Despite several plausible biological mechanisms linking proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) with colorectal tumorigenesis, their association with risk of colorectal cancer (CRC) has not been adequately assessed in prospective epidemiological studies.
We evaluated the association of acid-suppressive medication use with CRC risk among 175,871 (PPI) and 208,831 (H2RA) participants from three large prospective cohort studies. Medication use was assessed at baseline and updated biennially. The association was evaluated using multivariate Cox proportional hazards regression models.
There was no significant association between baseline PPI use (hazard ratio (HR) = 0.89, 95% confidence interval (CI), 0.71–1.12) or PPI use after a lag of 8–10 years (HR = 1.12, 95% CI, 0.78–1.59) with CRC risk. We observed no significant association between H2RA use after a lag of 8–10 years and CRC risk (HR = 1.02, 95% CI, 0.81–1.28), while risk was lower for participants with baseline H2RA use (HR = 0.76, 95% CI, 0.60–0.95). Duration of PPI use or H2RA use was not associated with CRC risk (P-trend = 0.21 and 0.95, respectively).
Among participants from three large prospective cohorts, use of PPI or H2RA was not associated with higher risk of colorectal cancer.
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Center for Disease Control and Prevention. Selected Prescription Drug Classes Used in the Past 30 Days, By Sex and Age: United States, Selected Years 1988–1994 through 2011–2014 (2016).
Schubert, M. L. & Peura, D. A. Control of gastric acid secretion in health and disease. Gastroenterology 134, 1842–1860 (2008).
Savarino, V., Dulbecco, P., de Bortoli, N., Ottonello, A. & Savarino, E. The appropriate use of proton pump inhibitors (PPIs): need for a reappraisal. Eur. J. Intern. Med. 37, 19–24 (2017).
Johnson, D. A., Katz, P. O., Armstrong, D., Cohen, H., Delaney, B. C., Howden, C. W. et al. The safety of appropriate use of over-the-counter proton pump inhibitors: an evidence-based review and Delphi consensus. Drugs 77, 547–561 (2017).
Festen, H. P., Thijs, J. C., Lamers, C. B., Jansen, J. M., Pals, G., Frants, R. R. et al. Effect of oral omeprazole on serum gastrin and serum pepsinogen I levels. Gastroenterology 87, 1030–1034 (1984).
Lazzaroni, M., Sangaletti, O. & Bianchi Porro, G. Gastric acid secretion and plasma gastrin during short-term treatment with omeprazole and ranitidine in duodenal ulcer patients. Hepato-Gastroenterology 39, 366–370 (1992).
Ohsawa, T., Hirata, W. & Higichi, S. Effects of three H2-receptor antagonists (cimetidine, famotidine, ranitidine) on serum gastrin level. Int. J. Clin. Pharm. Res. 22, 29–35 (2002).
Koh, T. J., Dockray, G. J., Varro, A., Cahill, R. J., Dangler, C. A., Fox, J. G. et al. Overexpression of glycine-extended gastrin in transgenic mice results in increased colonic proliferation. J. Clin. Invest. 103, 1119–1126 (1999).
Watson, S. A., Morris, T. M., McWilliams, D. F., Harris, J., Evans, S., Smith, A. et al. Potential role of endocrine gastrin in the colonic adenoma carcinoma sequence. Br. J. Cancer 87, 567–573 (2002).
Watson, S. A. & Smith, A. M. Hypergastrinemia promotes adenoma progression in the APC(Min−/+) mouse model of familial adenomatous polyposis. Cancer Res. 61, 625–631 (2001).
Thorburn, C. M., Friedman, G. D., Dickinson, C. J., Vogelman, J. H., Orentreich, N. & Parsonnet, J. Gastrin and colorectal cancer: a prospective study. Gastroenterology 115, 275–280 (1998).
Freedberg, D. E., Lebwohl, B. & Abrams, J. A. The impact of proton pump inhibitors on the human gastrointestinal microbiome. Clin. Lab. Med. 34, 771–785 (2014).
Imhann, F., Bonder, M. J., Vich Vila, A., Fu, J., Mujagic, Z., Vork, L. et al. Proton pump inhibitors affect the gut microbiome. Gut 65, 740–748 (2016).
Jackson, M. A., Goodrich, J. K., Maxan, M. E., Freedberg, D. E., Abrams, J. A., Poole, A. C. et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut 65, 749–756 (2016).
Louis, P., Hold, G. L. & Flint, H. J. The gut microbiota, bacterial metabolites and colorectal cancer. Nat. Rev. Microbiol. 12, 661–672 (2014).
Sears, C. L. & Garrett, W. S. Microbes, microbiota, and colon cancer. Cell Host Microbe 15, 317–328 (2014).
Kostic, A. D., Gevers, D., Pedamallu, C. S., Michaud, M., Duke, F., Earl, A. M. et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res 22, 292–298 (2012).
Mima, K., Sukawa, Y., Nishihara, R., Qian, Z. R., Yamauchi, M., Inamura, K. et al. Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncol. 1, 653–661 (2015).
Nguyen, P. T., Baldeck, J. D., Olsson, J. & Marquis, R. E. Antimicrobial actions of benzimidazoles against oral streptococci. Oral Microbiol. Immunol. 20, 93–100 (2005).
Sheng, J., Nguyen, P. T., Baldeck, J. D., Olsson, J. & Marquis, R. E. Antimicrobial actions of benzimidazoles against the oral anaerobes Fusobacterium nucleatum and Prevotella intermedia. Arch. Oral Biol. 51, 1015–1023 (2006).
