Association between the antibiotics use and recurrence in patients with resected non-metastatic colorectal cancer: EVADER-1, a nation-wide pharmaco-epidemiologic study.

Importance: The impact of antibiotics (ATBs) on the risk of colorectal cancer (CRC) recurrence after curative resection remains unknown. Objective: We aimed to evaluate the effect of the type and the class of ATBs on recurrence in patients with resected non-metastatic CRC. Design: Our cohort study included patients between 01/2012 and 12/2014. Each CRC patient was followed up to 3 years after surgical resection. Setting: This study was conducted using extracted data from the French cancer cohort set up based on the National Health Data System by the French National Cancer Institute. Participants: All newly diagnosed non-metastatic CRC patients resected were included. We excluded patients not affiliated to the major health insurance scheme in France (n=16 857) and with immunosuppression (n=32,359). Exposures: The perioperative ATB intake (from 6 months before surgery until 1 year after) was classified according to the class, the period of use (pre- vs post-resection), the disease stage (localized and locally advanced), and the primary tumor location (colon and rectum/junction). Main Outcome and Measure: The primary endpoint was the 3-year disease-free survival (DFS). The impact of ATB was assessed using time-dependent multivariate Cox models. Results: A total of 35,496 CRC patients were included. Seventy-nine percent of patients had at least one ATB intake. Outpatient ATB intake after surgery was associated with unfavorable 3-year DFS mostly in patients with locally advanced stage and during chemotherapy (HR ranging from 1.22 to 1.41, P<0.0001), while no excess of mortality was observed in patients receiving ATBs as outpatient. The ATBs associated with decreased 3-year DFS were cephalosporins, streptogramins, quinolones, penicillin A with beta-lactamase inhibitors, and antifungals with differential effects according to the primary tumor location and disease stage. Conclusion and Relevance: These findings suggest that ATBs modulate the risk of recurrence after early CRC resection with a differential impact of the ATB classes depending on disease stage and tumor site. This study also gives important clues on how ATBs may modulate the efficacy of cancer treatments. Ultimately, EVADER-1 will pave the way for therapeutic interventions targeting the microbiome aiming to improve cancer outcome. ### Competing Interest Statement A.T. reports personal fees from SERVIER, personal fees from MYLAN, personal fees from MERCK SERONO, personal fees from AMGEN, non-financial support from MERCK, non-financial support from SANOFI, non-financial support from PFIZER, outside the submitted work. C.B. reports personal fees and non-financial support from Da Volterra, personal fees from MYLAN, outside the submitted work. J.V. reports personal fees from BMS, personal fees from Merck-Serono, personal fees from Novartis, personal fees from Guardant Health, personal fees from Sanofi, outside the submitted work. A.A. reports personal fees and other from DaVolterra, outside the submitted work; In addition, A.A. has a patent DaVolterra issued. B.R. reports consulting/advisory role for Neophore, Bayer, Roche, Novartis, Gilead, Servier; Travel, accommodations, and expenses from Bayer, Servier, Astellas; salary support from Nuovo Soldati Foundation in 2019 and funding including salary support from Swim Across America foundation in 2020. The remaining authors disclose no conflicts. ### Funding Statement This work was self-supported by the Institute National du Cancer. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The French cancer cohort protocol was approved by a national committee and authorized by the French Data Protection Agency (CNIL, number 2019-082), and was conducted in accordance with the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data are not publicly available due to privacy or ethical restrictions.