Association between Use of Proton Pump Inhibitors and Risk of Breast Cancer: A Systematic Review and Meta-analysis of Observational Studies PPIs and Breast Cancer Risk
Abstract
Background: Evidence on proton pump inhibitor (PPI) use and breast cancer risk is inconsistent and partly derived from overlapping source populations. We evaluated PPI exposure in relation to incident breast cancer and, separately, post-diagnosis outcomes.
Methods: PubMed, Web of Science, and Scopus were searched through 22 August 2026, supplemented by Google Scholar and citation tracking, for English-language cohort and case-control studies in women. Methodological quality and pharmacoepidemiological bias were assessed, and certainty was rated using GRADE. Any use and long-term/high use were analyzed separately. Overlapping studies were combined within their source population before random-effects pooling across independent populations.
Results: Thirteen studies were included: 8 on incidence and 5 on post-diagnosis outcomes. Any PPI use was not clearly associated with incidence across 3 independent populations (rate ratio, 0.98; 95% CI, 0.66-1.45; τ = 0.12). For long-term/high use, the pooled odds ratio was 0.87 (95% CI, 0.45-1.66; τ = 0.25); because exposure thresholds differed and heterogeneity was substantial, this estimate is exploratory. Inverse associations were confined to the overlapping Taiwanese analyses. Alternative frequentist and Bayesian analyses yielded similar findings. Post-diagnosis evidence was limited: recurrence HR 0.89 (95% CI, 0.78-1.04); breast-cancer-specific mortality HR 1.30 (95% CI, 1.18-1.43) in 1 probably confounded cohort.
Conclusion: Current observational evidence does not demonstrate a clear association between PPI use and breast cancer incidence. Given few independent populations and very low certainty, clinically meaningful benefit or harm cannot be excluded. The evidence does not support modifying PPI prescribing on the basis of breast cancer risk.
References
REFERENCES
Mössner J. The Indications, Applications, and Risks of Proton Pump Inhibitors. Dtsch Arztebl Int. 2016;113(27-28):477-83. doi: 10.3238/arztebl.2016.0477
Shanika LGT, Reynolds A, Pattison S, Braund R. Proton pump inhibitor use: systematic review of global trends and practices. Eur J Clin Pharmacol. 2023;79(9):1159-72. doi: 10.1007/s00228-023-03534-z
Morris N, Nighot M. Understanding the health risks and emerging concerns associated with the use of long-term proton pump inhibitors. Bull Natl Res Cent. 2023;47(1):134. doi: 10.1186/s42269-023-01107-9
Losurdo G, Caccavo NLB, Indellicati G, Celiberto F, Ierardi E, Barone M. Effect of Long-Term Proton Pump Inhibitor Use on Blood Vitamins and Minerals: A Primary Care Setting Study. J Clin Med. 2023;12(8). doi: 10.3390/jcm12082910
Wu CC, Liao MH, Kung WM, Wang YC. Proton Pump Inhibitors and Risk of Chronic Kidney Disease: Evidence from Observational Studies. J Clin Med. 2023;12(6). doi: 10.3390/jcm12062262
Abrahami D, McDonald EG, Schnitzer ME, Barkun AN, Suissa S, Azoulay L. Proton pump inhibitors and risk of gastric cancer: population-based cohort study. Gut. 2022;71(1):16-24. doi: 10.1136/gutjnl-2021-325097
Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M. Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast. 2022;66:15-23. doi: 10.1016/j.breast.2022.08.010
Tian L, Huang C, Fu W, Gao L, Mi N, Bai M. Proton pump inhibitors may enhance the risk of digestive diseases by regulating intestinal microbiota. Front Pharmacol. 2023;14:1217306. doi: 10.3389/fphar.2023.1217306
Singh A, Cresci GA, Kirby DF. Proton Pump Inhibitors: Risks and Rewards and Emerging Consequences to the Gut Microbiome. Nutr Clin Pract. 2018;33(5):614-24. doi: 10.1002/ncp.10181
McColl KEL, Kennerley P. Proton pump inhibitors differences emerge in hepatic metabolism. Dig Liver Dis. 2002;34(7):461-7. doi: 10.1016/S1590-8658(02)80102-5
Zeng Y, Dai Y, Zhou Z, Yu X, Shi D. Hepatotoxicity-Related Adverse Effects of Proton Pump Inhibitors: A Cross-Sectional Study of Signal Mining and Analysis of the FDA Adverse Event Report System Database. Front Med (Lausanne). 2021;8:648164. doi: 10.3389/fmed.2021.648164
Ashfaq M, Khan Q, Haroon MZ, Abid SMA, Sharif MJH, Alkahraman Y. Effects of long-term proton pump inhibitor use on sexual hormones and sexual and reproductive health in female patients. Endocrine. 2024;83(2):494-501. doi: 10.1007/s12020-023-03572-8
Ben Ghezala I, Luu M, Bardou M. An update on drug-drug interactions associated with proton pump inhibitors. Expert Opin Drug Metab Toxicol. 2022;18(5):337-46. doi: 10.1080/17425255.2022.2098107
