Abstract PS1-12-17: Frequency and Prognostic Significance of ESR1 Mutations Post-CDK4/6 inhibitors in ER+/HER2− Metastatic Breast Cancer: Real-World Data from the GEICAMRegistEM Study

Abstract Background: Endocrine resistance in ER+/HER2- metastatic breast cancer is frequently mediated by ESR1 mutations. These mutations typically arise after prolonged endocrine therapy (ET) exposure in the metastatic setting, particularly with aromatase inhibitors (AI). This study evaluates the real-world evidence incidence and prognostic impact of ESR1 mutations in Spanish patients (pts) with ER+/HER2- advanced breast cancer (ABC) progressing on 1st line CDK4/6 inhibitor (CDK 4/6i) + ET. Methods: The GEICAM/2014-03 RegistEM study (NCT02819882) is an ongoing non-interventional cohort that collects prospective data and biological samples from patients with ABC, across 38 sites in Spain. A subset of 125 pts with ER+/HER2- ABC and available plasma samples collected at progression after 1st line with CDK4/6i + ET (n=125) was analyzed using the Plasma-SeqSensei™ BC IVD kit (Sysmex Inostics) to identify and quantify ctDNA mutations in six BC-related genes, ESR1, AKT1, ERBB2, KRAS, PIK3CA and TP53. Median PFS and OS were estimated from the Kaplan-Meier survival curves. Hazard ratios with 95% confidence intervals were obtained from multivariable Cox regression and logistics regression models, adjusted by clinical confounders (age, first metastatic, visceral disease, prior sensitivity to ET). Results: ESR1 mutation rates after progression on 1st line CDK4/6i + ET were 41. 6%. The incidence of mutations increased with longer duration of 1st line therapy and varied according to the ET partner. Among patients treated with fulvestrant (FULV), mutation frequencies were 15. 8% for 12 months, 50. 0% for 12-24 months, and 14. 3% for 24 months. In contrast, with aromatase inhibitors (AI), frequencies were 22. 2%, 61. 1%, and 65. 2%, respectively. Overall, The most common ESR1 mutations were D538G (28%), Y537S (17%), Y537N (16%), and E380Q (11%), all more common with AI than with FULV. Specifically, D538G was found in 35% of AI-treated patients vs. 11% with FULV; Y537S in 21% vs. 8%; Y537N in 21% vs. 3%; and E380Q in 12% vs. 8%. The detection of ESR1 mutations after CDK4/6i + ET was significantly associated with shorter mPFS, and showed a consistent trend toward worse OS, particularly with polyclonal ESR1 mutations (Table 1). Co-occurrence of ESR1 with PIK3CA/AKT1 or TP53 mutations was in 16. 8% and 14. 4%, respectively. The negative impact of ESR1 mutations on PFS and OS was independent of co-mutations in PIK3CA/AKT1 or TP53. Conclusions: ESR1 mutations are frequent after progression on CDK4/6i + ET, particularly following 1 year of AI, and are associated with poorer outcomes, especially when polyclonal. Their prognostic impact is independent of co-mutations in PIK3CA/AKT1 and TP53 and varies according to specific ESR1 variants. These findings support the use of ESR1 mutation profiling to guide treatment decisions post-CDK4/6i. Citation Format: Á. Guerrero-Zotano, S. Antolín, A. Tibau Martorell, J. Cruz-Jurado, R. Andrés, S. Saura, C. Rodríguez-Sánchez, E. Galve, C. Falo, M. Margelí-Vila, Á. Rodríguez-Lescure, A. Miguel, J. Chacón, E. Adrover-Cebrian, M. Corbellas -Aparicio, M. Marin-Alcalá, I. González-Maeso, S. Varela-Ferreiro, C. Arqueros, A. Antón-Torres, S. Servitja, D. Moreno-Muñoz, M. Merino, A. Ballesteros-García, M. Echarri-González, J. Alonso-Romero, R. Seijas Tamayo, V. Iranzo-Cruz, J. De la Haba-Rodríguez, J. Guerra, L. Palomar Abad, J. Illarramendi Mañas, A. Godoy Ortiz, A. García-Palomo, M. Ruíz-Borrego, R. Villanueva, S. Zazo, Y. Jerez-Gilarranz, C. Reboredo Rendo, N. Ancizar Lizarraga, I. Ceballos-Lenza, L. Murillo Jaso, L. Figuero, J. Herranz, N. Martín, D. Fernández-García, I. Álvarez López, S. López-Tarruella, F. Rojo Todo. Frequency and Prognostic Significance of ESR1 Mutations Post-CDK4/6 inhibitors in ER+/HER2− Metastatic Breast Cancer: Real-World Data from the GEICAMRegistEM Study 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 PS1-12-17.