Key Points

Question? Is aspirin use associated with a reduction in colorectal cancer (CRC) incidence across a continuum of established lifestyle factors?

Findings? In this cohort study of 107?655 men and women receiving aspirin and followed up for more than 3 decades, the absolute reduction in CRC risk was more pronounced among those with an unhealthier lifestyle (ie, higher body mass index, greater amount of smoking, higher alcohol intake, less physical activity, and poorer diet quality) compared with those with a healthier lifestyle. In contrast, the relative reduction in CRC risk associated with aspirin use was similar.

Meaning? The findings of this study suggest that aspirin may be useful for CRC prevention for individuals with additional risk factors.

Importance? Aspirin reduces the risk of colorectal cancer (CRC). Identifying individuals more likely to benefit from regular aspirin use for CRC prevention is a high priority.

Objective? To assess whether aspirin use is associated with the risk of CRC across different lifestyle risk factors.

Design, Setting, and Participants? A prospective cohort study among women in the Nurses’ Health Study (1980-2018) and men in the Health Professionals Follow-Up Study (1986-2018) was conducted. Data analysis was performed from October 1, 2021, to May 22, 2023.

Exposures? A healthy lifestyle score was calculated based on body mass index, alcohol intake, physical activity, diet, and smoking with scores ranging from 0 to 5 (higher values corresponding to a healthier lifestyle). Regular aspirin use was defined as 2 or more standard tablets (325 mg) per week.

Main Outcome and Measures? Outcomes included multivariable-adjusted 10-year cumulative incidence of CRC, absolute risk reduction (ARR), and number needed to treat associated with regular aspirin use by lifestyle score and multivariable-adjusted hazard ratios for incident CRC across lifestyle scores.

Results? The mean (SD) baseline age of the 107?655 study participants (63?957 women from the Nurses’ Health Study and 43?698 men from the Health Professionals Follow-Up Study) was 49.4 (9.0) years. During 3?038?215 person-years of follow-up, 2544 incident cases of CRC were documented. The 10-year cumulative CRC incidence was 1.98% (95% CI, 1.44%-2.51%) among participants who regularly used aspirin compared with 2.95% (95% CI, 2.31%-3.58%) among those who did not use aspirin, corresponding to an ARR of 0.97%. The ARR associated with aspirin use was greatest among those with the unhealthiest lifestyle scores and progressively decreased with healthier lifestyle scores (P?<?.001 for additive interaction). The 10-year ARR for lifestyle scores 0 to 1 (unhealthiest) was 1.28%. In contrast, the 10-year ARR for lifestyle scores 4 to 5 (healthiest) was 0.11%. The 10-year number needed to treat with aspirin was 78 for participants with lifestyle scores 0 to 1, 164 for score 2, 154 for score 3, and 909 for scores 4 to 5. Among the components of the healthy lifestyle score, the greatest differences in ARR associated with aspirin use were observed for body mass index and smoking.

Conclusions and Relevance? In this cohort study, aspirin use was associated with a greater absolute reduction in risk of CRC among individuals with less healthy lifestyles. The findings of the study suggest that lifestyle risk factors may be useful to identify individuals who may have a more favorable risk-benefit profile for cancer prevention with aspirin.

Aspirin is the most established agent for the prevention of colorectal neoplasia.^1-4 Despite data supporting the preventive effect of aspirin, risks associated with long-term use could limit widescale adoption.^5,6 Identifying individuals most likely to benefit from aspirin use may allow for personalized preventive health recommendations.

Lifestyle modification has similarly been associated with a reduction in colorectal cancer (CRC) incidence. Observational studies have reported the benefit of a healthy diet and body mass index (BMI), engaging in physical activity, avoiding cigarette use, and limiting alcohol intake.^7-12 Data suggest a differential effect of aspirin use by dietary factors,^13-15 adiposity,^16-18 and smoking,^17,19,20 although these studies often highlighted heterogeneous responses in the context of a single risk factor. It remains unclear whether individuals with a greater overall lifestyle risk might benefit more from the use of aspirin. We therefore prospectively assessed whether aspirin use was associated with a reduction in CRC incidence across a continuum of established lifestyle factors linked to CRC.

We enrolled participants from 2 prospective cohort studies: women from the Nurses’ Health Study (NHS) and men from the Health Professionals Follow-Up Study (HPFS). The NHS enrolled 121?700 female nurses between the ages of 30 and 55 years at baseline in 1976. The HPFS included 51?529 male health professionals between the ages of 40 and 75 years at enrollment in 1986. Follow-up time accrued from enrollment until the date of CRC diagnosis, death, or the end of follow-up (June 30, 2018, for NHS and January 31, 2018, for HPFS), whichever occurred first. Data analysis for the present study was performed from October 1, 2021, to May 22, 2023. The cohorts have been described previously.^21,22 Participants completed biennial questionnaires that included a validated assessment of diet, lifestyle factors, medication use, and disease outcomes, including CRC. Follow-up among participants exceeds 90% of available person-time.^23,24 The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital, Harvard T. H. Chan School of Public Health, and those of participating registries as required. Voluntary return of study questionnaires indicated written informed consent to participate. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology () reporting guideline.

