Intrinsic molecular subtypes of HER2+ breast cancer

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 HRnegative 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 (i.e. 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, this biomarker (HER2-E vs not) deserves to be tested in samples from pivotal phase III trials that led to the approval of pertuzumab in the (neo)adjuvant setting (APHINITY) and metastatic setting (CLEOPATRA). Another area of great interest is to identify patients that might be cured with dual HER2 blockade-only in the absence of chemotherapy. In this direction, the results of two chemotherapy-free neoadjuvant trials (i.e. TBCRC006 [6] and NeoSphere [7]) further support this hypothesis. In the TBCRC006 study [6], 64 patients with primary HER2+ breast cancer were treated with trastuzumab and lapatinib without chemotherapy for 12 weeks in the neoadjuvant setting. Patients with HR+ disease also received endocrine therapy. The pCR rate in the breast was 27.0%. In the NeoSphere trial [7], the pCR rate in the breast was 16.8% after 12 weeks of trastuzumab and pertuzumab. Of note, no endocrine therapy was added in patients with HR+ disease in the NeoSphere trial. Overall, these results suggest that a subset of patients with HER2+ breast cancers is sensitive to the dual HER2 blockade and potentially could be treated without cytotoxic therapy. According to the previous results, HER2+ tumors of the HER2-E subtype show high activation of the HER2/EGFR signaling pathway; thus, HER2-E tumors should benefit the most from HER2 blockade. The PAMELA phase II neoadjuvant clinical trial was designed specifically to test this hypothesis [1]. In this study, 151 patients with stage I-III HER2+ disease were treated for 18 weeks with neoadjuvant trastuzumab and lapatinib (and endocrine therapy if the tumor was HR+) [1]. The primary hypothesis was that the HER2-E subtype would obtain a Editorial