The ability of aspirin and related nonsteroidal anti-inflammatory drugs (NSAIDs) to protect against colorectal cancer depends on an individual's genetic make-up, according to a new study.
In fact, the drugs confer no benefit on some people, and can cause harm in others.
"Many studies, including randomized trials, have demonstrated that NSAIDS, particularly aspirin, protect against colorectal cancer," said study author Andrew T. Chan, MD, MPH, associate professor in the Department of Medicine at Harvard Medical School in Boston. "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 use for the purpose of cancer prevention may allow us to better personalize our recommendations."
The findings, published in the March 17 issue of JAMA, come from a review of studies involving 19,000 Europeans, among whom were 8634 patients with colorectal cancer and 8553 control subjects.
Overall, the risk for colorectal cancer was lower in people who regularly used aspirin, NSAIDs, or both than in people who did not (odds ratio [OR], 0.69).
But not everybody benefits.
The association between the use of aspirin, NSAIDs, or both and a reduction in the risk for colorectal cancer was linked to a genetic variation at two highly correlated single-nucleotide polymorphisms (SNPs) at chromosome 12p12.3 (rs2965667 and rs10505806), as well as a third SNP, rs16973225.
For 96% of the cohort, the regular use of aspirin or NSAIDs was significantly associated with a lower risk for colorectal cancer.
However, for individuals with a rare genotype (found in 4% to 5% of the cohort), aspirin use was associated with a higher risk for colorectal cancer.
There was no benefit or risk for 9% of the cohort with variations in the rs16973225 SNP.
Validation Needed
"We found that an individual's genetic background may predict whether he or she might benefit from aspirin for prevention," Dr Chan told Medscape Medical News. "These findings may allow us to target specific individuals, defined by their genetic profile, for aspirin chemoprevention."
"In addition, we found that the variation in genes that influence benefit were associated with biologically plausible pathways," he explained. "Thus, these results illuminate potential molecular targets for novel chemopreventive agents."
The results need to be validated before they can be used in the clinical setting. "But even though it is premature to recommend genetic screening to guide clinical care, our findings provide proof-of-principle for a precision-medicine strategy for prevention and highlight the need to validate our results in other populations," Dr Chan noted.
Another expert agrees that further verification is needed.
"The results of the study are interesting, but it pays to be cautious. We need to see confirmation in other studies," Peter Rothwell, MD, PhD, a professor of clinical neurology at the University of Oxford, United Kingdom, and an expert in the health effects of aspirin, said in a statement.
"The genetic variants on which the findings are based are only present in 4% of the population, so the number of people who carried them in the study will have been relatively small," said Dr Rothwell, who was not involved in the study.
"In this situation, there is always a significant possibility of chance findings," he added. "The result needs to be repeated in further studies, ideally in randomized controlled trials of aspirin, before it can be regarded as being valid."
Illuminating the Road
It is not surprising that the population-wide protective effect of aspirin is roughly similar to the effect observed in people with protective genotype rs2965567 TT genotype, which is present in about 96% of the population, explains Richard C. Wender, MD, from the American Cancer Society, in an accompanying editorial.
According to Dr Wender, the complexity lies more in making clinical decisions when considering the 4% of the population with genotype TA or AA. "Among these individuals, not only was no protective association found, but use of aspirin, NSAIDs, or both was associated with an increased risk of colon cancer," he writes.
"Clinical decision making regarding preventive interventions requires balancing the risks and benefits of the intervention," he notes. "Since the majority of individuals exposed to the intervention will never develop the targeted disease, most individuals cannot possibly experience a benefit, yet they are at risk for harms."
These new data add "complexity to a clinical question" that the oncology community has been grappling with for years. Numerous studies have shown a protective effect, so should healthy adults take aspirin regularly to reduce their risk for colon cancer? he asks.
The US Preventive Services Task Force endorses aspirin use for individuals with established cardiovascular and cerebrovascular disease, and given the "proven value of screening to prevent colon cancer and to reduce risk of death, aspirin for chemoprevention is a more attractive option for people who refuse screening and who are at high risk for cardiovascular disease," Dr Wender explains.
In the not-too-distant future it might be possible to offer affordable and effective genetic testing to healthy individuals to more accurately determine the benefits and risks of such prevention, Dr Wender notes. But for now, research "needs to test different approaches to translating this complex information into practical methods to share information and improve clinical decisions."
Even though the ability to translate genetic profiling into tailored preventive-care plans is still years away, this study by Dr Chan's team has helped to clearly illuminate that road, he concludes.
Dr Chan reports receiving personal fees from Bayer HealthCare, Pozen, and Pfizer. Coauthor John Baron, MD, from the University of North Carolina School of Medicine in Chapel Hill, reports holding a use patent for aspirin as a colorectal chemopreventive agent. Coauthor Brent Zanke, MD, from the Ottawa Hospital Research Institute in Ontario, Canada, reports holding a patent licensed to ArcticDx. Dr Wender has disclosed no relevant financial relationships.
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