Non-BRCA germline pathogenic variants and response to neoadjuvant systemic therapy in triple-negative breast cancer...

Most patients with triple-negative breast cancer (TNBC) undergo neoadjuvant therapy (NAT). Prospective studies on the landscape of non-BRCA germline pathogenic variants (PVs) in patients with TNBC and their impact on response to NAT are sparse.

On a prospective trial, patients received NAT with doxorubicin and cyclophosphamide with or without immunotherapy followed by paclitaxel with or without carboplatin vs. targeted therapy. Before NAT, DNA was extracted from blood samples and sequenced. Germline variants were identified. Variants deemed deleterious and present in genes found in a 103 pan-cancer susceptibility gene panel were tabulated. Univariate logistic regression models assessed the relationship between variants and pathologic complete response (pCR), pCR and minimal residual cancer burden I (RCB I) as a combined outcome, and radiologic response.

Of 184 patients, 72% were White, 19% were Black, and 8% were Asian. 36% had PVs in pan-cancer susceptibility genes. PVs were found in 31 genes not previously found to have PVs in other known US cohorts. Of 181 patients with NAT response data, 67 (37%) had pCR; 22 (12%), 69 (38%), and 23 (13%) had RCB I, II, and III, respectively. There was no significant difference in pCR rates vs. RCB I/II/III, achievement of a pCR/RCB I vs. RCB II/III, or radiologic response between those with and without a PV.

Over one-third of patients had germline PVs in pan-cancer susceptibility genes, suggesting multigene panels should be considered. The presence of non-BRCA germline PVs was not associated with a difference in pathologic response.