AbstractBackgroundInvasive lobular carcinoma (ILC) accounts for 10–15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) andERBB2non-amplified. Somatic mutations inERBB2/3are emerging as a tractable mechanism underlying enhanced human epidermal growth factor 2 (HER2) activity. We tested the hypothesis that therapeutically targetableERBB2/3mutations in primary ILC of the breast associate with poor survival outcome in large public datasets.MethodsWe performed in silico comparison ofERBB2non-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 byERBB2mutation and amplification status was performed using weighted average differences and an in silico model of response to neratinib derived from breast cancer cell lines.ResultsILC tumors comprised 17.7% of all cases in the dataset but accounted for 47.1% ofERBB2-mutated cases. Mutations inERBB2were 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.ERBB3mutations were not enriched in ILC (1.1%,N = 3 vs. 1.8%,N = 23;p = 0.604). Median OS for patients withERBB2-mutant ILC tumors was 66 months vs. 211 months forERBB2wild-type (p = 0.0001), and 159 vs. 166 months (p = 0.733) for IDC tumors. TargetableERBB2mutational 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 novelERBB2mutation gene enrichment score (HR for 10-year OS in ILC = 2.3, 95% CI 1.04–5.05;p = 0.040).ConclusionsTargetableERBB2mutations 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 withERBB2-mutated primary ILC.