Oral Antibiotic Use and Risk of Colorectal Cancer in the United Kingdom, 1989-2012: A Matched Case-Control Study

Background: Microbiome dysbiosis predisposes to colorectal cancer (CRC), but a population-based study of antibiotic exposure and risk patterns is lacking. In this study, oral antibiotic use on CRC incidence was assessed. Methods: A matched case-control study (incident CRC cases and up to 5 matched controls) was performed using the Clinical Practice Research Datalink (CPRD; January 1, 1989 to December 31, 2012). Conditional logistic regression was used to assess CRC association with oral antibiotic use, adjusting for potential confounders. Antibiotic exposure in categorical and continuous terms (spline) was investigated for pattern of risk, stratified by specific tumour location. Findings: 28,980 CRC cases and 137,077 controls were identified. Oral antibiotic use was associated with CRC risk, but effects differed by anatomic location. Antibiotic use was found to be associated with excess risk of colon cancer in a dose-dependent fashion (Ptrend 60 days (Adjusted Odds Ratio [AOR], 0·85, 95% CI 0·79-0·93) as compared with no antibiotic exposure. Penicillins were associated with increased risk of colon cancer (AOR,1·09, [1·05-1·13]) whereas tetracyclines were associated with risk reduction for rectal cancer (AOR, 0·90, [0·84- 0·97]). Significant interactions were detected between antibiotic use and tumour location (colon vs rectum, Pinteraction ten years before diagnosis (AOR, 1·17, [1·06-1·31]). Interpretation: Oral antibiotic use is associated with an increased risk of colon cancer risk but a reduced risk for rectal cancer. This effect heterogeneity may suggest differences in gut microbiota and carcinogenesis mechanisms along the lower intestine tract. Funding Statement: This project was funded by Johns Hopkins Fisher Center Discovery Program and Bloomberg~Kimmel Institute for Cancer Immunotherapy. Declaration of Interests: All authors have no directly relevant conflicts of interest to disclose. DP reports grant and patent royalties through institution from Bristol Myers Squibb, grant from Compugen, stock from Trieza Therapeutics and Dracen Pharmaceuticals, and founder 22 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 ImmunomicTherapeutics; being scientific advisory board of Five Prime Therapeutics, Camden Nexus II, WindMil; being board of director for Dracen Pharmaceuticals outside the submitted work. SC reports being consultant for Novartis and Theravance outside the submitted work. CS reports grants from Bristol Myers Squibb for microbiome research outside the submitted work. All other authors have nothing to declare. Ethics Approval Statement: This study was approved by the Institutional Review Board of the Johns Hopkins University