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

Abstract

Alterations in human epidermal growth factor receptor 2 (HER2; <i>ERBB2</i> gene) may be clinically relevant when considering HER2-targeted therapies. We have characterized the breadth of <i>ERBB2</i> alterations (mutation, fusion, and copy number amplification) in breast cancer and explored the relationship between <i>ERBB2</i> alterations and prognosis. 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 <i>ERBB2</i> 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. Pathogenic <i>ERBB2</i> mutations (<i>ERBB2-</i>mut) were identified in 3.2% (N = 388) of tumors overall, most common in liver metastases (113/1,972, 5.7%). <i>ERBB2-</i>mut was more common among breast lobular than ductal (10% <i>v</i> 2.1%; <i>P</i> < .001) and HER2-positive (HER2+)/low tumors (≥3.8% <i>v</i> 1.5% TNBC; <i>P</i> < .05). The most common variant was <i>ERBB2</i>-L755S (1.0% prevalence), enriched in metastatic tumors (1.2% <i>v</i> 0.6% in primary; <i>P</i> < .001). <i>ERBB2</i> fusions were rare (0.3% prevalence). Coalterations associated with <i>ERBB2</i>-mutated tumors compared with <i>ERBB2</i> wildtype (WT) included <i>CDH1</i> (40.0% <i>v</i> 10.2%; <i>P</i> < .001) and <i>ERBB3</i> (10.6% <i>v</i> 0.8%; <i>P</i> < .001). Of the 10,115 tumor samples with outcome data, <i>ERBB2-</i>mut was associated with worse OS compared with WT. <i>ERBB2-</i>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.