Deciphering interactions between colorectal cancer risk factors

From the GECCO Coordinating Center, Public Health Sciences Division

Colorectal cancer (CRC) is the third most common form of cancer diagnosed in the United States. Several lifestyle, dietary, and genetic factors are known to influence the risk for development of the disease, and of these factors, regular use of non-steroidal anti-inflammatory drugs (NSAIDs) is well established to lower CRC risk. However, results from some previous studies suggest that other CRC risk factors may modify the beneficial effect of regular NSAID use. A paper recently published in Cancer Research by researchers in the Public Health Sciences Division and led by postdoctoral fellow Dr. Wendy Wang investigated the interaction between NSAIDs use and dietary and lifestyle factors on risk for CRC.

In the new study, the authors used data available from the large-scale Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry collaboration. The use of these data was a major strength, as described by Dr. Wang, “Our study is the first large study, with a collaborative effort from 12 studies from North America, Australia and Europe, that had sufficient statistical power to systematically investigate whether subgroups in the general population may benefit most from aspirin use in CRC prevention.”

The authors included nearly 12,000 CRC cases and 16,000 controls (individuals without a history of CRC at time of selection) in their analyses. Environmental exposures, including NSAID use, were self-reported by study participants. The large number of participants allowed the authors to stratify by demographic, lifestyle, and dietary risk factors such as BMI, smoking, physical activity, education, family history, and dietary variables. Statistical analyses were then conducted to determine associations between three categories of NSAID use (any NSAID use, aspirin use, and non-aspirin NSAID use) and the other lifestyle and dietary factors.

Graphical representation of association between regular use of aspirin and colorectal cancer risk by subgroups of body mass index (BMI) and pack-years of smoking.
Association between regular use of aspirin and colorectal cancer risk by subgroups of body mass index (BMI) and pack-years of smoking. Image provided by Dr. Wang

Regular use of any NSAID, as compared to non-regular use, was associated with a 25% lower risk of CRC overall when all lifestyle and dietary factors were adjusted for. The authors also found that the regular use of any NSAID, aspirin, or non-aspirin NSAID was associated with a significantly lower risk of CRC in nearly all subgroups assessed. However, the associations between NSAID use and CRC risk stood out specifically for two of the factors (see figure). The authors found that smoking status modified the association, with the greatest benefit of regular aspirin use on CRC risk in non-smokers (29% lower risk) as compared to that of smokers below (19% lower risk) and above (17% lower risk) the median of pack-years of smoking. There was also a trend for level of adiposity to modify the association between regular aspirin use and CRC risk. The greatest benefit of regular use was found for normal weight and overweight individuals while the association was weaker and not significant for obese individuals.

The impact of these findings was summarized by Dr. Wang, “Our study suggested that the benefit of aspirin was offset by the risky lifestyle factors including obesity and heavy smoking, suggesting that the chemopreventive mechanisms of aspirin may differ among subgroups of population by other lifestyle factors.” In addition, because the interaction effects were found only for regular use of aspirin and not non-aspirin NSAIDs, these results could suggest that “there are some unique mechanisms of actions of aspirin that are not shared by other NSAIDs,” said Dr. Wang. The authors also hypothesized that the differential effects of aspirin on CRC risk in smokers and non-smokers may be due to targeting of different carcinogenic pathways of carcinogenesis.

When asked about the direction of the next steps, Dr. Wang said “Findings from our study may help to improve more targeted CRC prevention guidelines. However, validation studies as well as risk-benefit evaluation of aspirin use in CRC prevention among the general population are needed.” Due to concerns of gastrointestinal bleeding, regular use of NSAIDs is not generally recommended for prevention of CRC [1], and such future studies may be especially helpful addressing these concerns.

This research was supported by the National Institutes of Health.

Wang X, Chan AT, Slattery ML, Chang-Claude J, Potter JD, Gallinger S, Caan B, Lampe JW, Newcomb PA, Zubair N, Hsu L, Schoen RE, Hoffmeister M, Brenner H, Le Marchand L, Peters U, White E. 2018. Influence of smoking, body mass index and other factors on the preventive effect of nonsteroidal anti-inflammatory drugs on colorectal cancer risk. Cancer Res. doi: 10.1158/0008-5472.CAN-18-0326

Additional Citation:

1.     Chubak J, Whitlock EP, Williams SB, Kamineni A, Burda BU, Buist DS, Anderson ML. 2016. Aspirin for the prevention of cancer incidence and mortality: systematic evidence reviews for the U.S. Preventive Services Task Force. Ann Intern Med.164:814-25.