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Oral antibiotic use and risk of colorectal cancer in the United Kingdom, 1989–2012: a matched case–control study
  1. Jiajia Zhang1,2,
  2. Charles Haines3,
  3. Alastair J M Watson4,5,
  4. Andrew R Hart4,5,
  5. Mary Jane Platt4,
  6. Drew M Pardoll1,2,
  7. Sara E Cosgrove3,
  8. Kelly A Gebo3,6,
  9. Cynthia L Sears1,3
  1. 1 The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  2. 2 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  3. 3 Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  4. 4 Department of Medicine, University of East Anglia Norwich Medical School, Norwich, Norfolk, UK
  5. 5 Department of Gastroenterology, Norfolk and Norwich University Hospital NHS Trust, Norwich, Norfolk, UK
  6. 6 Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
  1. Correspondence to Cynthia L Sears, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine Baltimore, MD 21287, USA; csears{at}jhmi.edu

Abstract

Background Microbiome dysbiosis predisposes to colorectal cancer (CRC), but a population-based study of oral antibiotic exposure and risk patterns is lacking.

Objective To assess the association between oral antibiotic use and CRC risk.

Design A matched case–control study (incident CRC cases and up to five matched controls) was performed using the Clinical Practice Research Datalink from 1989 to 2012.

Results 28 980 CRC cases and 137 077 controls were identified. Oral antibiotic use was associated with CRC risk, but effects differed by anatomical location. Antibiotic use increased the risk of colon cancer in a dose-dependent fashion (ptrend <0.001). The risk was observed after minimal use, and was greatest in the proximal colon and with antibiotics with anti-anaerobic activity. In contrast, an inverse association was detected between antibiotic use and rectal cancers (ptrend=0.003), particularly with length of antibiotic exposure >60 days (adjusted OR (aOR), 0.85, 95% CI 0.79 to 0.93) as compared with no antibiotic exposure. Penicillins, particularly ampicillin/amoxicillin increased the risk of colon cancer (aOR=1.09 (1.05 to 1.13)), whereas tetracyclines reduced the risk of rectal cancer (aOR=0.90 (0.84 to 0.97)). Significant interactions were detected between antibiotic use and tumour location (colon vs rectum, pinteraction<0.001; proximal colon versus distal colon, pinteraction=0.019). The antibiotic–cancer association was found for antibiotic exposure occurring >10 years before diagnosis (aOR=1.17 (1.06 to 1.31)).

Conclusion Oral antibiotic use is associated with an increased risk of colon cancer but a reduced risk of rectal cancer. This effect heterogeneity may suggest differences in gut microbiota and carcinogenesis mechanisms along the lower intestinal tract.

  • colorectal cancer
  • antibiotics
  • tumor location
  • cancer risk
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Footnotes

  • JZ and CH contributed equally.

  • KAG and CLS contributed equally.

  • Contributors Study concept and design; acquisition, analysis or interpretation of data: all authors. Drafting of the manuscript: JZ, CH, CS. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: JZ, CH. Obtained funding: CS. Administrative, technical or material support: CS. Study supervision: SC, KG, CS.

  • Funding This study was funded by the Johns Hopkins Fisher Center Discovery Program and Bloomberg~Kimmel Institute for Cancer Immunotherapy.

  • Competing interests DP reports grant and patent royalties through institution from Bristol Myers Squibb, grant from Compugen, stock from Trieza Therapeutics and Dracen Pharmaceuticals, and founder equity from Potenza; being consultant for Aduro Biotech, Amgen, Astra Zeneca (Medimmune/Amplimmune), Bayer, DNAtrix, Dynavax Technologies Corporation, Ervaxx, FLX Bio, Rock Springs Capital, Janssen, Merck, Tizona, and Immunomic-Therapeutics; being on the scientific advisory board of Five Prime Therapeutics, Camden Nexus II, WindMil; being on the board of director for Dracen Pharmaceuticals outside the submitted work. SC reports being consultant for Novartis and Theravance outside the submitted work. CS reports a grant from Bristol Myers Squibb for microbiome research outside the submitted work.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Not required.

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