BRCA1/2, PALB2 mutations and first-line CDK4/6 inhibitor efficacy in HR+ metastatic breast cancer.

To evaluate outcomes of first-line ET + CDK4/6i for HR+/HER2 metastatic breast cancer (MBC) based on BRCA/PALB2 mutations status known at treatment initiation. This cohort study included patients from 18 French comprehensive cancer centers treated with first-line ET and CDK4/6i between August 1, 2013, and December 31, 2023. Multivariable models including a Cox proportional hazard with a time-varying approach and landmark analyses at different timepoints (at the initiation of the first-line therapy and at 6 months after the initiation of the first line) assessed the association between germline and/or somatic BRCA and PALB2 genes alteration (categorized as "BRCA/PALB2m" (mutated) "BRCA/PALB2wt" (wild type), and "untested"), with progression-free (PFS) and overall survival (OS). Among 4283 eligible patients, baseline status was categorized as BRCA/PALB2m in 80 patients (1.9%), BRCA/PALB2wt in 467 patients (10.9%), and untested in 3736 patients (87.2%). Median follow-up was 43.7 months [95%CI, 42.6-44.9]. Median PFS was significantly shorter in BRCA/PALB2m patients (9.9 months [7.6-13.0]) compared to BRCA/PALB2wt (15.4 months [13.9-17.3]) and untested patients (18.3 months [17.6-19.3]). In the multivariable analysis ((including age, number of metastatic sites, presence of visceral metastases, de novo status, and tumor grade), BRCA/PALB2m carriers had a shorter PFS compared to BRCA/PALB2wt (adjusted HR [95% CI] 1.61 [1.24-2.09]; p < 0.001). Time-varying approach, landmark analysis at 6-months and propensity score matching analysis showed consistent results. In this cohort, using a careful methodology, BRCA1/2 and PALB2 mutation carriers had reduced PFS with first-line ET + CDK4/6i compared to wild-type patients.