Targetable ERBB2 mutation status is an independent marker of adverse prognosis in estrogen receptor positive, ERBB2 non-amplified primary lobular breast carcinoma: a retrospective in silico analysis of public datasets

Background Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) and ERBB2 non-amplified. Somatic mutations in ERBB2/3 are emerging as a tractable mechanism underlying enhanced human epidermal growth factor 2 (HER2) activity. We tested the hypothesis that therapeutically targetable ERBB2/3 mutations in primary ILC of the breast associate with poor survival outcome in large public datasets. Methods We performed in silico comparison of ERBB2 non-amplified cases of ER+ stage I-III primary ILC ( N =279) and invasive ductal carcinoma (IDC, N =1,301) using METABRIC, TCGA and MSK-IMPACT information. Activating mutations amenable to HER2-directed therapy with neratinib were identified using existing functional data from in vitro cell line and xenograft experiments. Multivariate analysis of 10-year overall survival (OS) with tumor size, grade and lymph node status was performed using a Cox regression model. Differential gene expression analyses by ERBB2 mutation and amplification status was performed using weighted average differences and an in-silico model of response to neratinib derived from breast cancer cell lines. Results ILC tumors comprised 17.7% of all cases in the dataset but accounted for 47.1% of ERBB2 -mutated cases. Mutations in ERBB2 were enriched in ILC versus IDC cases (5.7%, N =16 vs . 1.4%, N =18, p <0.0001) and clustered in the tyrosine kinase domain of HER2. ERBB3 mutations were not enriched in ILC (1.1%, N =3 vs . 1.8%, N =23; p =0.604). Median OS for patients with ERBB2 -mutant ILC tumors was 66 months versus 211 months for ERBB2 wild-type ( p =0.0001), and 159 vs . 166 months ( p =0.733) for IDC tumors. Targetable ERBB2 mutational status was an independent prognostic marker of 10-year OS – but only in ILC (hazard ratio, HR=3.7, 95% CI 1.2–11.0; p =0.021). Findings were validated using a novel ERBB2 mutation gene enrichment score (HR for 10-year OS in ILC=2.3, 95% CI 1.04–5.05; p =0.040). Conclusions Targetable ERBB2 mutations are enriched in primary ILC and their detection represents an actionable strategy with the potential to improve patient outcomes. Biomarker-led clinical trials of adjuvant HER-targeted therapy are warranted for patients with ERBB2 -mutated primary ILC.