In this large, prospective study of two well-characterized, population-based cohorts, we found that statin use was not significantly associated with overall risk of colorectal cancer. However, we did observe a potential inverse association with risk of rectal cancer. In addition, our results suggest a possible differential association according to KRAS mutation status. To our knowledge, our study is the first to examine statin use and colorectal cancer according to molecular features of the tumor.
Substantial experimental data support a potential anti-cancer effect of statins. Statins induce apoptosis, inhibit cell proliferation, attenuate angiogenesis, and delay the metastatic process in in vitro
and in vivo
). However, the results from human studies have not been consistent. Two systematic reviews observed modest reductions in colorectal cancer with statin use in case-control studies, but no clear association in randomized clinical trials or cohort studies (1
). The lack of association between statin use and overall colorectal cancer we observed in this study is largely consistent with prior cohort studies. Generally, cohort studies may be less prone to the biases of case-control studies, which include differential sampling of cases and controls and differential recall of statin use or other confounding factors by cases compared with controls.
We did observe a potential inverse association between statin use and rectal cancer. Because this finding is based on a relatively limited number of rectal cancer cases, these results should be interpreted cautiously. However, a test for heterogeneity of the association of statin use with colon or rectal cancer was statistically significant and a differential effect by site is biologically plausible. There are significant differences in risk factors, prevalence of specific molecular alterations, and gene expression levels that have been described according to cancer site (10
). A few studies have similarly observed inverse associations between statin use and rectal cancer (37
). Statin use was associated with 30- 62% lower risk of rectal cancer in case-control studies that included 136 cases in US (39
) and 344 cases Israel (38
). Using information from a pharmacy database linked to hospital records in the Netherlands, a prospective cohort study observed a RR of 0.48 (0.95% CI = 0.16-1.48) of rectal cancer associated with statin use. However, others have not found inverse associaions (40
). Further investigation of the effect of statins on rectal cancer compared with colon cancer is warranted.
We examined the effect of statin use according to risk of cancers defined by KRAS
mutation status. Although the specific mechanism by which statins are chemopreventative is not known, statins are hypothesized, at least in part, to modulate KRAS
, which mediates downstream signaling of the epidermal growth factor receptor (EGFR). Statins inhibit the mevalonate pathway thereby suppressing biosynthesis of cholesterol as well as isoprenoids utilized for the post-translational prenylation of RHO and RAS proteins, including KRAS
. Prenylation is a requisite step for functional KRAS
in its signaling and transforming activities (6
). Mutations in KRAS
, found in 40% of colorectal cancers, lead to a constitutively active state of cell growth and proliferation independent of EGFR signaling. Previous work has demonstrated that EGFR inhibitors are effective in treatment of KRAS
-wildtype colorectal cancer but not KRAS
-mutant colorectal cancer (45
). Our data similarly suggest that a potential inverse association between statin use and colorectal cancer may be limited to KRAS
-wildtype tumors. This highlights the possibility that statins have a more important effect on KRAS
signaling driven by EGFR activation than KRAS
that is permanently activated through mutation. Nonetheless, these findings should be interpreted with caution since the p value for interaction was not statistically significant, particularly in view of the multiple hypotheses tested.
Beyond mevalonate pathways, statins have been proposed to inhibit cancer through its anti-inflammatory mechanisms (46
). Although experimental studies suggest that statins may act synergistically with NSAIDs (5
), most, but not all (4
) human studies have not seen significant modification of the effect of statins by concurrent use of NSAIDs (38
). In our study, we also did not observe a differential effect of statin use according to use of aspirin or expression of the pro-inflammatory enzyme PTGS2 (COX-2). However, it remains possible that statins may have anti-inflammatory effects that are independent of aspirin or COX-2 related pathways.
Finally, we also considered the effect of statins according to tumor subtypes defined by MSI or CIMP status. About 15% of sporadic colorectal cancers are MSI-H, arising primarily through epigenetic silencing of DNA mismatch repair proteins (49
). In contrast, the vast majority of sporadic colorectal cancers are MSS or MSI-L, developping through traditional chromosomal instability pathways. Colorectal cancer with CIMP-high status was associated with MSI and is well characterized as a major epigenetic marker in colorectal cancer (13
). However, in the present analysis, we did not observe a differential effect of statins on cancers subtyped by MSI or CIMP status.
Our study has several important strengths. First, our prospective cohort design minimized potential biases introduced by differential selection and recall found in case-control studies. Second, we collected detailed and updated information on statin use and other potential important confounding factors in a cohort with a high follow-up rate. Third, because our participants were all health professionals, the accuracy of self-reported statin use is likely to be high and is more likely to reflect their actual use than prescription records. Finally, we examined the effect of statins on molecularly-defined subtypes of colorectal cancer, an example of the emerging interdisciplinary field of “Molecular Pathologic Epidemiology
), Through molecular pathologic epidemiology studies, a known or suspected etiologic or modifying lifestyle factor, such as statin use, can be related to a specific somatic molecular change to gain insight into mechanism, provide evidence for causality, and potentially lead to more targeted approaches to prevention or therapy (8
There are several limitations to our study. First, our study is observational. Thus, we cannot rule out the possibility of residual confounding. However, our overall findings are consistent with most prospective cohort studies. Moreover, our results suggesting an inverse association with KRAS
-wildtype tumors has biological plausibility given our understanding of the effect of statins on the mevalonate pathway. Second, the prevalence of statin use, especially in the longer duration categories, was relatively low. However, as a prospective cohort study, our prevalence reflects secular trends in statin use (15% of current use) in the U.S. over the time period of the study (1994-2006) and is consistent with the prevalence of statin use described in another U.S. population-based cohort (20% of current use) conducted in an overlapping time period (1997-2001)(47
). Nonetheless, as the number of individuals prescribed statins increases over time, further studies with more extended follow-up are needed. Third, we did not specifically examine different types of statins. Although it has been suggested that specific statins may have distinct effects depending on whether they are hydrophilic or lipophilic, no studies that have directly compared various statins in the same population have observed significant differences in associations. Finally, we did not have tumor tissue available from all cases of confirmed colorectal cancer ascertained in the two cohorts. However, the characteristics of cases without available tumor tissue did not appreciably differ from those of cases with available tumor tissue (17
In summary, our study does not support an overall effect of statin use on risk of colorectal cancer. However, a possible inverse association with risk of rectal cancer or KRAS-wildtype colorectal cancer requires further investigation. If confirmed, our results would provide mechanistic insight into the anti-cancer effects of statins and support the potential use of molecular markers to tailor chemoprevention.