Aspirin Therapy for Colorectal Cancer With PIK3CA Mutation: Simply Complex!

Abstract

Prospective observational studies and randomized clinical trials have demonstrated that regular use of aspirin and selective cyclooxygense-2 (COX-2) inhibitors reduces the risk of developing colorectal cancer (CRC) and adenoma. More recently, large observational studies have suggested that regular aspirin use may also be associated with improved survival among patients with established CRC. The mechanisms by which aspirin influences CRC risk and possibly survival are poorly understood. COX-2 (or prostaglandinendoperoxide synthase 2 [PTGS2]) promotes inflammation and cell proliferation, and most adenomas and CRCs overexpress this enzyme. Previous studies have reported that aspirin may preferentially reduce the risk of COX-2–expressing CRC and also preferentially improve the survival of patients with CRC with COX-2–expressing tumors. Nonetheless, in laboratory models, aspirin seems to decrease proliferation and increase apoptosis in CRC cell lines without detectable COX activity. Ongoing studies have sought to define the molecular basis for the effect of aspirin on CRC risk and progression. In a large observational study of patients with CRC, Liao et al found that aspirin conferred improved survival in patients with PIK3CA-mutated CRC, but not among those with PIK3CA–wild-type tumors. In the report accompanying our article in Journal of Clinical Oncology, Domingo et al similarly observe a preferential benefit for aspirin in PIK3CA-mutated CRC in a large randomized trial of rofecoxib in patients with stage II/III CRC (VICTOR [Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime] trial), potentially moving us closer to clinical use of PIK3CA mutation as a predictive biomarker for aspirin use in patients with CRC. Here, we review some of the relevant complex relationships between aspirin, phosphatidylinositol 3-kinase (PI3K) signaling, and other cellular interactions.