PIK3CA Mutations Predict for Response to Aspirin Therapy

Regular aspirin use has been suggested to lower cancer risk, but the underlying mechanisms are incompletely understood. Predictive biomarkers are also needed to determine which patients may benefit most from adjuvant aspirin therapy. Aspirin's role as a prostaglandin-endoperoxide synthase 2 (PTGS2; also known as cyclooxygenase-2) inhibitor may contribute to its protective effect, but molecular biomarkers other than PTGS2 expression that can be assessed in a standardized manner would be preferable. Based on previous evidence suggesting that PTGS2 inhibition down-regulates phosphatidylinositol 3-kinase (PI3K) activity, Liao and colleagues hypothesized that regular aspirin use might selectively prolong survival in the 15% to 20% of patients with colorectal cancer who harbor activating mutations in PIK3CA, which encodes PI3Kα. Individuals with colorectal cancer were identified among over 170,000 participants in 2 long-term prospective cohort studies that documented information on lifestyle factors, including aspirin use. Tumor tissue specimens were collected from the hospitals that participants visited, and PIK3CA status was determined in 964 patients from whom tumor DNA and data on postdiagnosis aspirin use were available. Regular use of aspirin following diagnosis was associated with significantly longer cancer-specific and overall survival only among patients with PIK3CA-mutant tumors. Furthermore, among patients with PIK3CA-mutant tumors, 26% of those who did not use aspirin died within 5 years of diagnosis, compared with only 3% of patients who took aspirin, whereas the 5-year cancer-specific mortality was 15% for patients with PIK3CA–wild-type tumors regardless of aspirin use. Although these findings obtained with a molecular pathological epidemiology approach require confirmation in larger, independent data sets, they suggest that cross-talk be tween PTGS2 and PI3K may contribute to the protective effect of aspirin use in patients with cancer and that PIK3CA mutation may represent a predictive biomarker for adjuvant aspirin therapy in colorectal cancer.

Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, et al. Aspirin use, tumor PIK3CA mutation, and colorectal cancer survival. N Engl J Med 2012;367:1596–606.

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