Clinicogenomic Landscape and Function of PIK3CA , AKT1 , and PTEN Mutations in Breast Cancer

作者：Jacqueline J. Tao, Saumya D. Sisoudiya, Hanna Tukachinsky, Alexa B. Schrock, E. Ebot, Smruthy Sivakumar, Ethan S. Sokol, Neil Vasan · 发表于：JCO Precision Oncology · 年份：2026 · DOI：10.1200/po-25-00609 · 被引用次数：1 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Advanced Breast Cancer Therapies、PARP inhibition in cancer therapy

PURPOSE To comprehensively characterize the clinical and genomic landscapes of PIK3CA , AKT1 , and PTEN alterations and examine their functional and therapeutic implications in AKT-driven breast cancer. METHODS Comprehensive genomic profiling of 51,767 breast tumors was performed using FoundationOne CDx or FoundationOne. We examined the genomic landscape of PIK3CA , AKT1 , and PTEN alterations and their distribution across clinical variables of interest. Prior deep mutational scanning (DMS) data were used to functionally characterize clinical PTEN variants. Real-world clinical outcomes were assessed in patients treated with capivasertib plus fulvestrant. RESULTS A total of 29,157 variants were identified across the three genes, including pathogenic variants and variants of uncertain significance. The most frequently altered gene was PIK3CA (37.4% of cases), followed by PTEN (13.5%) and AKT1 (5.4%). The most common alterations in each gene were PIK3CA H1047R (35.6% of PIK3CA -altered cases), E545K (19.7%), and E542K (11.7%); AKT1 E17K (69.7%); and PTEN homozygous copy number deletion (37.3%). PIK3CA alterations were less prevalent in patients of African genetic ancestry (27.1% vs 38.6% in European genetic ancestry), whereas AKT1 and PTEN alterations were balanced across ancestries. DMS data on missense PTEN mutations revealed that 32.5% showed discordant effects on protein stability and phosphatase activity. A subset of patients with rare AKT pathway variants derived meaningfu...