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Prediction of Trastuzumab Benefit in HER2-Positive Breast Cancers: Is It in the Intrinsic Subtype?

The HER2 (ERBB2) gene is amplified and overexpressed in approximately 15% of breast cancers (1), and its protein product human epidermal growth factor receptor 2 (HER2) is the predictive marker and molecular target of anti-HER2 therapies such as the humanized monoclonal antibodies trastuzumab and pertuzumab and tyrosine kinase inhibitors, including lapatinib (2). The clinical benefit of trastuzumab in HER2-positive breast cancer patients, as defined by immunohistochemical and/or fluorescence in situ hybridization (FISH) analysis, has been widely demonstrated; however, primary and in particular secondary resistance to these treatments has been documented in a substantial proportion of these patients (3). Despite the identification of several mechanisms of resistance to trastuzumab, the development of clinically useful biomarkers to identify the subset of HER2-positive breast cancer patients unlikely to benefit from the current mainstay anti-HER2 therapies has proven challenging, and the predictive markers in the metastatic setting may not be entirely applicable to the adjuvant setting (4). HER2-positive breast cancers have been shown to constitute a heterogeneous disease at the molecular level, and the repertoire of somatic genetic alterations in tumors harboring HER2 gene amplification appears to vary according to estrogen receptor (ER) status and potentially according to the “intrinsic” subtypes (5–8). In addition, contrary to the hypothesis that HER2positive tumors, as defined by immunohistochemistry and/or FISH, would be generally classified as HER2-enriched if they were ER-negative/HER2-positive and of luminal B subtype if they were ER-positive/HER2-positive, several studies have now demonstrated that all intrinsic subtypes can be identified within clinically HER2-positive breast cancers (4,9,10). It should be noted, however, that intrinsic subtyping of breast cancers is not a trivial task (11–13), and substantial disagreement has been reported when research versions of subtyping methods are used (14–16). In this issue of the Journal, Perez and colleagues (17) sought to define whether the benefit of the addition of trastuzumab to chemotherapy in patients with HER2-positive disease would vary as a function of intrinsic subtypes. To test this hypothesis, they performed a retrospective analysis of 1392 tumors from the prospective North Central Cancer Treatment Group (Alliance) N9831 trial of patients with early-stage HER2-positive breast cancer (18,19), who were randomly assigned to receive chemotherapy (n 1⁄4 484, arm A) or chemotherapy and trastuzumab (n 1⁄4 908, arms B and C) in the adjuvant setting. The HER2 status was assessed centrally by immunohistochemistry and/or FISH as part of the N9831 study (18). The Prosigna algorithm was applied to a custom NanoString CodeSet that included the PAM50 genes plus five housekeeping genes (employed for normalization purposes), and adjustment factors were derived from the analysis of 30 samples that were processed with the custom CodeSet and reprocessed with the Prosigna CodeSet. Adjustment factors for each of the PAM50 genes were derived and applied to the PAM50 counts in the original data set, prior to subtyping (17). Using these gene expression data, intrinsic subtypes, risk of recurrence scores (RORs), and risk categories were defined and correlated with relapse-free survival (RFS) in the chemotherapy and chemotherapy plus trastuzumab arms. These analyses revealed that, as expected for a HER2-positive cohort, almost all (95.9%) of the samples analyzed were classified as high risk, with the majority of tumors displaying ROR scores above 70 (75.1%). All four intrinsic subtypes were identified in the N9831 cohort; tumors were classified as of HER2-enriched (1004/1392, 72.1%), luminal A (132/1392, 9.5%), luminal B (159/1392, 11.4%), and basal-like (97/1392, 7.0%) subtypes. A statistically significant association between intrinsic subtyping and relapse-free survival (RFS) was observed when all patients were analyzed as a group irrespective of treatment arms, with HER2-positive tumors classified as of basal-like subtype having the worst outcome (17). In arm A (the chemotherapy-only arm), no association between intrinsic subtype and RFS was observed.