Pathogenic germline variants in breast cancer patients associated with different HER2 expression levels.

e12543 Background: Germline pathogenic/likely pathogenic variants (PV) were evaluated in 530 Chinese breast cancer patients and 98 patients with atypical ductal hyperplasia or a family history of breast cancer using NGS-based analysis. Methods: An NGS-based multigene panel was used to identify germline PVs among 102 genes, and the results were stratified by phenotypic characteristics, including HER2 expression. Results: There were 26,847 germline variants identified, including 59 PVs across 102 genes. These were organized into four pathway clusters: DDR, HRR, FANC, and Other. The PV incidence differed among the patients in these distinct clusters: 1) 10% expressed the breast cancer gene 2 (BRCA2), similar in both BC and unaffected groups; 2) 6% expressed the ATM serine/threonine kinase mutation (ATM) from the DDR pathway; 3) 5% expressed the BRCA1 mutation from the HRR pathway, and 4) 79% expressed a variety of other mutation at a lower frequency. The P/LP variants among the HER2-high and non-BC cohorts were similar to each other, with a distribution scattered among the 4 pathway clusters, while sharing two mutated genes, FANCM and NTRK1. Breast cancer patients carried more HRR related gene PVs and less in FANC/DDR related genes than non-BC (p=0.019). The distribution of different pathway related genes was significantly different between HER2-high and HER2-zero group (p=0.017), HER2-low and non-BC group (p=0.023), HER2-zero and non-BC group (p=0.015). HER2-zero and HER2-low BC patients carried much less FANC and DDR pathway related germline PVs, and HER2-high BC PV carriers show the similar PV preference with the unaffected patients. BC patients with different HER2 expression status exhibited distinct germline mutational signatures and differential clinical outcomes after neoadjuvant systemic therapy. Conclusions: Chinese breast cancer patients with different HER2 expression status were associated with varying germline PVs, which correlated with different clinical outcome after neoadjuvant therapy. Multigene genetic test for pathogenic germline variants should be offered to breast cancer patients and high-risk individuals who would benefit from prevention and early detection programs.