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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  = 1301) 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 vs. 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 vs. 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.

breast cancer research

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