HER2-positive (HER2+) breast cancer is a clinically and biologically heterogeneous disease. According to gene expression profiling, 4 main intrinsic molecular subtypes of breast cancer (Luminal A, Luminal B, HER2-enriched [HER2-E], Basal-like) can be identified, although HER2-E predominates (~ 50-60%). From a molecular perspective, HER2-E tumors are characterized by high expression of ERBB2 and other genes of the 17q amplicon, such as GRB7, and low to intermediate expression of luminal genes such as ESR1 and PGR. Although the majority of HER2-E tumors are hormone receptor (HR)-negative by immunohistochemistry,~ 30% are typically HR+[1]. Conversely, within HR+ disease, 40-50% are HER2-E and the rest are Luminal A and B tumors and, within HR-negative disease, 80-90% are HER2-E and 10-20% are Basal-like [1]. Thus, HR status does not fully recapitulate these molecular entities.

Accumulating evidence suggests that the intrinsic subtypes might provide predictive value within HER2+ disease. For example, in retrospective analyses of 4 prospective neoadjuvant trials (ie NeoALTTO [2], CALGB40601 [3], NOAH [4] and CHER-LOB [5]), HER2-E subtype has been associated with a higher likelihood of achieving a pathological complete response (pCR) following anti-HER2-based chemotherapy compared to the other subtypes. Importantly, in patients with chemotherapy and dual HER2 blockade with trastuzumab combined with lapatinib, the pCR rate is~ 80%[3]. Overall, this data suggests that HER2+/HER2-E tumors benefit the most from chemotherapy plus anti-HER2 therapy. Based on all of this evidence,