Molecular characterization of HER2-negative breast cancers reveals a distinct patient subgroup with 17q12 deletion and heterozygous loss of ERBB2

Background: The approval of trastuzumab deruxtecan has prompted the subgrouping of human epidermal growth factor receptor 2-negative (HER2-) breast cancers (BCs) to HER2 0 and HER2 low on the basis of immunohistochemistry, although the biological significance of these subgroups remains uncertain. This study is aimed to better understand the molecular and genetic differences among HER2- tumors stratified by quantitative levels of HER2. Patients and methods: We analyzed the transcriptomic and genomic data from the Molecular Taxonomy of BC International Consortium (discovery cohort) and The Cancer Genome Atlas (independent validation cohort). HER2BCs, including hormone receptor positive and triple negative, were divided into three subgroups based on ERBB2 messenger RNA (mRNA) levels: minimal, moderate and enhanced. Results: We observed significant differences in mutational and transcriptional profiles across the subgroups. Tumors with enhanced ERBB2 mRNA expression had a higher prevalence of PIK3CA mutations and increased estrogen receptor signaling, while tumors with minimal ERBB2 mRNA expression displayed higher expression of proliferation and immune-related genes. We identified a distinct subgroup of BCs characterized by a large deletion of chromosome 17q12 (17q12del) with heterozygous loss of ERBB2, very low ERBB2 mRNA and HER2 protein expression. This subgroup was also enriched for heterozygous losses of TP53 and other tumor suppressor genes. Analysis of two large real-world cohorts of patients with HER2- metastatic BC (Dana-Farber Cancer Institute cohort n = 1063 and Memorial Sloan Kettering MetTropism cohort n = 1018) showed that patients with 17q12del and heterozygous loss of ERBB2 had poorer overall survival (OS). Conclusions: We identified a biologically and clinically distinct subgroup of BCs characterized by a 17q12del with a heterozygous loss of ERBB2 and low ERBB2 mRNA and HER2 protein expression. In two large real-world cohorts of patients with HER2- metastatic BC, this subgroup was associated with poor OS, highlighting its clinical significance.