Germline Pathogenic Variants in HER2-Positive Breast Cancer: Spectrum and Clinical Implications in a High-Risk...

Hereditary 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.

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.

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.

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.

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.