Beginning in 1980 for the NHS and 1986 for the HPFS and every 2 years thereafter, we collected information on participants’ regular aspirin use. Participants were asked about standard-dose (325-mg) aspirin tablets. Between 1994 and 1998, participants converted intake of 4 low-dose (81-mg) tablets to 1 standard-dose tablet. Since 2000, participants reported regular use of low-dose aspirin separately from standard-dose aspirin. Consistent with prior studies, we defined regular aspirin use as 2 or more standard-dose (325-mg) tablets per week or 6 or more low-dose (81-mg) tablets per week.^21,22,25-27 Aspirin use information was updated during each questionnaire cycle.

We evaluated 5 lifestyle factors that have been associated with CRC: BMI,^28,29 smoking,^30-32 alcohol intake,³³ physical activity,^34,35 and diet.^36,37 Height, weight, smoking, and physical activity were self-reported through biennial questionnaires. Physical activity was defined by the total hours per day of moderate to vigorous activity that requires the expenditure of at least 3 metabolic equivalents per hour.³⁸ Self-reported dietary intake was assessed through semiquantitative food frequency questionnaires every 4 years.³⁹ Diet quality was defined by adherence to the 6 recommendations by the World Cancer Research Fund and American Institute for Cancer Research Third Expert Report for the intake of red meat, processed meat, dietary fiber, dairy products, whole grains, and calcium supplements.⁴⁰ To capture long-term exposures and reduce random within-person variation, we calculated the cumulative average of all exposures.

A healthy lifestyle score was created by dichotomizing data on the 5 lifestyle factors, as described previously.⁴¹ This method modeled CRC lifestyle scores in other cohorts.^12,41-43 The score was defined as a BMI of 18.5 to 25.0 (calculated as weight in kilograms divided by height in meters squared), never smoking or past smoking with less than 5 pack-years, no to moderate alcohol intake (≤1 drink per day for women and ≤2 drinks per day for men), moderate to vigorous physical activity for 30 minutes per day or more, and meeting at least 3 of 6 dietary recommendations by the World Cancer Research Fund and American Institute for Cancer Research. For each factor, participants were given a score of 1 if they met the criteria and 0 if not, and the healthy lifestyle score was calculated by summing across the factors. Healthy lifestyle scores ranged from 0 to 5, with higher scores indicating a healthier lifestyle. We collected self-reported information on a history of CRC among first-degree relatives and screening endoscopy within the prior 2 years. Race was self-reported and collected as part of routine cohort procedures.

Incident CRC cases were reported by participants on biennial questionnaires or were identified by next of kin, postal authorities, the National Death Index, or death certificates.⁴⁴ Blinded study physicians reviewed records to confirm cases.

We excluded participants with a history of cancer (including CRC) or inflammatory bowel disease before baseline, missing information on exposures at baseline, and those with implausible energy intake (<500 and >3500 kcal/d for women and <800 or >4200 kcal/d for men) at baseline (eFigure in Supplement 1).

To examine the absolute benefit of regular aspirin use according to healthy lifestyle score, we calculated the multivariable-adjusted 10-year cumulative incidence of CRC according to regular aspirin use and healthy lifestyle score. For missing data during follow-up, nonmissing data from 1 previous data cycle were carried forward. We ran Cox proportional hazards regression models and adjusted for age, sex, and the individual components of the lifestyle score expressed continuously. We controlled for the individual components of the lifestyle score expressed across a wider distribution to reduce possible residual confounding, as the overall score was a global estimate of risk. Multivariable models were additionally adjusted for history of CRC in first-degree relatives (yes/no) and endoscopic screening in the past 2 years (yes/no). Participants were censored after 10 years of follow-up, diagnosis of CRC, or death, whichever occurred first. For each healthy lifestyle score, we calculated the absolute risk reduction (ARR) associated with regular aspirin use by subtracting the cumulative risk in regular aspirin users from the cumulative risk in nonregular users. Number needed to treat (NNT) was calculated as 1/ARR. P values for additive interaction were calculated by regressing cumulative risk on aspirin use, healthy lifestyle score, and their cross-product, whose P value was considered the P value for additive interaction, as described previously.^45,46

We calculated the multivariable-adjusted 20-year cumulative incidence of CRC according to regular aspirin use and healthy lifestyle score to address a potential latency effect of aspirin, given prior data that suggested approximately 10 years of use was required to see a reduction in CRC risk.⁴⁷ To better understand the association between aspirin use, healthy lifestyle score, and CRC risk, we calculated the ARR associated with aspirin use for each component of the healthy lifestyle score.

