Abstract PS2-10-10: Ten-year outcomes of Chinese early breast cancer patients with PIK3CA/AKT1 mutations: A retrospective cohort study

Abstract Background: Multiple clinical trials have demonstrated that PI3Kα and AKT inhibitors improved survival in advanced hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- breast cancer patients with PIK3CA/AKT1 mutations. However, their prognostic relevance in early breast cancer (EBC) remains unclear. This study aimed to evaluate the prevalence and long-term prognostic impact of PIK3CA/AKT1 mutations among EBC patients in China. Methods: Based on the Breast Cancer Information Management System (BCIMS) in West China Hospital (WCH), Sichuan University, we retrospectively enrolled patients diagnosed with stage I-III breast cancer between Jan 2008 and Dec 2014 from WCH BC Cohort. Patients with available fresh-frozen tumor tissue were included. Those receiving neoadjuvant therapy were excluded. Clinical and follow-up data were extracted from BCIMS. Whole exons of PIK3CA and AKT1 were detected in fresh-frozen primary tumors by next-generation sequencing. Descriptive statistics were performed for baseline characteristics. Prognostic outcomes were analyzed by Kaplan-Meier survival curves, and hazard ratios (HRs) were calculated via multivariable Cox regression models. Results: A total of 569 EBC patients were included, with a median follow-up duration of 12.4 years. The overall mutation rate of PIK3CA/AKT1 was 50.1% (HR+/HER2-: 59.6%, HER2+: 41.3%, TNBC: 29.6%). Specifically, 47.3% patients harbored PIK3CA mutations, while 3.9% carried AKT1 mutations. Forty-five patients (7.9%) carried ≥2 variants in PIK3CA and/or AKT1. PIK3CA mutations were more common in HR+ (vs. HR-, 50.7% vs. 36.9%), HER2- (vs. HER2+, 50.0% vs. 41.3%), and WHO grade I-II tumors (vs. grade III, 52.8% vs. 44.0%). 522 patients with ≥10 years of follow-up were included in survival analysis. The 10-year invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival (OS) rates for patients with PIK3CA/AKT1 mutations were 87.1%, 87.5%, and 91.1%, respectively. However, compared to wild-type patients, those with PIK3CA/AKT1 mutations showed no significant outcome differences. Furthermore, after adjusting for age, menopausal status, T stage, N stage, and treatment, multivariable Cox regression indicated that patients with ≥2 PIK3CA/AKT1 mutations conferred a significantly higher risk of progression or death compared to wild-type patients (aHR = 2.13, 95% CI: 1.02-4.45, p = 0.045), whereas single PIK3CA/AKT1 mutation did not show significant impact on prognosis. Similar trends persisted within the HR+ subgroup treated with endocrine therapy (≥2 mutations vs. wild-type, aHR = 2.39, 95% CI: 1.07-5.34, p = 0.034). Conclusion: Half of Chinese EBC patients harbored PIK3CA/AKT1 mutations, with a notably higher prevalence in the HR+/HER2- subgroup. While the long-term prognosis of patients with PIK3CA/AKT1 mutations overall was generally comparable to that of wild-type patients, those harboring multiple mutations may exhibit an increased risk of disease progression or mortality. Citation Format: T. Luo, W. Zeng, J. Peng, J. Yan, Y. Gui, Y. Song, Z. Li, X. Zhong. Ten-year outcomes of Chinese early breast cancer patients with PIK3CA/AKT1 mutations: A retrospective cohort study [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 PS2-10-10.