Abstract P2-09-23: Differential outcomes of patients with HR-positive/HER2-negative metastatic breast cancer and a pathogenic BRCA1/2 or PALB2 variant under first line CDK4/6 inhibition

Abstract Background: Patients (pts) with HR-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) and pathogenic BRCA1/2 or PALB2 variants may derive less absolute benefit from CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET). Methods: The ESME MBC platform (NCT03275311) is a French real-world database including data from each newly diagnosed MBC patient having initiated at least one treatment from 2008 onwards in 18 comprehensive cancer centers. All women who initiated a first line treatment with CDK4/6i + ET between 2013 and 2023 were selected. 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 BRCA and PALB2 status (categorized as BRCA/PALB2m (mutated), BRCA/PALB2wt (wild type), and untested), with progression-free (PFS) and overall survival (OS). Results: Among 21696 pts with HR+/HER2- MBC, 4820 received 1st line ET + CDK4/6i and were eligible for this analysis (n=90 BRCA/PALB2m, n=523 BRCA/PALB2wt, n=4207 untested at the initiation of the first line). CDK4/6i included palbociclib (74%), ribociclib (17%), abemaciclib (13%) while ET partner included aromatase inhibitor (78,3%), fulvestrant (15,5%), or other (6,3%). BRCA/PALB2m carriers were younger and has less de novo MBC compared to untested patients. At the cut-off date of 2024/05/16, the median follow-up was 44.0m [43.1-45.1]. Median first line PFS was significantly shorter in BRCA/PALB2m pts compared with BRCA/PALB2wt and untested ones: 11.2m [8.9-16.1], 15.7m [14.2-17.3] and 18.9m [18.0-20.0] in BRCA/PALB2m, BRCA/PALB2wt and untested patients, respectively. In the multivariable analysis (including age, number of metastatic sites, presence of visceral metastases, de novo status, tumor grade and type of relapse (endocrine sensitive/resistant status), BRCA/PALB2m patients had a lower PFS compared to BRCA/PALB2wt patients (adjusted HR [95% CI] 1.48 [1.15; 1.90], p=0.003). Time-varying approach and landmark analysis at 6-month showed consistent results. This lower PFS did not translate into a lower adjusted OS with a median OS of 49.7m [42.2-not reached] and 50.1m [45.1; 57.2] in BRCA/PALB2m and BRCA/PALB2wt patients respectively (adjusted HR [95% CI] 0.93 [0.64; 1.36]). Conclusion: In this large cohort of HR+/HER2− MBC patients treated with first line CDK4/6i+ ET, pathogenic variants identified in BRCA or PALB2 genes are associated with a significantly lower PFS. The role of PARPi as first line therapy for these patients is currently investigated (NCT06380751) and further research is needed to determine if similar differences are observed in early breast cancer. Citation Format: Timothé Guinel, Amélie Lusque, Audrey Mailliez, Vincent Massard, Isabelle Desmoulins, Monica Arnedos, Anthony Gonçalves, Thomas Bachelot, Suzette Delaloge, Jean-Sebastien. Differential outcomes of patients with HR-positive/HER2-negative metastatic breast cancer and a pathogenic BRCA1/2 or PALB2 variant under first line CDK4/6 inhibition [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-09-23.