Abstract Purpose: Germline mutations were evaluated in 530 Chinese breast cancer (BC)patients with different HER2 expression status plus 98 patients with atypical ductalhyperplasia or a breast cancer family history. Methods: DNA extracted from blood samples was analyzed with a next generationsequencing based multigene panel, with reporting of likely pathogenic and pathogenicvariants (PV) of 102 cancer associated genes, and correlation betweenclinicopathologic 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 withinthese clusters differed significantly between BC patients and unaffected individuals(p=0.031). This difference was primarily driven by the BRCA/FANC, FANC, and DDRclusters, 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 PVdistributions. Both the HER2-low and HER2-zero BC groups showed significantlydifferent distributions compared to unaffected individuals (p=0.0132 and p=0.0081,respectively). The BRCA/FANC cluster was the predominant pathway enriched in bothHER2-low (59.6%) and HER2-zero (81.8%) groups. Furthermore, the PV distributionin 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 thatobserved in non-BC individuals. These findings indicate that BC patients with differentHER2 expression statuses harbor distinct germline PV signatures, which correlate withdifferential clinical outcomes following neoadjuvant systemic therapy. Discussion: Chinese breast cancer patients with different HER2 expression statusdemonstrated different pathogenic germline variant, which correlated with differentclinical outcome after neoadjuvant therapy. Multi-gene genetic test for pathogenicgermline variant should be offered to breast cancer patients as well as high-riskindividuals at risk for future breast cancer who would benefit from prevention and earlydetection programs. Citation Format: N. Liao, J. Wu, G. Zhang, J. Weitzel, C. Balch. Pathogenic germline variants associated with different HER2 expression among breast cancer patients abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-05-21.
Liao et al. (2026) studied this question.