Impact of germline BRCA1/2 status on outcomes for patients with HR+/HER2- metastatic breast cancer treated with CDK4/6 inhibitors: a systematic review and meta-analysis.

Almost 60 % of breast cancers (BCs) diagnosed in germline BRCA1/2 mutation (gBRCAm) carriers are HR+/HER2-. Sparse data suggest limited CDK4/6 inhibitors benefit among gBRCAm carriers. However, prespecified subgroup analyses from pivotal trials are lacking, and current data quality is poor given the small patient populations. We conducted a systematic review and meta-analysis of studies evaluating CDK4/6 inhibitors outcomes in patients with HR+/HER2-metastatic BC according to gBRCA status. Progression free survival (PFS) and overall survival (OS) were compared between gBRCAm patients and those with wild type (wt) or unknown (wt/unk) gBRCA status. Of 1339 potentially eligible records, 14 studies were included, covering a population of 618 gBRCAm patients. Studies were mostly retrospective, with moderate-to-high risk of bias according to ROBINS-E algorithm. Three studies included only gBRCA tested patients; all others also allowed gBRCA untested patients. Meta-analysis of studies with available data for gBRCAm vs. gBRCAwt patients resulted in an HR for PFS of 1.68 (95 %CI 1.37-2.05) and an HR for OS of 1.73 (95 %CI 1.12-2.67). Inclusion of patients with unknown gBRCA status led to similar results (gBRCAm vs. gBRCAwt/unk), with an HR for PFS of 2.02 (95 %CI 1.59-2.57) and for OS of 1.46 (95 %CI 1.08-2.00). Emerging data suggest that gBRCAm patients with advanced HR+/HER2- BC may experience shorter PFS and OS with CDK4/6 inhibitor compared to gBRCAwt. Given the low level of evidence and the high risk of bias in available studies, further research is needed to understand molecular mechanisms and identify the optimal treatment sequence.