Statin use and colorectal cancer risk according to molecular subtypes in two large prospective cohort studies

Use of statins is hypothesized to reduce colorectal cancer risk, but the evidence remains inconsistent. This may be partly explained by differential associations according to tumor location or molecular subtypes of colorectal cancer. We examined the association between statin use and colorectal cancer risk according to tumor location, KRAS mutation status, microsatellite instability (MSI) status, PTGS2 (cyclooxygenase-2, COX-2) expression, or CpG island methylator phenotype (CIMP) status in two large prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study. We applied Cox regression to a competing-risks analysis. We identified 1818 colorectal cancers during 1990-2006. Compared to non-users, current statin use was not associated with colorectal cancer (Relative Risk [RR] = 0.99, 95% CI = 0.86 to 1.14) or colon cancer (RR = 1.10, 95% CI = 0.94 to 1.29), but was inversely associated with rectal cancer (RR = 0.59, 95% CI = 0.41 to 0.84, P for heterogeneity <0.001). When we examined the association within strata of KRAS mutation status, we found no association with KRAS-mutated cancers (RR = 1.20, 95% CI = 0.87 to 1.67), but did observe a possible inverse association among KRAS-wildtype cancers (RR = 0.80, 95% CI = 0.60 to 1.06, P for heterogeneity=0.06). The association did not substantially differ by PTGS2 expression, microsatellite instability (MSI) status or CIMP status. Current statin use was not associated with risk of overall colorectal cancer. The possibility that statin use may be associated with lower risk of rectal cancer or KRAS-wild type colorectal cancer requires further confirmation.