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

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 meaningful progression-free survival and overall survival benefit from capivasertib.

CONCLUSION

Here, we present the landscape of PIK3CA, AKT1, and PTEN alterations in, to our knowledge, the largest clinical cohort examined to date. The functional complexity of rare PTEN 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.