Chubak, J., Boudreau, D. M., Rulyak, S. J. & Mandelson, M. T. Colorectal cancer risk in relation to use of acid suppressive medications. Pharmacoepidemiol. Drug Saf. 18, 540–544 (2009).
Lai, S. W., Liao, K. F., Lai, H. C., Lin, C. L. & Sung, F. C. Use of proton pump inhibitors correlates with increased risk of colorectal cancer in Taiwan. Asia Pac. J. Clin. Oncol. 9, 192–193 (2013).
Robertson, D. J., Larsson, H., Friis, S., Pedersen, L., Baron, J. A. & Sorensen, H. T. Proton pump inhibitor use and risk of colorectal cancer: a population-based, case–control study. Gastroenterology 133, 755–760 (2007).
Siersema, P. D., Yu, S., Sahbaie, P., Steyerberg, E. W., Simpson, P. W., Kuipers, E. J. et al. Colorectal neoplasia in veterans is associated with Barrett’s esophagus but not with proton-pump inhibitor or aspirin/NSAID use. Gastrointest. Endosc. 63, 581–586 (2006).
van Soest, E. M., van Rossum, L. G., Dieleman, J. P., van Oijen, M. G., Siersema, P. D., Sturkenboom, M. C. et al. Proton pump inhibitors and the risk of colorectal cancer. Am. J. Gastroenterol. 103, 966–973 (2008).
Yang, Y. X., Hennessy, S., Propert, K., Hwang, W. T., Sedarat, A. & Lewis, J. D. Chronic proton pump inhibitor therapy and the risk of colorectal cancer. Gastroenterology 133, 748–754 (2007).
Hwang, I. C., Chang, J. & Park, S. M. Emerging hazard effects of proton pump inhibitor on the risk of colorectal cancer in low-risk populations: a Korean Nationwide Prospective Cohort Study. PLoS ONE 12, e0189114 (2017).
Kozuka, S., Nogaki, M., Ozeki, T. & Masumori, S. Premalignancy of the mucosal polyp in the large intestine: II. Estimation of the periods required for malignant transformation of mucosal polyps. Dis. Colon Rectum 18, 494–500 (1975).
Belanger, C. F., Hennekens, C. H., Rosner, B. & Speizer, F. E. The nurses’ health study. Am. J. Nurs. 78, 1039–1040 (1978).
Colditz, G. A. & Hankinson, S. E. The Nurses’ Health Study: lifestyle and health among women. Nat. Rev. Cancer 5, 388–396 (2005).
Troy, L. M., Michels, K. B., Hunter, D. J., Spiegelman, D., Manson, J. E., Colditz, G. A. et al. Self-reported birthweight and history of having been breastfed among younger women: an assessment of validity. Int. J. Epidemiol. 25, 122–127 (1996).
Giovannucci, E., Ascherio, A., Rimm, E. B., Colditz, G. A., Stampfer, M. J. & Willett, W. C. Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann. Intern. Med. 122, 327–334 (1995).
Lee, D. H., Keum, N. & Giovannucci, E. L. Colorectal cancer epidemiology in the Nurses’ Health Study. Am. J. Public Health 106, 1599–1607 (2016).
DerSimonian, R. & Laird, N. Meta-analysis in clinical trials. Control Clin. Trials 7, 177–188 (1986).
Bardou, M., Barkun, A. N. & Martel, M. Obesity and colorectal cancer. Gut 62, 933–947 (2013).
Zauber, A. G., Winawer, S. J., O’Brien, M. J., Lansdorp-Vogelaar, I., van Ballegooijen, M., Hankey, B. F. et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N. Engl. J. Med. 366, 687–696 (2012).
Giovannucci, E., Egan, K. M., Hunter, D. J., Stampfer, M. J., Colditz, G. A., Willett, W. C. et al. Aspirin and the risk of colorectal cancer in women. N. Engl. J. Med. 333, 609–614 (1995).
Minalyan, A., Gabrielyan, L., Scott, D., Jacobs, J. & Pisegna, J. R. The gastric and intestinal microbiome: role of proton pump inhibitors. Curr. Gastroenterol. Rep. 19, 42 (2017).
We would like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY. The authors assume full responsibility for analyses and interpretation of these data.
Ethics approval and consent to participate
This study was approved by the Institutional Review Boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. Completion of the baseline questionnaire was considered to imply informed consent.
Information on obtaining access to NHS, NHSII and HPFS data is available at https://www.nurseshealthstudy.org/researchers (email: firstname.lastname@example.org) and https://sites.sph.harvard.edu/hpfs/for-collaborators.
The authors declare no competing interests.
This work was supported by following research grants from the National Institutes of Health (NIH): UM1 CA167552, UO1 CA176726, UO1 CA186107, P01 CA55075 and P01 CA87969. Additional support from NIH K07 CA222159 to A.B.; NIH K07 CA188126 and American Cancer Society Research Scholar Grant (RSG130476) to X.Z.; NIH R01 CA151993 and R35 CA197735 to S.O.; NIH R01 CA118553 to C.S.F.; Cancer Research UK Grand Challenge OPTIMISTICC Project award to S.O. and K.N.; Crohn’s and Colitis Foundation to P.L., NIH R01 CA205406, DOD CA160344 and Project P Fund to K.N. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding sources played no role in study design, data collection, data analysis, interpretations of results or manuscript preparation.
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Babic, A., Zhang, X., Morales-Oyarvide, V. et al. Acid-suppressive medications and risk of colorectal cancer: results from three large prospective cohort studies. Br J Cancer 123, 844–851 (2020). https://doi.org/10.1038/s41416-020-0939-y
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