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

Purpose: 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. Methods: 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. Results: 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. Discussion: 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.