title: Relationship Between Metformin Use and Recurrence and Survival in Patients With Resected Stage III Colon Cancer Receiving Adjuvant Chemotherapy: Results From North Central Cancer Treatment Group N0147 (Alliance).
abstract: Preclinical and epidemiological data suggest that metformin might have antineoplastic properties against colon cancer (CC). However, the effect of metformin use on patient survival in stage III CC after curative resection is unknown. The survival outcomes were comparable regardless of the duration of metformin use.
  
  
  
  Before randomization to FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) with or without cetuximab, 1,958 patients with stage III CC enrolled in the N0147 study completed a questionnaire with information on diabetes mellitus (DM) and metformin use. Cox models were used to assess the association between metformin use and disease-free survival (DFS), overall survival (OS), and the time to recurrence (TTR), adjusting for clinical and/or pathological factors.
  
  
  
  Of the 1,958 patients, 1,691 (86%) reported no history of DM, 115 reported DM with metformin use (6%), and 152 reported DM without metformin use (8%). The adjuvant treatment arms were pooled, because metformin use showed homogeneous effects on outcomes across the two arms. Among the patients with DM (n = 267), DFS (adjusted hazard ratio [aHR], 0.90; 95% confidence interval [CI], 0.59-1.35; p = .60), OS (aHR, 0.99; 95% CI, 0.65-1.49; p = .95), and TTR (aHR, 0.87; 95% CI, 0.56-1.35; p = .53) were not different for the metformin users compared with the nonusers after adjusting for tumor and patient factors. The survival outcomes were comparable regardless of the duration of metformin use (<1, 1-5, 6-10, ≥11 years) before randomization (ptrend= .64 for DFS, ptrend= .84 for OS, and ptrend= .87 for TTR). No interaction effects were observed between metformin use and KRAS, BRAF mutation status, tumor site, T/N stage, gender, or age.
  
  
  
  Patients with stage III CC undergoing adjuvant chemotherapy who used metformin before the diagnosis of CC experienced DFS, OS, and TTR similar to those for non-DM patients and DM patients without metformin use.
  
  
  
  The present study did not find any relationship between metformin use or its duration and disease-free survival, time to recurrence, and overall survival in a large cohort of patients with resected stage III colon cancer receiving adjuvant FOLFOX (folinic acid, fluorouracil, oxaliplatin)-based chemotherapy. This relationship was not modified by KRAS or BRAF mutation or DNA mismatch repair status. Metformin use did not increase or decrease the likelihood of chemotherapy-related grade 3 or higher adverse events.
authors.affiliation: Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA psingh@springfieldclinic.com.
authors.forename: Preet Paul
authors.initials: PP
authors.lastname: Singh
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.affiliation: Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Grothey
authors.affiliation: Lehigh Valley Health Network, Allentown, Pennsylvania, USA.
authors.forename: Suresh G
authors.initials: SG
authors.lastname: Nair
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA.
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Shields
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.affiliation: University of British Columbia, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Sharlene
authors.initials: S
authors.lastname: Gill
authors.affiliation: Surgical Oncology Associates of South Texas, San Antonio, Texas, USA.
authors.forename: Morton S
authors.initials: MS
authors.lastname: Kahlenberg
authors.affiliation: Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
authors.affiliation: Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.affiliation: Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Alberts
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D053843:DNA Mismatch Repair; D005260:Female; D006801:Humans; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000209:etiology*; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D008687:Metformin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Adjuvant chemotherapy; Colon cancer; Diabetes mellitus; Metformin; Recurrence; Survival