Potential Mechanisms

The mechanism by which aspirin and related agents could reduce gastric cancer risk is uncertain. Previous studies have reported increased expression of prostaglandin synthase-2 (cyclo-oxygenase-2 [COX-2]) in metaplastic, adenomatous, and cancer cells in the stomach, suggesting that prostaglandin synthesis may be involved in carcinogenesis.6

Helicobacter pylori infection causes inflammation and cell proliferation, inhibits apoptosis, induces COX-2 expression, and is recognized as an important pathogen in gastric tumorigenesis.7 NSAID treatment inhibits prostaglandin synthesis and reduces the growth of H pylori in a dose-dependent manner in vitro.

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To ascertain study participants’ H pylori infection status, Dr Chan and colleagues performed an exploratory analysis using data from 32,826 women in the NHS trial and 18,159 men in the HPFS trial.3,4

Regular aspirin use was associated with a lower likelihood H pylori infection in women (odds ratio, 0.62; 95% CI, 0.44-0.87) but not in men (odds ratio, 0.87; 95% CI, 0.60-1.26). This result is consistent with a sex-specific influence of aspirin on the likelihood of H pylori infection.

Strengths and Limitations

A strength of Dr Chan’s study is that the aspirin data were collected prospectively, were updated regularly, and ultimately encompassed 4.5 million person-years over 34 years of follow-up. The data were collected in a manner that minimized risks of recall bias or misclassification. The models used to calculate risk for gastric cancer were adjusted for a wide range of possibly confounding dietary and lifestyle factors.

A potential limitation was that the investigators could not fully ascertain H pylori infection in the entire cohort and could not rule out residual confounding.

In addition, more than 90% of participants in the NHS and HPFS were White, limiting generalizability to other races and ethnicities.

Similarly, the overall cohort in this study was predominantly female. Larger studies of aspirin use by male participants might uncover an association with gastric cancer incidence in men that is significant but somewhat weaker than that in women.

Although the information on aspirin use was detailed, it was inadequate to determine the optimal dose or duration of use and the drug’s benefit relative to that of other NSAIDS.


Dr Chan’s study contributes to the mounting body of evidence suggesting a preventive benefit of aspirin on the development of gastrointestinal cancer generally.1,8

Prior studies, primarily among Asian participants, suggested that aspirin use could reduce gastric cancer risk.9 Heterogeneity of the association of aspirin use and gastric adenocarcinoma incidence by sex has not been previously reported.

The USPSTF guidelines summarize broad-based evidence supporting aspirin use to reduce the risk of colorectal cancer.10 The literature on aspirin and gastric cancer risk is less robust and less compelling, and it leaves unanswered questions about dose, duration, mechanism, and biomarkers of benefit.

As Dr Chan suggested, additional epidemiologic cohort studies are needed to confirm the current findings and determine the causal associations and molecular bases on which precision chemoprevention from aspirin hinges.

Disclosures: Dr Chan declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


  1. US Preventive Services Task Force. Aspirin use to prevent cardiovascular disease and colorectal cancer. Published April 11, 2016. Accessed February 12, 2022.
  2. Seewaldt VL. Aspirin and chemoprevention—Have we arrived? JAMA Oncol. 2018;4(12):1668-1669. doi:10.1001/jamaoncol.2018.4138
  3. Kwon S, Ma W, Drew DA, et al. Association between aspirin use and gastric adenocarcinoma: A prospective cohort study. Cancer Prev Res. Published online January 3, 2022. doi:10.1158/1940-6207.CAPR-21-0413
  4. Chan AT, Grossman D. AACR Virtual Journal Club: Cancer Prevention Research. Released January 14, 2022. Accessed February 12, 2022
  5. Huang X-Z, Chen Y, Wu J, et al. Aspirin and non-steroidal anti-inflammatory drugs use reduce gastric cancer risk: A dose-response meta-analysis. Oncotarget. 2017;8(3):4781-4795. doi:10.18632/oncotarget.13591
  6. Cheng J, Fan X-M. Role of cyclooxygenase-2 in gastric cancer development and progression. World J Gastroenterol. 2013;19(42):7361-7368. doi:10.3748/wjg.v19.i42.7361
  7. Zhang LJ, Wang SY, Huo XH, et al. Anti-Helicobacter pylori therapy followed by celecoxib on progression of gastric precancerous lesions. World J Gastroenterol. 2009;15(22):2731-2738. doi:10.3748/wjg.15.2731
  8. Simon TG, Ma Y, Ludvigsson JF, et al. Association between aspirin use and risk of hepatocellular carcinoma. JAMA Oncol. 2018;4(12):1683-1690. doi:10.1001/jamaoncol.2018.4154
  9. Cheung KS, Chan EW, Wong AYS, et al. Aspirin and risk of gastric cancer after Helicobacter pylori eradication: A territory-wide study. J Natl Cancer Inst. 2018;110(7):743-749. doi:10.1093/jnci/djx267
  10. Bibbins-Domingo K, on behalf of the US Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164(12):836-845. doi:10.7326/M16-0577