Phosphorylated AKT Expression Is Associated With PIK3CA Mutation, Low Stage, and Favorable Outcome in 717 Colorectal Cancers

BACKGROUND: AKT (AKT1, AKT2, and AKT3) was a downstream effector of phosphatidylinositide-3-kinase (PI3K) and played crucial roles in protein synthesis, cellular metabolism, survival, and proliferation. The PI3K/AKT pathway was commonly activated in human cancers and was recognized as a potential target for anticancer therapy. Nonetheless, clinical, molecular, or prognostic features of AKT-activated colon cancer remained uncertain. METHODS: Using a database of 717 colon and rectal cancers in the Nurses' Health Study and the Health Professionals Follow-up Study, Ser473 phosphorylated AKT (p-AKT) expression was detected in 448 (62%) tumors by immunohistochemistry. Cox proportional hazards model was used to compute mortality hazards ratio (HR), adjusting for clinical and tumoral features, including PIK3CA, KRAS, BRAF, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), LINE-1 methylation, TP53 (p53), and FASN (fatty acid synthase). RESULTS: Tumor p-AKT expression was associated with PIK3CA mutation (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.12-2.80; P = .015). p-AKT expression was significantly associated with longer colorectal cancer-specific survival in Kaplan-Meier analysis (log-rank P = .0005), univariate Cox regression (HR, 0.62; 95% CI, 0.47-0.82; P = .0006) and multivariate analysis (adjusted HR, 0.75; 95% CI, 0.56-0.99; P = .048) adjusting for clinical and molecular variables including PIK3CA, MSI, CIMP and LINE-1 hypomethylation. p-AKT expression was inversely associated with high stage (III-IV) (adjusted OR, 0.63; 95% CI, 0.45-0.88, P = .0071). CONCLUSIONS: p-AKT expression in colorectal cancer is associated with low stage and good prognosis. p-AKT may serve as a tissue biomarker to identify patients with superior prognosis and a possible therapeutic target (analogous to estrogen receptor ESR1 in breast cancer). Cancer 2011; 117: 1399-408. (C) 2010 American Cancer Society.