Abstract P3-10-13: A Comprehensive Analysis of Dysregulation in the PTEN/PI3K/AKT Pathway in Breast Cancer Among the Chinese Population

Abstract Background: Breast cancer (BC) has the highest incidence rate among cancers in females in China. The PTEN/PI3K/AKT pathway regulates key biological processes, including apoptosis, metabolism, cell proliferation and growth in BC. This is the first comprehensive study to explore the association between these pathway gene alterations and clinical outcomes in a large cohort of Chinese BC patients. Methods: We retrospectively reviewed 1018 Chinese BC patients with clinical information from OrigiMed Chinese Real-World Database between 2016 and 2023. Tumor tissue samples and paired peripheral blood leukocytes were analyzed using an OrigiMed 450 gene next-generation sequencing panel. Chi-square test and Fisher’s exact test assessed differences in these genetic alterations across different subgroups and to examine the co-occurrence of alterations between these genes and other genes. Results: A total of 38.5%, 5.3% and 8.4% of Chinese BC patients exhibited alterations in PIK3CA, AKT1 and PTEN genes, respectively, which is similar to the Caucasian-dominated MSK-IMPACT cohort (PIK3CA: 38.5% vs. 35.2%, P =0.102; AKT1: 5.3% vs. 5.3%, P =0.995; PTEN : 8.4% vs. 7.0%, P =0.232). Subgroup analysis revealed higher PTEN alteration in stage Ⅳ patients compared to stage I-III (12.7% vs. 6.4%, P =0.001). Furthermore, HR+/HER2- BC patients exhibited a significantly higher incidence of PIK3CA (45.2% vs. 30.8%, P <0.001) and AKT1 (7.7% vs. 2.5%, P <0.001) gene alterations, compared to other subtypes. The overall incidence of alterations in the PTEN/PI3K/AKT pathway was 50.9%, which was higher among HR+/HER2- BC patients compared to other subtypes (57.0% vs. 43.9%, P <0.001). PIK3CA alterations were associated with lower AKT1 alterations (3.1% vs. 6.7%, P =0.011). ERBB2 alterations were associated with lower AKT1 (0.4% vs. 6.9%, P<0.001) and PTEN (4.4% vs. 9.7%, P =0.009) alterations. TP53 alterations were associated with higher PTEN/PI3K/AKT pathway alterations (55.4% vs. 45.9%, P =0.002). No significant differences in PIK3CA (25.6% vs. 21.4%), AKT1 (7.0% vs. 9.5%), and PTEN (14.0% vs. 23.8%) gene alterations were observed between primary and metastatic lesions in the same patients (N=41, P >0.05). No significant differences were found in the alterations of PIK3CA (38.7% vs. 41.1%), AKT1 (5.8% vs. 5.4%), and PTEN (10.4% vs. 7.6%) between samples taken before and after treatments such as chemo-immunotherapy and targeted therapy (N=840, P >0.05). Survival analysis (median follow-up: 32.7 months) showed PTEN alterations correlated with higher mortality risk (HR 2.779, 95% CI 1.083-7.132, P =0.034), while PIK3CA alterations were associated with reduced mortality risk (HR 0.338, 95% CI 0.141-0.820, P =0.016), with overall survival (OS) as the outcome. Conclusion: This study highlights the significant role of PIK3CA, AKT1 and PTEN gene alterations in Chinese BC patients. In Chinese BC patients, alterations in the PTEN/PI3K/AKT signaling pathway are common, and the frequencies of PIK3CA, AKT1 and PTEN gene are similar to that observed in Western countries. The gene alterations in this pathway are associated with clinicopathological features as well as prognosis, such as disease stage and BC subtypes, but not with primary/metastatic status or treatment. PIK3CA alterations were a benign predictor of survival, whereas PTEN alterations were a negative predictor. These findings suggest that genetic profiling of the PTEN/PI3K/AKT pathway could guide treatment strategies and prognosis prediction in Chinese BC patients. Future studies should focus on validating these findings in prospective cohorts and exploring targeted therapies based on these genetic alterations. Citation Format: Ziang Li, Meizhen Hu, Fei Pang, Bo Peng, Aodi Wang, Huanwen Wu. A Comprehensive Analysis of Dysregulation in the PTEN/PI3K/AKT Pathway in Breast Cancer Among the Chinese Population [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-10-13.