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

Abstract

To comprehensively characterize the clinical and genomic landscapes of <i>PIK3CA</i>, <i>AKT1</i>, and <i>PTEN</i> alterations and examine their functional and therapeutic implications in AKT-driven breast cancer. Comprehensive genomic profiling of 51,767 breast tumors was performed using FoundationOne CDx or FoundationOne. We examined the genomic landscape of <i>PIK3CA</i>, <i>AKT1</i>, and <i>PTEN</i> alterations and their distribution across clinical variables of interest. Prior deep mutational scanning (DMS) data were used to functionally characterize clinical <i>PTEN</i> variants. Real-world clinical outcomes were assessed in patients treated with capivasertib plus fulvestrant. 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 <i>PIK3CA</i> (37.4% of cases), followed by <i>PTEN</i> (13.5%) and <i>AKT1</i> (5.4%). The most common alterations in each gene were <i>PIK3CA</i> H1047R (35.6% of <i>PIK3CA</i>-altered cases), E545K (19.7%), and E542K (11.7%); <i>AKT1</i> E17K (69.7%); and <i>PTEN</i> homozygous copy number deletion (37.3%). <i>PIK3CA</i> alterations were less prevalent in patients of African genetic ancestry (27.1% vs 38.6% in European genetic ancestry), whereas <i>AKT1</i> and <i>PTEN</i> alterations were balanced across ancestries. DMS data on missense <i>PTEN</i> 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. Here, we present the landscape of <i>PIK3CA</i>, <i>AKT1</i>, and <i>PTEN</i> alterations in, to our knowledge, the largest clinical cohort examined to date. The functional complexity of rare <i>PTEN</i> 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.