Germline Pathogenic Variants in HER2 ‐Positive Breast Cancer: Spectrum and Clinical Implications in a High‐Risk Chinese Cohort

ABSTRACT Objective H ereditary cancer risk assessment has predominantly focused on HER2‐negative breast cancer (BC), with limited characterization of germline pathogenic variants (GPVs) in HER2‐positive disease. This study aimed to delineate the prevalence, clinicopathological correlates, and clinical implications of GPVs in a cohort of HER2‐positive BC patients. Methods We retrospectively reviewed BC patients who had undergone genetic testing at the Sun Yat‐sen University Cancer Center from 2014 to 2024. GPV profiles, clinicopathological features, and survival outcomes were compared between HER2‐positive and HER2‐negative patients, with additional stratified analysis in HER2‐positive GPV carriers. Results Among 1692 BC patients, 1,499 patients met NCCN high‐risk criteria. In multigene panel testing, GPVs were identified in 18.1% (52/288) of HER2‐positive BC and 22.4% (269/1,201) of HER2‐negative BC patients. HER2‐positive GPV carriers exhibited distinct molecular profiles, with higher frequencies of BRCA2 (23/52, 44.2%) and TP53 (14/52, 26.9%) mutations and a lower BRCA1 prevalence (6/52, 11.5%) compared to HER2‐negative carriers ( BRCA2 : 106/269, 37.9%; TP53 : 9/269, 3.3%; BRCA1 : 117/269, 43.5%). Clinically, HER2‐positive carriers were diagnosed at a younger median age, had higher hormone receptor (HR) positivity, and less frequently reported a family history of BRCA ‐related cancers. GPVs were not associated with increased locoregional recurrence or distant metastasis in HER2‐positive BC but significantly elevated the risk of contralateral BC and other secondary primary cancers—a risk particularly pronounced in TP53 carriers. Conclusions HER2‐positive BC patients harbored a distinct GPV spectrum compared to HER2‐negative patients. While GPVs did not worsen primary BC‐specific outcomes, they conferred a significantly increased risk of second primary cancers, underscoring the clinical utility of multigene panel testing for comprehensive risk stratification and long‐term management in this population. Study Limitations This retrospective, single‐center study comprised a clinically enriched high‐risk cohort, which may limit the generalizability of prevalence estimates. The extended inclusion period and evolving classification standards, despite reannotation, represent inherent methodological constraints.