Abstract
BACKGROUND: The emergence of novel human epidermal growth factor receptor 2 (HER2)-targeting drugs has provided a new therapeutic option for HER2-low triple-negative breast cancer (TNBC) patients who had limited treatment choices previously. However, the biological implications and prognostic significance of HER2-low status in TNBC are still not fully appreciated. METHODS: Utilizing a single-center multi-omics cohort of TNBC patients that includes whole exome sequencing and RNA sequencing data, this study aims to explore the clinical and molecular characteristics between HER2-low and HER2-0 TNBC. RESULTS: The study comprised 207 patients with HER2-low TNBC and 153 patients with HER2-0 TNBC. Findings revealed that HER2-low tumors exhibited lower tumor grade, more nodal involvement and lower Ki-67 index compared to HER2-0 tumors. Additionally, HER2-low TNBC were associated with more mutations in PIK3CA and its corresponding pathways, a more prominent clock-like mutation signature, along with activation of androgen receptor (AR)-related pathways and fatty acid metabolism. While HER2-low status did not significantly influence recurrence-free survival (RFS) across the entire study population, HER2-low patients showed significant better RFS compared to HER2-0 patients within the luminal androgen receptor (LAR) subtype. This distinction was also evident at molecular level. CONCLUSION: HER2-low TNBC demonstrated unique clinical, transcriptomic and genomic characteristics when contrasted with HER2-0 TNBC. In the LAR subtype, a clear molecular and prognostic discrepancy between HER2-0 and HER2-low tumors was identified.