Real-world prevalence, co-occurrence, and descriptive analysis of ESR1 and PIK3CA mutations in metastatic breast cancer: A retrospective analysis.

e13060 Background: The approval of alpelisib for PIK3CA-mutated breast cancer in 2019 and elacestrant for ESR1-mutated cases in 2023 has significantly changed the therapeutic landscape. However, real-world data on the prevalence and demographic association of co-occurrence of these mutations remain limited. Understanding how these mutations coexist and influence clinical outcomes is essential for better patient management. This retrospective study aims to provide comprehensive insights into mutation prevalence and clinical characteristics in a real-world setting. Methods: This is a single institution retrospective chart review of patients diagnosed with metastatic breast cancer at Loyola University Medical Center who underwent next-generation sequencing (NGS) using commercial platforms (e.g., Tempus, Guardant360, FoundationOne) between 2018 and 2025. Data extracted included NGS evidence of mutation in PIK3CA and ESR1, demographics (age, sex), clinical comorbidities, and prior treatment history, including the type and line of endocrine and targeted therapies. Results: A total of 42 patients with hormone receptor–positive, HER2-negative metastatic breast cancer (MBC) with either ESR1 mutations, PIK3CA mutations, or both were included. Among these, 26.2% (11/42) demonstrated co-occurring ESR1 and PIK3CA mutations, with the number of detected mutations per patient ranging from 2 to 6. The most frequently observed mutations included ESR1 D538G, Y537S, and PIK3CA H1047R, H1047Y. The median age at diagnosis of metastatic disease in the co-occurrence group was 60 years (range: 48–76). Racial distribution included 72.7% White, 18.2% Black or African American, and 9.1% Other. The median time from diagnosis of MBC to detection of both ESR1 and PIK3CA mutations was 33.8 months (range 8.2–120.8 months). Among 11 patients with actionable ESR1 and/or PIK3CA mutations in the cohort, six (54.5%) received ESR1- and/or PIK3CA-targeted therapy following mutation detection. Prior to initiation of targeted therapy, patients had received a median of four prior lines of systemic therapy (range, 1–8). In the co-occurrence group, the median overall survival was 47.6 months, and the median progression-free survival was 15.1 months. Conclusions: Co-occurring ESR1 and PIK3CA mutations were observed in ~26% of patients with HR-positive, HER2-negative metastatic breast cancer. These patients were mostly older, White, and had received a median of four prior lines of therapy, with only half receiving mutation-directed treatment, likely reflecting the recent approval of these targeted agents.