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April 11, 2026JCO Precision Oncology1 citations

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

JTJacqueline J. TaoColumbia University Irving Medical Center SSSaumya D. SisoudiyaFoundation Medicine (United States)HTHanna Tukachinsky

Key Points

The research aims to characterize the clinical and genomic landscapes of PIK3CA, AKT1, and PTEN mutations in breast cancer.
Conducted comprehensive genomic profiling of 51,767 breast tumors.
Examined genomic landscapes and distribution of gene alterations across clinical variables.
Utilized deep mutational scanning data to analyze PTEN variants.
Assessed real-world clinical outcomes for patients treated with capivasertib and fulvestrant.
Identified 29,157 variants across PIK3CA, AKT1, and PTEN.
PIK3CA was the most altered gene in 37.4% of cases, followed by PTEN at 13.5% and AKT1 at 5.4%.
Most common PIK3CA alterations included H1047R, E545K, and E542K; PTEN homozygous deletion appeared in 37.3% of cases.
Patients with rare AKT pathway variants showed significant progression-free survival benefits from capivasertib.

Abstract

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.

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