HER2-enriched Molecular Subtype of Breast Cancer More Responsive to Dual, Single HER2-targeting Regimens

Pathologic complete response (pCR) rates to dual human epidermal growth factor receptor (HER)2-targeted neoadjuvant therapy in women with stage 2 to 3 HER2-positive breast cancer was not significantly higher than single HER2 targeting, results of a randomized phase 3 trial published in the Journal of Clinical Oncology have found.¹

“HER2-positive breast cancer is molecularly heterogeneous in ways that impact on response to HER2-targeting,” Lisa A. Carey, MD, of the Division of Hematology/Oncology at the University of North Carolina at Chapel Hill, NC, told Cancer Therapy Advisor in an e-mail interview. “This may explain long-known heterogeneity in response by hormone receptor subsets.”

In the CALGB 40601 trial, 305 women underwent tumor biopsy and then were randomly assigned to paclitaxel plus trastuzumab alone (n = 120) or trastuzumab plus lapatinib (n = 118) for 16 weeks prior to surgery. “Primary end point was pCR in the breast; correlative end points focused on molecular features identified by gene expression–based assays,” the authors wrote.

They found the pCR rate to be 56% (95% CI, 47 – 65) with trastuzumab plus lapatinib and 46% (95% CI, 37 – 55) with trastuzumab alone (P = .13). No effect of trastuzumab plus lapatinib was observed in the hormone receptor–positive subset; however, a significant increase in pCR was seen with dual therapy in women with hormone receptor–negative disease (P = .01).

Gene expression analysis using mRNA sequencing found tumors to be molecularly heterogeneous, with pCR rates differing significantly by intrinsic subtype: HER2 enriched, 70%; luminal A, 34%; and luminal B, 36% (P < .001).

“The HER2-enriched molecular subtype is significantly more responsive to both dual and single HER2-targeting regimens than the other subtypes within HER2-positive disease,” Dr. Carey told Cancer Therapy Advisor. “Expression of immune signatures is directly associated with response to HER2-targeting, and is independent of other factors such as dual or single HER2-targeting or molecular subtype.”