Prediction of Response to Anti-HER2 Therapy Using A Multigene Assay

HER2-positive breast cancer (BC), which constitutes 13% to 15% of cases, shows variable response to anti-HER2 therapies. HER2 positivity, defined as protein overexpression (immunohistochemistry [IHC] score 3+) or equivocal expression (IHC 2+) with evidence of HER2 gene amplification, determines the eligibility for anti-HER2 therapy. The MammaTyper assay (Cerca Biotech GmbH) is an RT-qPCR BC subtyping platform based on the micro RNA expression of ERBB2, ESR1, PGR, and MKI67. This study aimed to evaluate the accuracy of the MammaTyper assay in predicting the response of HER2-positive patients to therapy. A well-characterized HER2-positive BC cohort of 287 cases diagnosed at Nottingham University hospitals between 2006 and 2018 was included. The cohort was divided into 2 groups: a trastuzumab-treated group (n = 159) and a chemotherapy-only treated group (n = 128). Tumor clinicopathologic characteristics were matched between the 2 groups. Cases with discordant HER2 status were validated through staining of surgical excision specimens. ERBB2 micro RNA identified 251/287 (87.5%) cases as HER2-positive, 10.8% (31/287) as HER2 low and 1.7% (5/287) as HER2 negative. According to the MammaTyper assay, ERBB2-positive patients treated with anti-HER2 therapy had significantly prolonged 5-year disease-free survival and distant metastasis-free survival (hazard ratio = 0.56, P = .003 and hazard ratio = 0.62, P = .023, respectively). MammaTyper-defined HER2-enriched subtype showed a better response to anti-HER2 therapy compared with IHC-defined subtypes, with significant differences in both 5-year disease-free survival and BC-specific survival (P = .01 and < .001, respectively). Patients who were ERBB2 negative did not show a survival difference between the group of patients who were treated with trastuzumab and those who were treated with chemotherapy only (P > .05). Validation analysis revealed that 11/36 ERBB2-negative cases were IHC 2+/ISH positive with very low level of gene amplification and 25 cases were false classified as HER2-positive using current protocols. Combining the MammaTyper assay with IHC to assess HER2 status improves the identification of HER2-positive patients with BC who would benefit from anti-HER2 therapy.