Abstract
Background: The use of statins has been associated with a reduced incidence of colorectal cancer. Potentially, statins may also have an influence on survival of colon cancer patients when used after diagnosis. The primary aim of this observational study was to evaluate the influence of statin use after diagnosis of colon cancer on overall survival. The secondary aim was to investigate the molecular background in which statins are effective adjuvant therapeutic agents, specifically KRAS mutational status and Bone Morphogenetic Protein pathway functionality, as these are the two most promising and frequently mentioned potential molecular mechanisms. Methods: Data was derived from the PHARMO database network (PHARMO, Netherlands) and was linked to a colon cancer cohort (Eindhoven Cancer Registry). A Tissue Micro Array (TMA) consisting of 999 colon cancer specimens was constructed from patients who had a surgical resection between 2002 and 2008. Survival was analyzed with statin user status after diagnosis as a time-dependent covariate. Multivariate Poisson regression survival models were used to study the effect of statins on overall survival (OS). The tumors were analyzed for SMAD4, BMPR1a, BMPR1b and BMPR2 expression, and KRAS mutations to perform stratified analyses for intact BMP signaling status and KRAS mutation status. Results: In this cohort 21.0% (210/999) of the patients were defined as statin users after colon cancer diagnosis. Statin use after diagnosis was significantly associated with an improved OS with an adjusted Rate Ratio (RR) of 0.67 (95% CI 0.51-0.87, P= 0.003). When stratified for intact BMP signaling status, survival benefit of statin use after diagnosis was stronger in tumors with intact BMP signaling (adjusted RR 0.46 (95% CI 0.29-0.74, P=0.001) than in tumors with a non-intact BMP signaling pathway (adjusted RR 0.75, 95% CI 0.53-1.06, P=0.106). Statin use after diagnosis was not associated with an improved OS in KRAS wild-type tumors (Adjusted RR 0.81, 95% CI 0.56-1.18, P=0.273) or KRAS mutated-tumors (Adjusted RR 0.59, 95% CI 0.35-1.03, P=0.062). Conclusion: Statin use after diagnosis is associated with an improved overall survival in colon cancer patients. This survival benefit is more prominent in tumors with intact BMP signaling. The survival benefit is independent of KRAS mutation status.
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