To evaluate a potential differential relative benefit of aspirin across healthy lifestyle scores, we used Cox proportional hazards regression models to estimate the hazard ratios (HRs) and 95% CIs for CRC incidence according to aspirin use across strata of healthy lifestyle score. P values for multiplicative interaction were calculated using a likelihood ratio test that compared a model using cross-referenced groupings of healthy lifestyle risk score and aspirin use against a model with healthy lifestyle score and aspirin entered individually. Analyses were conducted using SAS, version 9.4 (SAS Institute Inc). All tests were 2-sided, and P?<?.05 was the threshold for statistical significance.

Among 107?655 participants (63?957 women from the NHS and 43?698 men from the HPFS), we documented 2544 cases of incident CRC over 3?038?215 person-years. Regular aspirin users accrued 40.8% of follow-up time. The frequency of weekly aspirin use is displayed in eTable 1 in Supplement 1. The mean (SD) baseline age was 49.4 (9.0) years. Participant characteristics during follow-up are displayed in Table 1.

Overall, nonregular aspirin users had a 10-year multivariable-adjusted cumulative incidence of CRC of 2.95% (95% CI, 2.31%-3.58%) compared with 1.98% (95% CI, 1.44%-2.51%) among regular users, corresponding to an absolute risk reduction (ARR) of 0.97% and NNT of 103 (Table 2). The ARR associated with regular aspirin use progressively decreased with higher lifestyle scores (P?<?.001 for additive interaction) (Figure). The 10-year ARR associated with aspirin use was 1.28% (NNT?=?78) for participants with lifestyle scores 0 to 1 (unhealthiest), 0.61% (NNT?=?164) for score 2, 0.65% (NNT?=?154) for score 3, and 0.11% (NNT?=?909) for scores 4 to 5 (healthiest) (Table 2).

We observed similar findings for the 20-year multivariable-adjusted cumulative incidence of CRC. Across lifestyle groups, the multivariable-adjusted 20-year cumulative incidence of CRC among nonregular aspirin users was 5.56% (95% CI, 4.54%-6.55%), compared with 4.05% (95% CI, 3.13%-4.95%) among regular users, corresponding to an ARR of 1.51% (NNT?=?66) (Table 3). We observed a progressive decrease in the ARR associated with aspirin use with increasing lifestyle scores (P?<?.001 for additive interaction). The overall ARR associated with aspirin use was 1.39% (NNT?=?72) for participants with lifestyle scores 0 to 1, compared with 0.04% (NNT?=?2500) for scores 4 to 5.

Among the individual components of the healthy lifestyle score, we observed a greater 10-year ARR associated with aspirin use among participants with BMI greater than or equal to 25, moderate/heavy smoking, moderate/heavy alcohol intake, less physical activity, and lower adherence to dietary recommendations (P?<?.001 for additive interaction) (Table 4). The greatest differences in ARR were observed among strata defined by BMI and smoking.

In an analysis examining the relative risk reduction associated with the use of aspirin, regular aspirin users had an 18% lower risk of incident CRC compared with nonregular users (eTable 2 in Supplement 1). The relative reduction in CRC incidence associated with regular aspirin use was similar across strata of healthy lifestyle score (P?=?.34 for multiplicative interaction). In a supplemental analysis, we evaluated the relative risk reduction associated with aspirin use by the individual components of the healthy lifestyle score and found differences by BMI and alcohol, but not by other factors (eTable 3 in Supplement 1).

In 2 large prospective cohorts, participants with unhealthier lifestyles had the greatest absolute benefit from aspirin use compared with their healthier counterparts. Among the components of the healthy lifestyle score, the greatest differences in ARR associated with aspirin use were observed for BMI and smoking. Regular aspirin use was associated with a similar relative reduction in CRC incidence across lifestyle profiles.

The preventive effect of aspirin has been observed across numerous basic, epidemiologic, and clinical studies over the past decades. This effect may be the result of inhibition of proinflammatory signals that promote cellular proliferation and angiogenesis, alteration of Wnt/β-catenin signaling, and modulation of antitumor response, among others.^5,48-51 Aspirin use has been associated with a 20% to 30% CRC risk reduction,^52,53 consistent with our findings. Recognizing these data, the US Preventive Services Task Force previously recommended low-dose aspirin for the prevention of CRC in adults aged 50 to 59 years in 2016.⁵⁴ In 2022, they revised this broad recommendation, citing concern about the risk-benefit balance, including potential adverse effects such as bleeding. Consequently, identifying individuals who are more likely to benefit from aspirin is a priority.

