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Effect of aspirin, NSAIDS on colorectal cancer risk differs by genetic variables
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Use of aspirin or NSAIDs is associated with a reduced risk for colorectal cancer, although the extent of the risk reduction varied based on genetic factors, according to results of a case-control study.
Prior studies have demonstrated an association between aspirin or NSAID use with reductions in risk for colorectal cancer; however, the reasons for this association has not been clearly defined.
Andrew T. Chan
Andrew T. Chan, MD, MPH, program director of the gastroenterology training program at Massachusetts General Hospital, and colleagues looked to identify genetic markers that may be associated with differential chemoprevention benefits from aspirin or NSAIDs.
“Many studies, including randomized trials, have demonstrated that NSAIDs — particularly aspirin — protect against the development of colorectal cancer,” Chan told HemOnc Today. “However, these medications are known to have serious side effects — especially gastrointestinal bleeding. Thus, determining whether certain subsets of the population might not benefit from aspirin or NSAID use for the purpose of cancer prevention is an important strategy for better personalizing our recommendations for individual patients.”
Chan and colleagues conducted a genome-wide analysis of gene-by-environment interactions between single-nucleotide polymorphisms and the regular use of aspirin, NSAIDs or both in relation to colorectal cancer risk.
The investigators used data from five case-control and five cohort studies launched in the United States, Canada, Australia and Germany between 1976 and 2003.
They identified 8,634 colorectal cancer case patients and 8,553 matched controls. All participants were of European ancestry.
Overall, results showed regular use of aspirin and NSAIDs, either alone or together, was associated with lower risk for colorectal cancer compared with nonregular use (prevalence, 28% vs. 38%; OR = 0.69; 95% CI, 0.64-0.74).
Results of conventional logistic regression analysis revealed a genome-wide significant interaction between SNP rs2965667 and aspirin and/or NSAID use (P = 4.6 x 10-9).
Among patients with the rs2965667-TT genotype, aspirin and/or NSAID use was associated with a reduced risk for colorectal cancer (prevalence, 28% vs. 38%; OR = 0.66; 95% CI, 0.61-0.7). However, those with rare rs2965667-TA or rs2965667-AA genotypes — observed in 4% of patients in the cohort — use of aspirin or NSAIDs was linked to an increased risk for colorectal cancer compared with nonregular use (prevalence, 35% vs. 29%; OR = 1.89; 95% CI, 1.27-2.81).
A case-only interaction analysis showed a genome-wide significant interaction between SNP rs16973225 and use of aspirin and/or NSAIDs (P = 8.2 x 10-9). Among patients with the rs16973225-AA genotype, regular use was associated with a reduced risk for colorectal cancer (prevalence, 28% vs. 38%; OR = 0.66; 95% CI, 0.62-0.71). However, researchers did not observe this reduced risk among patients with AC or CC genotypes, observed in 9% of the cohort (prevalence, 36% vs. 39%; OR = 0.97; 95% CI, 0.78-1.2).
Confirmation of these findings could help facilitate targeted prevention strategies for colorectal cancer, the researchers concluded.
“We found that an individual's genetic background may predict whether he or she might not benefit from aspirin or NSAIDs for prevention,” Chan said. “Although it is premature to recommend genetic screening to guide clinical care, our findings do provide proof-of-principle for such a strategy and highlight the need to validate our results in other populations.”
In an accompanying editorial, Richard C. Wender, MD, chief cancer control officer for the American Cancer Society, suggested the study was noteworthy for four reasons: It advanced the understanding of how to do research that can detect gene–environment interactions; it proved that interventions can be genetically targeted to treatment and preventive interventions; it provides an understanding of how aspirin changes colorectal cancer risk; and it identifies the need to conduct future implementation research to make certain clinicians are equipped to implement gene–environment research in their daily practices.
“The ability to translate genetic profiling into tailored preventative care plans for individuals is still years away,” Wender wrote. “But with [this] study … the road, arduous as it may be, is more clearly illuminated.” – by Anthony SanFilippo
For more information:
Andrew T. Chan, MD, MPH, can be reached at Massachusetts General Hospital, 55 Fruit St., #148, Boston, MA 02114; email: achan@mgh.harvard.edu.
Perspective
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Jai N. Patel, PharmD
Although several studies have shown regular aspirin use has consistently been associated with a (dose-dependent) lower risk for developing colorectal cancer, the report by Nan and colleagues identified that about 9% of subjects experience no reduction in risk and 4% actually appear to have an increased colorectal cancer risk, based on genetic variables. As such, it is critical to identify whether benefits of aspirin outweigh toxicity on an individual patient level.Although limitations such as inclusion of heterogenous populations and nonstandardized definitions of regular aspirin use are evident in this study, the results are notable as they establish proof-of-concept that genetics may predispose patients to beneficial or nonbeneficial effects of aspirin chemoprevention. Given low minor allele frequencies and need for replication studies in homogenous cohorts of patients with standardized aspirin use, in addition to current U.S. Preventive Services Task Force recommendations against routine chemoprevention, the results are not likely to impact clinical practice in the near future.
However, these results and future research may be critical for subpopulations, such as younger patients without high risk for cardiovascular disease (ie, not already receiving routine aspirin for cardioprotection) and those at high risk for colorectal cancer (ie, Lynch syndrome). In addition to these findings, genetic predictors in drug metabolism genes (eg, cytochrome P450s, uridine diphosphate glucuronosyltransferases) and varying responses based on COX-2 pathway expression should be studied further. Nevertheless, proven methods that may reduce colorectal cancer risk — including routine screening, exercise, weight loss, diet, limiting alcohol intake and quitting smoking — should be routinely recommended in all patients as the data regarding personalized chemoprevention continues to mature.
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