Aspirin, Ibuprofen, and the Risk of Colorectal Cancer in Lynch Syndrome

Abstract

Background: Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 causes a high risk of colorectal and other cancers (Lynch Syndrome). Use of aspirin has been shown to be associated with a reduced risk of colorectal cancer for the general population as well as for MMR gene mutation carriers. The aim of this study was to determine whether use of aspirin and ibuprofen in a nontrial setting is associated with the risk of colorectal cancer risk for MMR gene mutation carriers.

Methods: We included 1858 participants in the Colon Cancer Family Registry who had been found to have a pathogenic germline mutation in a MMR gene (carriers). We used weighted Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.

Results: A total of 714 carriers (38%) were diagnosed with colorectal cancer at a mean age of 42.4 (standard deviation 10.6) years. A reduced risk of colorectal cancer was associated with aspirin use (for 1 month to 4.9 years: HR = 0.49, 95% CI = 0.27 to 0.90, P = .02; for ≥5 years: HR = 0.25, 95% CI = 0.10 to 0.62, P = .003) and ibuprofen use (for 1 month to 4.9 years: HR = 0.38, 95% CI = 0.18 to 0.79, P = .009; for ≥5 years: HR = 0.26, 95% CI = 0.10 to 0.69, P = .007), compared with less than one month of use.

Conclusion: Our results provide additional evidence that, for MMR gene mutation carriers, use of aspirin and ibuprofen might be effective in reducing their high risk of colorectal cancer.

Figure 1.

Cox regression analysis for association between aspirin only use and the risk of colorectal cancer over time for mismatch repair gene mutation carriers. Adjusted for year of birth (1914–43, 1944–54, 1955–65, 1966–90) and average lifetime alcohol intake (0, 1, ≥2 drinks per day) and stratified by sex, country (USA, Australia/ New Zealand, Canada), cigarette smoking status (never, former, current), regular physical activity (at least 30 minutes per week for at least three months), and multivitamin intake (<1 month, ≥1 month). Upper and lower dashed lines represent upper and lower limit of 95% confidence interval, respectively. Solid line represents the hazard ratio.

Figure 2.

Cox regression analysis for association between ibuprofen only use and the risk of colorectal cancer over time for mismatch repair gene mutation carriers. Adjusted for year of birth (1914–43, 1944–54, 1955–65, 1966–90) and average lifetime alcohol intake (0, 1, ≥2 drinks per day) and stratified by sex, country (USA, Australia/ New Zealand, Canada), cigarette smoking status (never, former, current), regular physical activity (at least 30 minutes per week for at least three months), and multivitamin intake (<1 month, ≥1 month). Upper and lower dashed lines represent upper and lower limit of 95% confidence interval, respectively. Solid line represents the hazard ratio.