Abstract PS1-12-09: Therapeutic Implications of Concurrent ESR1 and PI3K Pathway Mutations in HR+/HER2- Metastatic Breast Cancer

Abstract Individualized cancer treatments have revolutionized oncologic care for patients. Mutations in the ESR1 gene confer resistance to endocrine therapies by enabling estrogen receptor (ER) activity independent of estrogen binding. Similarly, PIK3CA mutations activate the PI3k/AKT/mTOR signaling pathway, promoting cellular proliferation, signaling, and metabolism. This signaling can sustain ER transcription in the absence of estrogen, resulting in resistance to anti-estrogen therapies. Recent therapeutic advances targeting ESR1 and the PI3k pathway have demonstrated improved progression-free survival (PFS). The EMERALD trial showed that elacestrant significantly prolonged PFS in patients with advanced hormone positive breast cancer and ESR1 mutations. Likewise, alpelisib and capivasertib improved PFS in patients with PIK3CA-mutated, HR+, HER2- advanced breast cancer who had progressed on prior endocrine therapy. Little is known about the clinical significance of concurrent ESR1 and PIK3CA mutations in breast cancer patients. Both are associated with worse prognosis and resistance to endocrine therapy. We identified 58 patients at our institution with ESR1 mutations and 99 patients with PIK3CA mutations. Our dataset specifically analyzed 30 patients with concurrent mutations who were treated with ESR1 andPIK3CA inhibitors. In this cohort, the median PFS of 6.0 months (mo) (95% CI: 3.91 – 8.09), and the median overall survival (OS) of 22 mo (95% CI: 19.71-24.29). All patients were female, with a median age of 56 years (range: 32-74 years). Most had previously received a CKD4/6 inhibitor (91.7%). The cohort was predominantly non-Hispanic white (83.3%), with 4% black and 1% Hispanic. At the time of analysis, 76.7% had experienced disease progression or death. Patients with concurrent mutations who were treated with alpelisib had a median PFS of 14.50 mo (95% CI: 8.01-20.91) and a median OS of 24.56 mo (95% CI: 13.79-35.32). Patients treated with capivasertib had a median PFS of 6.79 mo (95% CI: 3.26-10.32) and all patients remain alive. Median PFS for those treated with elacestrant was 12.77 mo (95% CI: 7.19-18.34) and median OS was 19.32 mo (95% CI: 16.83-21.81). Patients who received both elacestrant and a PIK3CA inhibitor had a median PFS of 11.85 mo (95% CI: 5.79-17.91), median OS of 42.10 mo (95% CI: 30.26-53.94). When patients received elacestrant first, followed by a PIK3CA inhibitor, median PFS was 5.92 mo (95% CI: 3.40-8.44), median OS was 18.90 mo (95% CI: 15.74-22.06). Alternatively, if a PIK3CA inhibitor was given first followed by elacestrant, median PFS was 14.01 mo (95% CI: 5.48-22.54), median OS was not reached. Patients with concurrent mutations who had received both medications were further analyzed based on location of metastasis. Those with only bone metastases had a PFS of 15.93 mo (95% CI: 7.66-24.16), OS of 44.20 mo (95% CI: 27.54-60.87). Those with visceral metastases had PFS of 8.39 mo (2.55-14.23), OS of 20.54 mo (95% CI:14.75-26.32). These findings align with results from the SOLAR-1 and CAPItello-291 trials. However, our data uniquely demonstrates that patients with concurrent ESR1 and PIK3CA mutations, who were treated initially with PIK3CA inhibitor followed by elacestrant, had longer PFS and OS. This sequencing may offer improved outcomes, as PI3K mutations may confer a worse prognosis than ESR1 mutations. Prior studies, including EMERALD and EMBER-3, have indicated shorter PFS in patients with PI3K mutations treated with oral SERDs compared to those without PI3K pathway alterations. These findings highlight the need for future studies comparing institutional data across larger cohorts and prospective trials to better define optimal sequencing strategies for this subset of patients. Citation Format: K. Boldig, S. Ghosh, V. Dabak. Therapeutic Implications of Concurrent ESR1 and PI3K Pathway Mutations in HR+/HER2- 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 PS1-12-09.