The breast tumor immune microenvironment of DNA double-strand break repair pathogenic variant carriers is enriched with tumor-associated macrophages.

Background: Approximately 5% of breast cancer patients have a rare pathogenic germline genetic variant that is associated with increased breast cancer risk. Mutations in more than 12 genes have been associated with hereditary breast cancer risk, many of which are involved in genome stability pathways, including DNA double-strand break (DSB) repair. We hypothesized that carriers of DSB repair-related pathogenic variants may have a distinct tumor immune environment that differs from that of non-carriers.

Methods: We utilized tumor transcriptome data from 559 participants with invasive breast cancer from the Nurses' Health Studies (NHS) and NHSII to infer immune-related gene expression signatures and immune cell abundance.

Results: Thirty-three of the individuals (5.9%) had germline DSB repair-related pathogenic variants in one or more of the following genes: ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FANCC, FANCM, NBN, PALB2, RAD50, RAD51C, and/or RECQL. In covariate-adjusted analyses, DSB repair-related pathogenic variant carrier status was positively associated with both a STAT1 signature (standardized 𝛽 = 0.59, p = 3.5 × 10-3) and inferred M1 macrophage infiltration (standardized 𝛽 = 0.56, p = 1.4 ×10-3). Further, these immune features correlated with other features related to tumor interferon response signaling suggesting this enrichment is occurring in an inflammatory context.

Conclusions: These results indicate that breast tumors of DSB repair-related pathogenic variant carriers have distinct immune features, which may have therapeutic implications in this high-risk population.

Impact: These results support further characterization of macrophage characteristics and abundance in the breast tumor microenvironment of DSB repair-related pathogenic variant carriers.