Abstract PS2-06-11: Real World Experience of PIK3CA, AKT inhibitors, and oral SERD in patients with hormone receptor positive metastatic breast cancer

Abstract Background PIK3CA/AKT/PTEN pathway alteration is the most common cancer driver pathway in hormone-positive (HR+) metastatic breast cancer(MBC), and multiple PIK3CA/AKT targeted therapies were recently approved for routine clinical use. In addition, oral selected estrogen receptor downregulator (SERD) elacestrant is currently approved for ESR1-mutated HR+ MBC as a single agent only. Approximately 15% of HR+MBC harbor PIK3CA and ESR1 co-mutation. Restricted by available clinical trial eligibilities, there is no clear guideline for rational sequencing of these agents in post-CDK4/6 inhibitor setting. This report is aimed to describe the real-world experience of the PIK3CA pathway inhibitor and oral SERD use in patients with HR+ MBC. Method Patients with HR+/HER- breast cancer at the Cedars-Sinai Medical Center who received PIK3CA pathway inhibitors including alpelisib, inavolisib, or capivaserib were included and dated from January 2019 to June 2025. The retrospective study was conducted through an IRB-approved protocol. Genomic Alterations were identified via standard-of-care commercial NGS platforms. PFS was evaluated as the time to start treatment to disease progression or death from any cause. PFS was calculated by survival analysis and described with Kaplan-Meier curve. Result A total of 107 patients who had PIK3CA pathway alteration and received PI3CK/AKT inhibitors were identified: fulvestrant alpelisib (N=51), fulvestrant capivasertib (N=35), inavolisib (N=2), 2 or more PIK3CA/AKT inhibitors (N=11), and PIK3CA/AKT inhibitors and Elacestrant (N=8). The median age was 66 (34-86). Race: White, 77; African American,11; Asian, 9; other, 6; unknown, 3; declined, 1. 96 out of 107 patients had invasive ductal cancer; 11 patients had invasive lobular carcinoma. Median prior lines of therapy were 2 (0-9). 105 patients received prior CDK 4/6 inhibitors. Median PFS was: alpelisib 3.2 months (95% CI 2.6- 4.5) and 5.4months (CI 3.1-10.9) for capivasertib-treated patients by survival analysis. In 11 patients receiving 2 PIK3CA/AKT inhibitors, mPFS1 was 10.4 months (95% CI 5.8-24.4) and mPFS2 was 9.1 months (95% CI 2.2-N/A). 20 out of 107 patients had PIK3CA and ESR1 co-mutations. Among 20 patients, 8 patients received SERD and PIK3CA/AKT inhibitors sequentially. 3 patients started elacestrant first, and 5 received PIK3CA/AKT inhibitors first. The median PFSs of 3 patients who received 1st line elacestrant followed by AKT inhibitors were 1.6, 7.8, and 20.1 months, respectively. Otherwise, the PFS of 1st line PIK3CA/AKT inhibitor patients were 4.6, 6.7, 9.7, and 12.0 months. One patient with alpelisib experienced treatment interruption and dose reduction due to skin toxicity, while Elacestrant was well-tolerated without major adverse effects. Regarding other co-mutations, the most frequent alteration is CDH1, which is known to be a hallmark in ILC. ATM mutation was the 2nd common alteration (4 of 107), and BRCA1/CHEK2 mutation was observed in 2 patients. Conclusion In this retrospective analysis, 15% of patients with PIK3CA/AKT mutation reported ESR1 co-mutation. Our study is limited by its small sample size, and we observed most patients with ESR1 and PIK3CA pathway co-mutation were able to benefit from sequential therapy of oral SERD or PIK3CA pathway inhibitors, whichever treatment comes first, and showed a favorable response to either treatment. Future effort for a multi-institutional study is planned. Citation Format: Y. Choi, D. Lin, P. McAndrew, M. El-Masry, D. Park, N. Banerjee, C. T. Chung, D. M. Hoffman, J. Bitar, Y. Yuan. Real World Experience of PIK3CA, AKT inhibitors, and oral SERD in patients with hormone receptor positive metastatic 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 PS2-06-11.