Human Epidermal Growth Factor Receptor 2 Alterations and Prognostic Implications in All Subtypes of Breast Cancers

PURPOSE Alterations in human epidermal growth factor receptor 2 (HER2; ERBB2 gene) may be clinically relevant when considering HER2-targeted therapies. We have characterized the breadth of ERBB2 alterations (mutation, fusion, and copy number amplification) in breast cancer and explored the relationship between ERBB2 alterations and prognosis. METHODS DNA next-generation sequencing (592-gene panel and whole-exome sequencing) and RNA whole-transcriptome sequencing data from 12,153 breast samples were retrospectively reviewed for ERBB2 alterations. Clinicopathologic features were described, including breast cancer subtype, age, and biopsy site. HER2 status was determined according to ASCO guideline recommendations, including HER2-low. Overall survival (OS) data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank-sum tests. RESULTS Pathogenic ERBB2 mutations ( ERBB2- mut) were identified in 3.2% (N = 388) of tumors overall, most common in liver metastases (113/1,972, 5.7%). ERBB2- mut was more common among breast lobular than ductal (10% v 2.1%; P < .001) and HER2-positive (HER2+)/low tumors (≥3.8% v 1.5% TNBC; P < .05). The most common variant was ERBB2 -L755S (1.0% prevalence), enriched in metastatic tumors (1.2% v 0.6% in primary; P < .001). ERBB2 fusions were rare (0.3% prevalence). Coalterations associated with ERBB2 -mutated tumors compared with ERBB2 wildtype (WT) included CDH1 (40.0% v 10.2%; P < .001) and ERBB3 (10.6% v 0.8%; P < .001). Of the 10,115 tumor samples with outcome data, ERBB2- mut was associated with worse OS compared with WT. CONCLUSION ERBB2- mut and fusions were observed in all breast cancer subtypes—more commonly in HER2+/low, metastatic, and lobular histology tumors—and associated with poorer prognosis.