Debu Tripathy, MD: The APHINITY trial was designed to test the addition of pertuzumab to the standard chemotherapy and trastuzumab backbone that we have typically been using for many years for early-stage HER2-positive breast cancer. It was designed to enroll a slightly-higher-than-normal-risk group of patients that included anyone who was stage II or higher, but it also included some stage I patients who had tumors greater than 1 cm. If they were greater than 0.5 cm, they had to be high-grade or hormone receptor—positive.

These patients were randomized to get standard chemotherapy, and that could be either anthracycline-based or a taxane without anthracyclines: Those are standard NCCN [National Comprehensive Cancer Network]—recommended therapies, with trastuzumab given overlapping with a taxane and then continued to complete a full year of maintenance therapy. That was the control arm, and the experimental arm had pertuzumab added where trastuzumab was added. So it was dual antibody versus single antibody.

The design of the study was a 1:1 randomization, and it was stratified on the basis of the type of chemotherapy received and other risk factors. The main endpoint of the study was invasive disease—free survival, and it was powered to detect a fairly small but clinically significant improvement in that endpoint. The trial enrolled over 4000 patients and did, at the end of the day, show a statistically significant improvement in overall invasive disease–free survival. The absolute difference of the whole trial ended up being about 1.5% over the course of 3 years in invasive disease–free survival, but that difference was bigger in the subgroup of patients who had node-positive disease.

Nodal involvement is probably the single-most-important prognostic factor, regardless of the therapy used. Going from 0 to 1 node, of course, is a big increase in risk, and every additional node, of course, increases the risk as well. That is an important determination. For patients who have node-positive disease, I think that you definitely want to choose the most efficacious regimen out there because the absolute difference that a patient will have in their disease-free recurrence is proportional to the overall risk. Generally, for node-positive patients, I feel therapies that have clearly shown an improvement over standard chemotherapy and trastuzumab regimens would be favored. I would use a pertuzumab-containing regimen in anyone with node-positive disease regardless of tumor size. Now, in someone with node-negative disease, the tumor size does become important and tumor grade is also important, so you look at them both.

For example, someone with a 2-cm high-grade tumor is clearly someone whom I would treat with pertuzumab-containing therapy again. For someone with a grade 2 tumor that is 2 cm, I think I’d treat as well. But then you get into the really low-risk patients, and these are going to be patients who have hormone receptor—positive disease and low-grade or low-proliferative indices. For those patients, I think it is a toss-up. The benefit for those patients may even be difficult to distinguish. We did see that in the subgroup analysis of the APHINITY trial, the patients with node-negative disease didn’t benefit. But then, of course, the trial wasn’t designed to stand alone on those findings. It wasn’t statistically powered, so I generally feel that the benefit is proportional to risk. It may be such a small benefit that it may not be worth the additional toxicities.

The main toxicity that we encounter that has to be factored into this equation would be more diarrhea. I think that’s probably the biggest difference from adding pertuzumab. In terms of cardiac toxicity, we haven’t really seen much over and above what you would expect with trastuzumab. There may be some other subtle side effects that you see more, like GI [gastrointestinal] side effects, fevers, and fatigue.

For patients who receive neoadjuvant chemotherapy and trastuzumab or trastuzumab and pertuzumab, you do have an additional tool to look at prognosis. We know that some patients do not achieve a complete pathological response, and that’s defined by the absence of any invasive disease in the breast or in the lymph nodes. So any invasive disease in the breast, especially if it’s more than 1 cm, or any invasive disease in the nodes does portend a higher risk of recurrence. This was particularly more striking in patients who have hormone receptor—negative breast cancers, but even in hormone receptor–positive breast cancer, it probably does suggest a higher subsequent risk of recurrence. In that situation, I think that all patients should be considered at higher risk, and I would recommend using pertuzumab in the adjuvant setting for those patients.

Now, keep in mind that pertuzumab has, for a couple of years now, been approved in the neoadjuvant setting. If you are treating someone with preoperative stage II or higher disease, then they should receive pertuzumab with trastuzumab at least during the chemotherapy. Most likely, those patients will then continue to get maintenance pertuzumab the whole way through. But that does represent an additional tool that we have in prognosticating.

Transcript Edited for Clarity