Clinical outcomes in patients with germline pathogenic variants in homologous recombination repair (HRR) genes treated with CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET)

The effectiveness of CDK4/6i and ET in patients (pts) with germline pathogenic variants (gPV) in genes implicated in the HRR is unknown and the current evidence is conflicting. This is a retrospective study of 250 consecutive pts with hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer treated with CDK4/6i and ET in Hospital Clinic of Barcelona between 2016-2021. gPV were determined using the Trusight assay. Intrinsic subtypes and gene expression were assessed in formalin-fixed paraffin-embedded tumor samples. The objectives were to determine the associations of gPV with intrinsic subtype and clinical outcomes. The association between gPV and objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were evaluated with logistic (ORR) and Cox (PFS/OS) regression models. 31% (n=78) of pts fulfilled germline testing criteria for the Hereditary Breast and Ovarian Cancer Syndrome. gPV were found in 14(18%) pts: BRCA2 (58%), CHEK2 (14%), ATM (7%), BRIP1 (7%), PTEN (7%), RAD51C (7%). Three groups were analyzed according to gPV BRCA2 status: mutated (BRCA2-PV)(n=8), wild-type (BRCA2-WT)(n=70), and unknown (nontested) (BRCA2-UNK)(n=172). The mean age in pts with BRCA2-PV and BRCA2-UNK was 51 vs 66 years respectively (p=0.010). Intrinsic subtype was analyzed in 60% (n=151) of pts. The proportion of basal-like (25%) and HER2-enriched (38%) intrinsic subtypes in pts BRCA2-PV was higher than in pts BRCA2-WT (1.4% and 8.5%) and BRCA2-UK (4.6% and 8.7%) (p=0.003). No differences in ORR were seen across BRCA2 groups (p=0.500). Median PFS was 12.1, 12.6 and 13.6 months in BRCA2-PV, BRCA2-WT and BRCA2-UNK respectively (p>0,050). OS was 28.8, not reached and 35.8 months in BRCA2-PV, BRCA2-WT and BRCA2-UNK respectively (p>0,050, probably due to the low number of BRCA2-PV). We observed for the first time a substantially higher proportion of non-luminal subtypes (63%) in BRCA2-PV compared to BRCA2-WT/UNK tumors (12%), in patients with advanced HR+/HER2- breast cancer. This observation could explain the previously reported association of BRCA1/2 mutations with poor prognosis in this context.