Clinicogenomic Landscape and Function of <i>PIK3CA</i> , <i>AKT1</i> , and <i>PTEN</i> Mutations in Breast Cancer

PURPOSE: alterations and examine their functional and therapeutic implications in AKT-driven breast cancer. METHODS: variants. Real-world clinical outcomes were assessed in patients treated with capivasertib plus fulvestrant. RESULTS: mutations revealed that 32.5% showed discordant effects on protein stability and phosphatase activity. A subset of patients with rare AKT pathway variants derived meaningful progression-free survival and overall survival benefit from capivasertib. CONCLUSION: variants underscores the need for functional validation by tools such as DMS. Rare AKT pathway variants may predict clinical benefit from AKT inhibitors and warrant further clinical investigation.