Cyclin-Dependent Kinase 4/6 Inhibitor Outcomes in Patients With Advanced Breast Cancer Carrying Germline Pathogenic Variants in DNA Repair–Related Genes. (2nd March 2022)

• Record Type: Journal Article
• Authors: Bruno, Luisina; Ostinelli, Alexis; Waisberg, Federico; Enrico, Diego; Ponce, Carolina; Rivero, Sergio; Blanco, Albano; Zarba, Martín; Loza, Martín; Fabiano, Verónica; Amat, Mora; Pombo, María Teresa; Noro, Laura; Chacón, Matías; Coló, Federico; Chacón, Reinaldo; Nadal, Jorge; Nervo, Adrián; Costanzo, Victoria
• Is Part Of: JCO precision oncology. Volume 6(2022)
• Publication Date: 2022-03-02
• Subjects: Precision Medicine; Neoplasms; Pharmacogenetics; Molecular Targeted Therapy; Personalized medicine; Oncology; Pharmacogenomics; Periodical; Periodicals; 616.994
• DOI: 10.1200/PO.21.00140
• Languages: English
• ISSNs: 2473-4284

Abstract

Abstract : PURPOSE: In recent years, unprecedented benefits have been observed with the development of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for the treatment of hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer. However, there is scarce evidence of their value in specific populations, such as patients carrying germline pathogenic variants in DNA repair–related genes. PATIENTS AND METHODS: We retrospectively studied the efficacy of CDK 4/6 inhibitors plus endocrine therapy in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer. Three cohorts were compared, including patients harboring germline pathogenic variants in DNA repair–related genes (g BRCA 1/2- ATM - CHEK2 mutated), those tested without these mutations (wild type [WT]), and the nontested subgroup. Relevant prognostic factors including age, metastatic site (visceral v nonvisceral), Eastern Cooperative Oncology Group, and prior treatment with CDK 4/6 inhibitors were stratified by univariate and multivariate Cox regression models. RESULTS: Among the total population (n = 217), 15 (6.9%) patients carried g BRCA 1/2 (n = 10)- ATM (n = 4)- CHEK2 (n = 1) pathogenic variants, 45 (20.7%) were WT, and 157 (72.4%) were nontested. Gene pathogenic variant carriers were younger ( P < .001). Most patients (164, 75.6%) had not received prior endocrine therapy in the advanced setting. Median progression-free survival was shorter in patients with evaluated germline pathogenic variants (10.2 months [95% CI, 5.7 to 14.7]), compared with WT and nontested patients (15.6 months [95% CI, 7.8 to 23.4], and (17.6 months [95% CI, 12.9 to 22.2]; P = .002). Consistently, a worse median overall survival was observed in the subgroup with germline pathogenic variants than in the WT group ( P = .006). Multivariable analysis showed that mutation status was an independent prognostic factor of progression-free survival ( P = .020) and overall survival ( P = .012). CONCLUSION: In this retrospective real-world study, g BRCA1 / 2 - ATM-CHEK2 pathogenic variants were independently associated with poor outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors. Abstract :