Risk of basal cell carcinoma in a randomized clinical trial of aspirin and folic acid for the prevention of colorectal adenomas

Background: Aspirin may reduce the risk of several types of cancer. Objectives: To evaluate if folic acid is associated with risk of basal cell carcinoma (BCC). Methods: BCC incidence was evaluated in a randomized, double-blind, placebo-controlled clinical trial of aspirin (81 mg daily or 325 mg daily for ~3 years) and/or folic acid (1 mg daily for ~6 years) for the prevention of colorectal adenomas among 1121 participants with a previous adenoma. BCC was confirmed by blinded review of pathology reports. Results: One hundred and four of 958 non-Hispanic white participants were diagnosed with BCC over a median follow-up of 13·5 years. Cumulative incidence of BCC was 12% [95% confidence interval (CI) 7–17] for placebo, 16% (95% CI 11–21) for 81 mg aspirin daily and 15% (95% CI 10–20) for 325 mg aspirin daily [hazard ratio (HR) for any aspirin 1·45 (95% CI 0·93–2·26); HR for 81 mg daily 1·57 (95% CI 0·96–2·56); HR for 325 mg daily 1·33 (95% CI 0·80–2·20)]. BCC risk was higher with aspirin use in those without previous skin cancer but lower with aspirin use in those with previous skin cancer (P_interaction = 0·02 for 81 mg aspirin daily; P_interaction = 0·03 for 325 mg aspirin daily). Folic acid supplementation was unrelated to BCC incidence (HR 0·85; 95% CI 0·57–1·27). Conclusions: Neither aspirin nor folic acid treatment had a statistically significant effect on risk of BCC. Subgroup analysis suggested that chemopreventive effects of nonsteroidal anti-inflammatory drugs may be specific to those at high risk for BCC.