Abstract PS2-02-04: Real-world treatment patterns and clinical outcomes in patients with emerging estrogen receptor 1 (ESR1)-mutated ER+ metastatic breast cancer in the U.S., 2018-2024

Abstract Background: Estrogen receptor alpha 1 (ESR1) mutations (m) are a significant driver of resistance to endocrine therapy (ET) in estrogen receptor-positive (ER+) advanced breast cancer (BC), leading to disease progression. Although the PADA-1 and SERENA-6 clinical studies highlighted the clinical relevance of monitoring for ESR1m emergence during first-line therapy (1L) and showed improvement in outcomes when therapy is changed upon detection, less is known about the real-world practice for patients with emergent ESR1m before progression and their outcomes. This study aims to characterize treatment patterns of patients whose tumors were tested for ESR1m during 1L and assess the impact of ESR1m on clinical outcomes, including real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). Methods: This retrospective, observational cohort study used the US-based, deidentified Flatiron Health Research Database. Adult patients with a confirmed diagnosis of ER+/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC from 1/1/2018 to 6/30/2024 were included. Treatment patterns were descriptively analyzed. rwOS and rwPFS were estimated for those with ESR1m emergence at first ESR1 test during 1L (time zero) using the Kaplan-Meier methodology and compared to those without ESR1 emergence at first ESR1 test using 1:1 propensity score matching on key covariates (time from 1L start to first ESR1 test result, ER expression level, presence of liver metastases, age, duration of prior aromatase inhibitor (AI) therapy, menopausal status). Results: This study included 8581 eligible patients, of whom 7772 (91%) initiated 1L therapy. Tumor ESR1m status was evaluated for 1335 (17%) during 1L, and 1086 were eligible for rwOS and rwPFS analyses. Treatment patterns in 1L were comparable between patients with (n=240) and without (n=1095) ESR1m emerging during 1L, with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + AI being the most common 1L treatment for patients with (140/240; 58%) and without (591/1095; 54%) ESR1m. CDK4/6i + fulvestrant was the second most common treatment for patients with (56/240; 23%) and without (248/1095; 23%) ESR1m. Patients not receiving 1L CDK4/6i + AI or CDK4/6i + fulvestrant received either ET monotherapy (9%), chemotherapy (3%), or other therapy (8%). Among patients who initiated 2L, those with an ESR1m detected during 1L compared to those without an ESR1m were more likely to receive 2L CDK4/6i + fulvestrant (49/202; 24% vs 93/573; 16%) or 2L elacestrant (29/202; 14% vs 1/573; 0.2%). Among those with an ESR1m detected during 1L (n = 240), median time to positive ESR1 test result was 18 months (mos) (IQR, 4-33) Median time from ESR1m detection during 1L to progression was 5.9 months. Eligible patients with an ESR1m detected on their earliest ESR1 test during 1L (n = 105) had shorter median rwPFS and median rwOS compared with those without an ESR1m (n = 981, rwPFS 7.7 mos 95% CI: 5.8-11.4 vs. 15.3 mos 95% CI: 14.0-16.8) and (rwOS 32.2 mos 95% CI: 21.1-Not Reached (NR) vs 45.6 mos 95% CI: 41.7-54.0). After propensity score matching, both median rwPFS (7.7 mos 95% CI: 5.7-11.4 vs 13.6 mos 95% CI: 9.9-16.5; hazard ratio HR 0.68 95% CI: 0.48-0.96) and median rwOS (32.2 mos 95% CI: 21.1-NR vs NR 95% CI: 35.4-NR, HR: 0.58 95% CI: 0.36-0.95) were shorter in patients with an ESR1m detected during 1L. Conclusion: Patients with metastatic BC whose tumors were found to harbor an ESR1m during 1L had worse clinical outcomes than those who did not have an ESR1m. These findings highlight the potential clinical benefit of surveillance for ESR1m during 1L, and the need for treatment options that delay progression and improve clinical outcomes for patients with emerging ESR1-mutated, ER+ breast cancer. Citation Format: J. L. Meisel, T. Pham, C. Chen, A. Kris, J. Roose. Real-world treatment patterns and clinical outcomes in patients with emerging estrogen receptor 1 (ESR1)-mutated ER+ metastatic breast cancer in the U.S., 2018-2024 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 PS2-02-04.