HER2-Enriched Breast Cancer Subtype Responds Well to New Therapy Regimens

Data showed patients with the HER2-enriched subtype had a high pCR with both single and dual anti-HER2 therapy and a high level of intertumoral heterogeneity.

Lisa Carey, MD

Despite primary analysis of the phase III CALGB 40601 trial showing no stitistically significant differences in pathologic complete response (pCR) between dual HER2 blockade or anti-HER2 monotherapy, data did show patients with the HER2-enriched subtype had a high pCR with both single and dual anti-HER2 therapy and a high level of intertumoral heterogeneity.

Data from the study, published in the Journal of Clinical Oncology, examined the efficacy of combining trastuzumab (Herceptin) and lapatinib (Tykerb) with chemotherapy against trastuzumab in conjunction with chemotherapy.

The study contained 295 randomly assigned patients with stage II or III HER2-positive breast cancer. Eligibility criteria included patients who were newly diagnosed, histologically confirmed, or who had untreated clinical stage II or III HER2-positive disease. Criteria also stated patients must be over 18 years old, had tumors greater than 1 centimeter in size, and had a pretreatment left ventricular ejection fraction greater than 50%. All patients enrolled in the study agreed to have 16-gauge core biopsies taken prior to the start of therapy.

Patients received paclitaxel at 80 mg/m2 IV once weekly for 16 weeks, with the addition of trastuzumab or both agents. Trastuzumab was given at 4 mg/kg IV in week 1 with a subsequent dose of 2 mg/kg IV afterward. Lapatinib was administered orally at 1500 mg daily when given concurrently with trastuzumab.

“This trial paves the way for integrating molecular analyses into other trials in HER2-positive breast cancer, and may allow us to take a less-is-more approach for women who are selected to be highly sensitive to targeted treatments and to have a good prognosis,” said lead study author Lisa Carey, MD, a UNC Lineberger member, Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research at the University of North Carolina School of Medicine, physician-in-chief, North Carolina Cancer Hospital, in a statement.

The trial’s primary endpoint was pCR in the breast, while correlative endpoints focused on molecular features identified by gene expression—based assays. The pCR rate was 56% for those in the dual HER2 blockade plus chemotherapy arm (n = 118; 95% CI, 0.47-0.65), versus 46% for the single-agent plus chemotherapy arm (n = 120; 95% CI, 0.37-0.55; P = .13). An investigational arm of paclitaxel plus lapatinib (n = 67) was closed early, due to reports of inferiority and greater toxicity of lapatinib-only regimens.

Secondary endpoints included adverse events, pCR in the breast, and ipsilatereal axillary lymph nodes.

Through molecular profiling, researchers found that the HER2—enriched subgroup were highly sensitive to the treatment, regardless of whether they received one or two agents. In this group, the pCR was 70%; patients with luminal A or luminal B subtypes had a pCR of 34% and 36%, respectively (P <.001).

There was no effect of dual therapy in the hormone receptor—positive subset; however, there was a significant increase in pCR with dual therapy in those with hormone receptor–negative disease (P = .01).

PIK3CA mutations were detected in 36 patients (20%), including 14 (25%) of 57 HER2-enriched, 4 (7%) of 55 luminal A, and 16 (31%) of 51 luminal B tumors. Ninety-three percent of the mutations were in exons 9 and 20. The pCR rate was 39% among tumors with PIK3CA mutations and 47% among those with wild-type PIK3CA (P = .5).

Grade 3/4 adverse events differed between the two arms, with 25 and 16 patients experiencing diarrhea and rash in the trastuzumab, lapatinib, and paclitaxel arm versus 2 and 2 patients experiencing the toxicity in the trastuzumab and paclitaxel arm, respectively.

“These are important findings because we treat all of these tumors the same—with multiple chemotherapy drugs and now often 2 anti—HER2 drugs at a cost of more than $100,000,” Carey said. “These findings suggest that we may be able to be more sophisticated in determining up front which tumors need more aggressive treatment and which will do well with a less aggressive therapy.”

Trastuzumab has reduced death in stage I to III HER2-positive breast cancer by 37% when combined with adjuvant chemotherapy. Trastuzumab-based regimens often exceed $5000 per month, while dual therapy regimens can exceed $10,000 per month.


  1. Carey LA, Berry DA, Cirrincione CT, et al. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib [published online November 2, 2015]. J Clin Oncol. doi:10.1200/JCO.2015.62.1268.