Single-Cell Immune Signature and Response to Neoadjuvant Chemotherapy in BRCA1/2-Mutated Breast Cancer

The atlas of immune microenvironment at single-cell level in BRCA1/2-mutated breast cancer is largely unknown and whether an immune signature on the basis of single-cell atlas is associated with response to neoadjuvant chemotherapy remains to be investigated.

The immune microenvironment between BRCA1/2-mutated and BRCA wild-type breast tumors was explored using single-cell RNA sequencing (scRNA-seq) assay and was validated in an independent cohort of 40 BRCA1/2 carriers and 56 noncarriers via immunohistochemistry assay (IHC). Bulk RNA-seq was performed using RNA extracted from fresh-frozen pretreatment core-needle tumor tissues in 80 BRCA1/2 carriers with operable primary human epidermal growth factor receptor 2-negative tumors who received neoadjuvant chemotherapy, and the associations between immune cell subtypes defined by scRNA-seq and pathologic complete response (pCR) were investigated.

BRCA1/2-mutated tumors exhibited an enriched immune microenvironment compared with the wild-type counterparts at single-cell level, particularly regulatory T cells and exhausted T cells, which were validated in the IHC cohort. Among the neoadjuvant chemotherapy cohort of 80 BRCA1/2 carriers, 36.2% achieved a pCR. We established an immune signature on the basis of the single-cell and bulk RNA-seq data, named BRCA-IM. The BRCA-IM model exhibited an excellent prediction of pCR in the neoadjuvant chemotherapy cohort, with AUC values of 0.81(95% CI, 0.69 to 0.92) in the training set and 0.91(95% CI, 0.79 to 1.00) in the test set, respectively; and the BRCA-IM model remained as an independent predictor for pCR after adjusting for other factors. Moreover, higher BRCA-IM scores were significantly associated with more favorable survival in the neoadjuvant chemotherapy cohort.

BRCA1/2-mutated breast cancer shows an enriched tumor immune microenvironment, and the BRCA-IM model exhibits a good performance in prediction of pCR in BRCA1/2-mutated tumors.