Abstract PS1-11-09: Real-world prevalence of ESR1 mutations (ESR1m) among patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) after first-line (1L) treatment with endocrine therapy (ET) and/or a cyclin dependent kinase 4/6 inhibitor (CDK4/6i)

Abstract Background: Patients (pts) with ER+/HER2- MBC often develop ESR1m during or after 1L treatment with ET with or without a CDK4/6i. Reported ESR1m prevalence rates vary, ranging from 20% to 50% after ≥1 line of therapy in the metastatic setting. Here, we explore the real-world prevalence of ESR1m and co-occurring mutations after 1L ET and/or CDK4/6i among pts with MBC in the GuardantINFORM database. Methods: This was a retrospective cohort study of adults in the United States with ER+/HER2- MBC and a Guardant360 comprehensive genomic profiling blood test of cancer-related gene mutations in circulating tumor DNA (ctDNA) between Jan 1, 2014 and Aug 31, 2024. Eligible pts had received any of the following 1L treatments within 6 months of diagnosis of metastatic disease: ET monotherapy (aromatase inhibitor [AI], selective ER modulator [SERM], or selective ER degrader [SERD]), CDK4/6i monotherapy, or ET (AI/SERM and/or SERD) + CDK4/6i combination therapy. Pts must have subsequently discontinued 1L therapy and received second-line (2L) treatment with follow-up >3 months. Pts were considered ESR1 evaluable if they had an ESR1 test ≤90 days before initiating 2L therapy (to rule out false negatives) or had a positive ESR1m result at any time before starting 2L therapy. ESR1m positivity was defined as missense mutations in codons 310-547. The proportion of ESR1-evaluable pts who were ESR1m positive was stratified by the type and duration of 1L treatment. The incidence of co-occurring AKT1 E17K, PIK3CA, PTEN, CCND1, ERBB2, FGFR1, KRAS, MYC, NF1, and RB1 mutations was analyzed. Results: Of 8335 adults with MBC treated with 1L ET and/or a CDK4/6i who had a Guardant 360 test, 4790 went on to receive 2L treatment with sufficient follow-up, and 1511 were ESR1 evaluable. Of these, 686 pts (45%) were ESR1m-positive, with the highest rates of ESR1m positivity among pts who received 1L SERD monotherapy or SERD + AI/SERM, and those who received 1L treatment for 12 to <24 months (Table). Among pts with ESR1m, 68% (466/686) had ≥1 other co-occurring mutation at start of 2L therapy, most commonly in genes involved in the PI3K/AKT signaling pathway (AKT1 E17K, PIK3CA, or PTEN; 50% [341/686]). Conclusions: In this real-world analysis of the GuardantINFORM database, 45% of pts with ER+/HER2- MBC were ESR1m-positive following 1L treatment with ET and/or CDK4/6i. The ESR1m positivity rate remained >40% in most subgroups analyzed according to 1L therapy type and 1L treatment duration. Other mutations co-occurred in >65% of pts with ESR1m. Citation Format: D. Chandiwana, D. Benjumea, K. Greco, C. Grace Rose, S. Stergiopoulos, J. Liao, M. Edwards. Real-world prevalence of ESR1 mutations (ESR1m) among patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) after first-line (1L) treatment with endocrine therapy (ET) and/or a cyclin dependent kinase 4/6 inhibitor (CDK4/6i) [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 PS1-11-09.