Predictive and Prognostic Analysis of PIK3CA Mutation in Stage III Colon Cancer Intergroup Trial

Phosphatidylinositol-4,5-bisphosphonate 3-kinase (PI3K) can activate the AKT signaling pathway and facilitate cellular growth, proliferation, and survival (1). Activating mutations in PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha gene; HGNC ID; HGNC:8975) have been found in various human malignancies, including colon cancers (2). A subset (10%–30%) of colorectal cancers harbor PIK3CA mutations, which have been associated with various clinical and molecular features, including proximal tumor location and KRAS mutation (3–16). Despite many previous studies (10–24), a prognostic role of overall PIK3CA mutation status in colorectal cancer remains uncertain, although coexistence of PIK3CA mutations in both exons 9 and 20 may be associated with shorter survival (13). Most of these previous studies were underpowered for robust statistical analysis (mostly with total sample size of less than 500 and 10%–20% frequency of PIK3CA mutation). Therefore, additional studies with a large sample size are needed. A recent study suggests that PIK3CA mutation in colorectal cancer may serve as a molecular biomarker to predict response to aspirin therapy (25). Nonetheless, clinical utility of PIK3CA mutation test on colorectal cancer as a predictive tumor biomarker remains to be fully characterized (22,26–29). We therefore conducted this study to examine prognostic and predictive roles of PIK3CA mutation in stage III colon cancer patients who enrolled in the National Cancer Institute–sponsored randomized clinical trial comparing postoperative adjuvant 5-fluorouracil (FU)/leucovorin (LV) with irinotecan/FU/LV (IFL) (CALGB 89803 [Alliance]) (30). Because data on postoperative treatment, performance status, and disease stage were carefully recorded in the trial, we could assess prognostic and predictive roles of PIK3CA mutations in colon cancer while controlling for potential confounding by those covariables and key molecular characteristics, including KRAS, BRAF, and microsatellite instability (MSI) status. It is important to consider KRAS, BRAF, and MSI status because these are now routinely assessed in colorectal cancer for patient management.