Statins reduce the risk on colorectal cancer in relation to SMAD4 expression
R. J. Jacobs1*, L. L. Kodach1, N. L. Weil1, P.W. Voorneveld1, H. Morreau2, G. R. Van
den Brink1,3, D. W. Hommes1, J. C. Hardwick1
1
Gastroenterology and Hepatology, LUMC, Leiden, 2Pathology, LUMC, Leiden, 3Tytgat
Institute for Liver and Intestinal Research, AMC, Amsterdam
Statins are thought to be protective against colorectal cancer (CRC).We have shown, in
vitro, that the effect of statins on CRC is mediated through the Bone Morphogenetic
Protein (BMP) pathway. Importantly, cancer cells with SMAD4 mutations, a central
element within the BMP pathway, are insensitive to statins. This suggests that statin
therapy in CRC will need to be individualized on the basis of the tumor’s molecular
characteristics. Our study was designed to molecularly investigate tumors from patients
who developed CRC during statin therapy and compare these with patients who
developed CRC while not receiving statin therapy. If statins are growth inhibitory only
in SMAD4 expressing tumors, the risk reduction in this subgroup should be significantly
higher than in CRC overall.
The aim of this study is to provide evidence in humans that the action of statins in CRC is
dependent on SMAD4 expression and that within the subgroup of SMAD4 expressing
tumors, statins may lead to clinically meaningful reductions in CRC. We used two linked
databases: the Dutch National Pathology Registry (PALGA), containing all diagnosed
CRC in the Netherlands and the PHARMO drug record linkage system, containing a
record of all drug prescriptions of registered patients. These databases enable the
investigation of associations between drug exposure and pathological diagnoses in a large
cohort of patients. Statin users between 2000 and 2008 (≥6 months) with no prior history
of CRC, chemotherapy or radiotherapy were selected. To control for risk factors for
ischemic heart disease, which broadly overlap with CRC risk, both statin users and
controls were selected from among β blocker users. All patients were run through the
PALGA database for CRC development after ≥ 6 months treatment. From both groups
CRC tissue was obtained for molecular analysis of BMP pathway elements using
immunohistochemistry (IHC).
A total of 69,272 patients used statins + β blockers (statin group) and 94,753 β blockers
only (control group). 957 patients developed CRC in the statin group and 1348 patients
within the control group. Statin users have a 14% overall risk reduction for CRC (RR =
0.86, 95% CI [0,76 – 0.98], p-value < 0,03). 300 cancers from each group were randomly
selected and analyzed for SMAD 4 expression. Results were corrected for age and
gender. In SMAD4 expressing CRC statins lead to a risk reduction of 34% (RR = 0.66,
95% CI [0.53 – 0.82], p-value < 0,0002).
Conclusion: Patients receiving statins have a small but significant overall reduction of the
risk of developing CRC. Statin use in SMAD4 high CRC leads to a much larger risk
reduction of 34%.