Wedemeyer RS, Blume H. Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf. 2014;37(4):201-11. doi: 10.1007/s40264-014-0144-0
Ding DC, Sung FC, Chen W, Wang JH, Lin SZ. Proton pump inhibitors reduce breast cancer risk in gastric ulcer patients: A population-based cohort study. Breast J. 2020;26(3):474-8. doi: 10.1111/tbj.13519
Chen CH, Lee CZ, Lin YC, Kao LT, Lin HC. Negative Association of Proton Pump Inhibitors With Subsequent Development of Breast Cancer: A Nationwide Population-Based Study. J Clin Pharmacol. 2019;59(3):350-5. doi: 10.1002/jcph.1329
Nguyen NTH, Huang CW, Wang CH, Lin MC, Hsu JC, Hsu MH. Association between Proton Pump Inhibitor Use and the Risk of Female Cancers: A Nested Case-Control Study of 23 Million Individuals. Cancers (Basel). 2022;14(24). doi: 10.3390/cancers14246083
Hálfdánarson Ó, Fall K, Ogmundsdottir MH, Lund SH, Steingrímsson E, Ogmundsdottir HM. Proton pump inhibitor use and risk of breast cancer, prostate cancer, and malignant melanoma: An Icelandic population-based case-control study. Pharmacoepidemiol Drug Saf. 2019;28(4):471-8. doi: 10.1002/pds.4702
Ballinger TJ, Djuric Z, Sardesai S, Hovey KM, Andrews CA, Brasky TM. Proton Pump Inhibitor Use and Obesity-Associated Cancer in the Women's Health Initiative. Nutr Cancer. 2022;75(1):265-75. doi: 10.1080/01635581.2022.2108467
Hu J, Hu W, Sun C, Cheng C, Zhou Q, Yue L. Association between the Use of Proton Pump Inhibitors with the Risk and the Prognosis of Breast Cancer: A Systematical Review. World J Surg Surg Res. 2021. doi: 10.25107/2637-4625.1327
Zhang ML, Fan YX, Meng R, Cai WK, Yin SJ, Zhou T. Proton Pump Inhibitors and Cancer Risk: An Umbrella Review and Meta-analysis of Observational Studies. Am J Clin Oncol. 2022;45(11):475-85. doi: 10.1097/COC.0000000000000949
Senn SJ. Overstating the evidence double counting in meta-analysis and related problems. BMC Med Res Methodol. 2009;9:10. doi: 10.1186/1471-2288-9-10
Kristensen KB, Friis S, Lund LC, Hallas J, Cardwell CR, Andreassen BK. Identification of drug-cancer associations: a nationwide screening study. Cancer Res Commun. 2022;2(6):552-60. doi: 10.1158/2767-9764.CRC-22-0026
Støer NC, Botteri E, Thoresen GH, Karlstad Ø, Weiderpass E, Friis S. Drug use and cancer risk: a drug-wide association study (DWAS) in Norway. Cancer Epidemiol Biomarkers Prev. 2021;30(4):682-9. doi: 10.1158/1055-9965.EPI-20-1028
McDowell RD, Hughes C, Murchie P, Cardwell C. A systematic assessment of the association between frequently prescribed medicines and the risk of common cancers: a series of nested case-control studies. BMC Med. 2021;19(1):22. doi: 10.1186/s12916-020-01891-5
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi: 10.1136/bmj.n71
Rethlefsen ML, Kirtley S, Waffenschmidt S, Ayala AP, Moher D, Page MJ. PRISMA-S: an extension to the PRISMA statement for reporting literature searches in systematic reviews. Syst Rev. 2021;10(1):39. doi: 10.1186/s13643-020-01542-z
Bramer WM, Rethlefsen ML, Kleijnen J, Franco OH. Optimal database combinations for literature searches in systematic reviews: a prospective exploratory study. Syst Rev. 2017;6(1):245. doi: 10.1186/s13643-017-0644-y
Wells G, Shea B, O'Connell J. The Newcastle-Ottawa Scale (NOS) for Assessing The Quality of Nonrandomised Studies in Meta-analyses. Ottawa Health Research Institute; 2014;7.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603-5. doi: 10.1007/s10654-010-9491-z
Pottegård A, Friis S, Christensen R, Habel LA, Gagne JJ, Hallas J. Identification of Associations Between Prescribed Medications and Cancer: A Nationwide Screening Study. EBioMedicine. 2016;7:73-9. doi: 10.1016/j.ebiom.2016.03.018
An J. Association of breast cancer disease free survival (DFS) with omeprazole use. J Clin Oncol. 2018;36(15_suppl):e12544. doi: 10.1200/JCO.2018.36.15_suppl.e12544
Wang CJ, Li D, Danielson JA, Zhang EH, Dong Z, Miller KD. Proton pump inhibitors suppress DNA damage repair and sensitize treatment resistance in breast cancer by targeting fatty acid synthase. Cancer Lett. 2021;509:1-12. doi: 10.1016/j.canlet.2021.03.026
Dumas E, Grandal Rejo B, Gougis P, Houzard S, Abécassis J, Jochum F. Concomitant medication, comorbidity and survival in patients with breast cancer. Nat Commun. 2024;15(1):2966. doi: 10.1038/s41467-024-47002-3
Nielsen HV, Pedersen RN, Nørgaard M, Lash TL, Ejlertsen B, Christiansen P. Proton pump inhibitor (PPI) prescriptions and breast cancer recurrence: A Danish Nationwide Prospective Cohort Study. Pharmacoepidemiol Drug Saf. 2018;27:454.