While some studies suggested a differential relative benefit of aspirin in the prevention of colorectal neoplasia by lifestyle factors,^14-21,55 we found no significant difference in relative risk reduction. Across these studies, the magnitude and direction of benefit have been inconsistent. For example, studies suggested an attenuated relative effect of aspirin among those with increased BMI,^17,18 while another study found a greater relative effect.¹⁶ Others found an attenuated benefit associated with heavy smoking,^17,19 and one found an increased risk of CRC associated with aspirin use among smokers.²⁰ Prior data suggested a possible interaction between nonsteroidal anti-inflammatory drug use, physical activity,⁵⁵ and diet,^14,15 but evidence was weaker. The absence of a significant relative risk reduction by lifestyle factors may have been the result of a modest multiplicative effect of aspirin use and healthy lifestyle. In contrast, the greater absolute benefit of aspirin among unhealthier participants likely reflected their greater baseline risk of CRC, which aspirin use can proportionally reduce.

There are several strengths to this study. We leveraged data from 2 large prospective cohorts with more than 30 years of follow-up, allowing us to assess long-term relevant exposures. Recall and ascertainment bias were limited by the prospective data collection. Our quantification of absolute risk provides more clinically meaningful information about the long-term outcomes of aspirin use. To our knowledge, this is the first study to examine the ARR associated with aspirin use by lifestyle risk.

We acknowledge several limitations. The population consisted of health professionals who were predominantly White. Given that health care professionals observe a healthier lifestyle, we may have underestimated the outcomes associated with lifestyle factors.⁵⁶ Exposure data were self-reported and subject to measurement error. We did not systematically assess adverse outcomes potentially due to aspirin use or the presence of a known hereditary cancer syndrome. However, most cases of CRC are sporadic, and adherence to a healthier lifestyle may have an outsized benefit in those without a genetic predisposition. Risk estimates remained robust after adjusting for family history of CRC, which likely captured most individuals with hereditary syndromes.

In this cohort study, regular aspirin use was associated with a greater absolute reduction in CRC incidence among participants with unhealthier lifestyles. This outcome was primarily associated with differences in the absolute risk reduction associated with aspirin use among participants with higher BMI and heavier smoking. These results support the use of lifestyle risk factors to identify individuals who may have a more favorable risk-benefit profile for cancer prevention with aspirin.

Accepted for Publication: March 19, 2024.

Published Online: August 1, 2024. doi:10.1001/jamaoncol.2024.2503

Corresponding Authors: Andrew T. Chan, MD, MPH (achan@mgh.harvard.edu), and Long H. Nguyen, MD, MS (lnguyen24@mgh.harvard.edu), Clinical and Translational Epidemiology Unit, and Massachusetts General Hospital and Harvard Medical School, 100 Cambridge St, Boston, MA 02114.

Author Contributions: Drs Sikavi and Nguyen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Nguyen and Chan are co–senior authors.

Concept and design: Sikavi, Nguyen, Chan.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Sikavi.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Sikavi, Wang, Ma.

Obtained funding: Ogino, Chan.

Administrative, technical, or material support: Nguyen, Chan.

Supervision: Nguyen, Chan.

Conflict of Interest Disclosures: Dr Chan reported receiving personal fees from Boehringer Ingelheim, Pfizer Inc, and Freenome outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by infrastructure grants UM1 CA186107 and P01 CA87969 for the Nurses’ Health study; infrastructure grant U01 CA167552 for the Health Professionals Follow-Up Study; K99CA283146 (Dr Wang); American Gastroenterological Association AGA2021-13-01 and MGH Claflin Distinguished Scholar Award (Dr Ma); K01DK120742 (Dr Drew); R35 CA197735 (Dr Ogino); American Cancer Society CRP-23-1014041 (Dr Giovannucci); K07CA218377 and R37CA246175 (Dr Cao); K23DK125838, American Gastroenterological Association Research Scholars Award, Crohn’s and Colitis Foundation Career Development Award, MGH/Tianqiao & Chrissy Chen Institute Transformative Scholars Award (Dr Nguyen); and R35 CA253185 and American Cancer Society Research Professor (Dr Chan).

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention’s National Program of Cancer Registries and/or the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Central registries may also be supported by state agencies, universities, and cancer centers. Participating central cancer registries include the following: Alabama, Alaska, Arizona, Arkansas, California, Delaware, Colorado, Connecticut, Florida, Georgia, Hawaii, Idaho, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Mississippi, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Puerto Rico, Rhode Island, Seattle SEER Registry, South Carolina, Tennessee, Texas, Utah, Virginia, West Virginia, Wyoming. There was no financial compensation for these contributions.