PIK3CA Mutation Predicts Poor Prognosis in Stage I-III Colorectal Cancer
S Ogino, K Nosho, GJ Kirkner, K Shima, N Irahara, S Kure, AT Chan, JA Engelman, P Kraft, LC Cantley, EL Giovannucci, CS Fuchs. Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston; Dana-Farber Cancer Institute, Boston; Harvard School of Public Heath, Boston; Massachusetts General Hospital, Boston; Beth Israel Deaconess Medical Center, Boston
Background: PIK3CA mutation and subsequent activation of the AKT pathway play an important role in the development of a subset of colorectal cancers. However, little has been known on the prognostic significance of PIK3CA mutation in colorectal cancer.
Design: Utilizing 751 colorectal cancers (stage I-IV) in two independent prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study), we detected PIK3CA mutation in 117 (16%) tumors by Pyrosequencing. Cox proportional hazard models were used to compute hazard ratios (HRs) of colon cancer-specific and overall mortalities, unadjusted and adjusting for patient characteristics and tumoral molecular features, including AJCC stage, microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), LINE-1 methylation, KRAS, BRAF and p53. An interaction between PIK3CA and KRAS mutations was assessed using the cross product term of the PIK3CA and KRAS variables and likelihood ratio test.
Results: Among stage I-III colorectal cancers, PIK3CA mutation was associated with an increase in cancer specific mortality by univariate analysis [HR 1.64; 95% confidence interval (CI), 0.95-2.86], which became significant after adjusting for other potential prognostic factors in multivariate analysis (adjusted HR 2.23, 95% CI, 1.21-4.11). The effect of PIK3CA mutation on mortality appeared to differ according to KRAS-mutational status. Among patients with KRAS-wild-type tumors, the presence of PIK3CA mutation was associated with a significant increase in cancer-specific mortality (HR 3.80, 95% CI, 1.56-9.27). In contrast, PIK3CA mutation conferred no significant effect on cancer-specific mortality among patients with KRAS-mutated tumors (HR 1.25; 95% CI, 0.52-2.96), although the interaction was not statistically significant (Pinteraction=0.13). PIK3CA mutation was unrelated with prognosis in stage IV tumors.
Conclusions: PIK3CA mutation is associated with shorter cancer-specific survival in stage I-III colorectal cancer. The adverse effect of PIK3CA mutation may be potentially limited to patients with KRAS-wild-type tumors.
Monday, March 9, 2009 1:00 PM
Poster Session II # 73, Monday Afternoon