Study Reveals HER2 Breast Cancer Subtype Beneficial for Treatment Individualization

HER2 Breast Cancer Luminal Subtype

Peter Beitsch, MD

Approximately 33% of patients with HER2-positive breast cancer have also been found to have a luminal subtype resistant to chemotherapy and trastuzumab. In an interview withTargeted Oncology, Peter Beitsch, MD, chief physician, Dallas Surgical Group, discusses the triplet neoadjuvant regimen of pertuzumab, trastuzumab, and chemotherapy, and its effect on the subtype in the Neoadjuvant Breast Registry Symphony Trial (NBRST) study.

The phase IV registry NBRST study looks at Mammaprint and BluePrint analyses prior to neoadjuvant chemotherapy, and subsequently studies patients responses to chemotherapy. At the end of the treatment cycle, these participating patients then undergo surgery. The primary goal was to relate the Mammaprint and the BluePrint assays to either a pathological complete response (pCR) or a non-pCR, according to Beitsch.

"There were several major findings. The most important one is that we reclassified about 25% of the patients in the study," said Beitsch. "We looked at their functional molecular subtype, which is the way it was initially described with messenger RNA, as compared with the surrogate subtyping, which we do nowadays with immunostaining for ER-positivity and PR-positivity, and FISH testing for HER2."

Data in the study showed that 32.5% of patients with HER2-positive breast cancer also had luminal-type disease. In this resistant group, chemotherapy and trastuzumab alone showed a pCR rate of just 6% compared with 39% with the addition of pertuzumab (P= .0002), representing a distinct subgroup for tailoring treatment.

He added that the second major finding from the study was there was nearly no pCR in the luminal subtype, yet almost all of the pCR in the triple-positive patients came from the HER2-driven subtype. These results changed once pertuzumab was added to the therapy regimen.

"Before receiving pertuzumab, in [luminal subtype] patients who received chemotherapy and trastuzumab, they demonstrated a 4% pCR. When you add pertuzumab, there was a 40% pCR," said Beitsch.

"It’s apparent that in the triple-positive patients who are luminal subtype, which is about one-third of all HER2-positive patients, they need not just trastuzumab and chemotherapy; they need trastuzumab, pertuzumab, and chemotherapy to have an improvement in the survival—if you consider pCR to be a surrogate for survival, and I think most people consider that to be the case."

The pertuzamab combination was approved for the treatment of HER2-positive breast cancer in October 2013 based on the phase II NeoSphere trial, which showed that pertuzumab, trastuzumab, and chemotherapy, significantly improved pCR when compared with three other neoadjuvant regimens.

Beitsch says despite the combination only being approved in the neoadjuvant setting, this discovery could lead to the combination's use in the adjuvant setting.

"Our study creates an excellent argument to insurance companies to allow for pertuzumab to be given in addition to trastuzumab in the adjuvant setting," he said.

"I think it is going to make a major impact in the majority of triple-positive women and, probably, the subtyping should probably be routinely done on those patients who are triple-positive. This is to see if they are that luminal subtype, because they really need the pertuzumab/trastuzumab combination, even if it is in the adjuvant setting. I think this will have a major impact on women with HER2 disease."

Looking toward the future of this subtype and its treatment, Beitsch says he and his research group are planning on following up with the participating patients for 5 years and beyond to determine if their pCR rates translate into survival.

"We have some ongoing studies looking at the luminal subtypes. There are some that don’t really respond well with chemotherapy, but some do and so we want to tease out the luminal subtypes that are responding. Perhaps, there is a signature we can find to determine the luminal patients who need chemotherapy, because the vast majority does not," he said.

"We are probably planning on doing an NBRST '2' study to look at the low-risk group and see if they don’t need therapy beyond surgery—not even endocrine therapy. They are at such a low risk for recurrence. We will tease out the higher-risk groups that are basal. It is probably a heterogeneous group of patients, so we will try to split those up and see exactly what therapy might be directed at one of those basal subtypes."