Pathogenic germline variants associated with different HER2 expression among breast cancer patients

Germline mutations were evaluated in 530 Chinese breast cancer (BC) patients with different HER2 expression status plus 98 patients with atypical ductal hyperplasia or a breast cancer family history. DNA extracted from blood samples was analyzed with a next generation sequencing based multigene panel, with reporting of likely pathogenic and pathogenic variants (PV) of 102 cancer associated genes, and correlation between clinicopathologic characteristics and known BC-associated genes. The 71 identified PVs were categorized into five distinct pathway clusters: BRCA/FANC, DDR, HRR, FANC, and Other. The distribution of PVs enriched within these clusters differed significantly between BC patients and unaffected individuals (p = 0.031). This difference was primarily driven by the BRCA/FANC, FANC, and DDR clusters, with enrichment percentages of 57.7% vs. 16.7% (BRCA/FANC), 7.0% vs. 25.0% (FANC), and 15.5% vs. 41.7% (DDR) in BC vs. unaffected groups, respectively. Notably, the three BC groups stratified by HER2 expression level exhibited distinct PV distributions. Both the HER2-low and HER2-zero BC groups showed significantly different distributions compared to unaffected individuals (p = 0.0132 and p = 0.0081, respectively). The BRCA/FANC cluster was the predominant pathway enriched in both HER2-low (59.6%) and HER2-zero (81.8%) groups. Furthermore, the PV distribution in the HER2-zero group was significantly different from that in the HER2-high group (p = 0.0028). In contrast, the distribution in the HER2-high group resembled that observed in non-BC individuals. These findings indicate that BC patients with different HER2 expression statuses harbor distinct germline PV signatures, which correlate with differential clinical outcomes following neoadjuvant systemic therapy. Chinese breast cancer patients with different HER2 expression status demonstrated different pathogenic germline variant, which correlated with different clinical outcome after neoadjuvant therapy. Multi-gene genetic testing for pathogenic germline variants may be considered for breast cancer patients and high-risk individuals who could benefit from prevention and early detection programs.