Abstract PS1-08-10: Adherence to Guidelines Recommended Germline Testing and Mutational Status of BRCA1/2 Genes and Beyond as a Predictor of Response to CDK4/6 Inhibition in Advanced Breast Cancer

Abstract Objective: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard first-line treatment for hormone receptor-positive/HER2-negative advanced breast cancer (HR+ HER2- ABC). Germline BRCA1/2 mutation (gBRCAm) has been associated with poorer treatment outcomes in this setting, but the predictive value of other germline breast cancer susceptibility gene mutations (beyond-BRCAm) remains unexplored. Methods: We aimed to compare time to treatment failure (TTF) in gBRCAm and beyond-BRCAm vs. patients without confirmed germline mutations treated with CDK4/6i at the Department of Oncology of the University Hospital Centre Zagreb from 2018 to 2023. Clinical data were collected retrospectively and prospectively depending of the timing of germline testing. TTF, defined as discontinuation due to progression, toxicity, or patient preference, was analyzed using Kaplan-Meier estimates, and group comparisons were assessed with the log-rank test. Results: Among 389 patients treated with CDK4/6i at our institution in advanced setting, only 49 of them (12.6%) underwent germline genetic testing. Of these, 9 (18.4%) were gBRCAm (2 BRCA1, 4 BRCA2, 3 PALB2), 7 (14.3%) were beyond-BRCA (ATM, CHEK2, FANCI, FANCC, AIP, LZTR1, and MYC), and the remaining 33 (67.3%) were without confirmed germline mutations. Treatment failure occurred in 35 out of 49 patients. The overall median TTF was 20 months (95% CI, 16-29), with a mean TTF of 31.3 months (95% CI, 23.3-39.3). In the gBRCAm cohort (n=9), treatment failure occurred in 8 patients. Median TTF was 9 months (95% CI, 6-NA), and mean TTF was 19.9 months (95% CI, 6.0-33.8). In the non-gBRCAm cohort (n=40), treatment failure occurred in 27 patients. Median TTF was 23 months (95% CI, 18-56), and mean TTF was 34.6 months (95% CI, 25.4-43.8). TTF was significantly shorter in gBRCAm subgroup (log-rank χ2 = 4.7, p = 0.03). In the beyond-BRCA subgroup (n=7), treatment failure occurred in 5 patients. Median TTF was 17 months (95% CI, 10-NA), and mean TTF was 35.6 months (95% CI, 13.9-57.3). In the group without confirmed germline mutations (n=33), treatment failure occurred in 22 patients. Median TTF was 24 months (95% CI, 18-NA), and mean TTF was 35.2 months (95% CI, 24.9-45.5). Log-rank comparison for the three subgroups yielded χ2 = 4.7, p = 0.09. Conclusion: In this single-institution cohort, gBRCAm patients demonstrated significantly shorter TTF when treated with CDK4/6i combined with endocrine therapy, suggesting outcomes consistent with results of previous studies in this specific patient population. Patients with beyond-BRCAm showed TTF outcomes comparable to those without confirmed germline mutations, although interpretation is limited by the small sample size. Notably, only 12.6% of patients underwent germline genetic testing, highlighting a need to adhere to BRCA1/2 testing guideline recommendations for ABC to optimize individualized treatment strategies in HR+/HER2- ABC. Expanded genetic testing and further studies are warranted to clarify the predictive value and underlying mechanisms of resistance for both gBRCAm and beyond-BRCAm. Citation Format: E. Paponja, K. Čular, K. Kanceljak, K. Bilić, M. Križić, M. Matec, M. Popović, I. Rako, N. Dedić Plavetić. Adherence to Guidelines Recommended Germline Testing and Mutational Status of BRCA1/2 Genes and Beyond as a Predictor of Response to CDK4/6 Inhibition in Advanced Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-10.