Tvingsholm SA, Dehlendorff C, Østerlind K, Friis S, Jäättelä M. Proton pump inhibitor use and cancer mortality. Int J Cancer. 2018;143(6):1315-26. doi: 10.1002/ijc.31529
Guo H, Zhang R, Zhang P, Chen Z, Hua Y, Huang X. Association of proton pump inhibitors with gastric and colorectal cancer risk: A systematic review and meta-analysis. Front Pharmacol. 2023;14:1129948. doi: 10.3389/fphar.2023.1129948
Chang Y, Lin WY, Chang YC, Huang CH, Tzeng HE, Abdul-Lattif E. The Association between Baseline Proton Pump Inhibitors, Immune Checkpoint Inhibitors, and Chemotherapy: A Systematic Review with Network Meta-Analysis. Cancers (Basel). 2022;15(1). doi: 10.3390/cancers15010284
Zhang J, Zhang C, Zhang Q, Yu L, Chen W, Xue Y. Meta-analysis of the effects of proton pump inhibitors on the human gut microbiota. BMC Microbiol. 2023;23(1):171. doi: 10.1186/s12866-023-02895-w
Larnder AH, Manges AR, Murphy RA. The estrobolome: Estrogen-metabolizing pathways of the gut microbiome and their relation to breast cancer. Int J Cancer. 2025;157(4):599-613. doi: 10.1002/ijc.35427
Chapadgaonkar SS, Bajpai SS, Godbole MS. Gut microbiome influences incidence and outcomes of breast cancer by regulating levels and activity of steroid hormones in women. Cancer Rep. 2023;6(11):e1847. doi: 10.1002/cnr2.1847
Ashfaq M, Khan Q, Haroon MZ, Abid SMA, Sharif MJH, Alkahraman YMSA. Long-Term Proton Pump Inhibitor Therapy and its Effect on Endocrine Hormones in Selected Patient Population. Horm Metab Res. 2023;55(03):205-11. doi: 10.1055/a-2009-9629
Parida S, Sharma D. The Microbiome-Estrogen Connection and Breast Cancer Risk. Cells. 2019;8(12):1642. doi: 10.3390/cells8121642
Cao Y, Chen M, Tang D, Yan H, Ding X, Zhou F. The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses. Cell Death Dis. 2018;9(6):604. doi: 10.1038/s41419-018-0642-6
Kench U, Sologova S, Smolyarchuk E, Prassolov V, Spirin P. Pharmaceutical Agents for Targeting Autophagy and Their Applications in Clinics. Pharmaceuticals (Basel). 2024;17(10):1355. doi: 10.3390/ph17101355
Rais R, Trikalinos NA, Liu J, Chatterjee D. Enterochromaffin-like Cell Hyperplasia-Associated Gastric Neuroendocrine Tumors May Arise in the Setting of Proton Pump Inhibitor Use. Arch Pathol Lab Med. 2022;146(3):366-71. doi: 10.5858/arpa.2020-0315-OA
Sanduleanu S, Jonkers D, De Bruine A, Hameeteman W, Stockbrügger RW. Non-Helicobacter pylori bacterial flora during acid-suppressive therapy: differential findings in gastric juice and gastric mucosa. Aliment Pharmacol Ther. 2001;15(3):379-88. doi: 10.1046/j.1365-2036.2001.00888.x
Authors
Copyright (c) 2026 Mehdi Karimi , Samira Pirzad; Sahar Pirzad; Aryan Taghvaei Sourouei , Benyamin Behrouzi, Mohammad Amin Karimi
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright©. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International License, which permits copy and redistribution of the material in any medium or format or adapt, remix, transform, and build upon the material for any purpose, except for commercial purposes.