title: Treatment with metformin is associated with higher remission rate in diabetic patients with thyroid cancer.
abstract: BACKGROUND
  Clinical trials demonstrated that metformin increases the efficiency of systemic therapy in cancer patients.
  
  
  OBJECTIVE
  We examined whether the efficacy of conventional treatment of differentiated thyroid cancer (DTC) is affected by therapy with metformin in diabetic patients.
  
  
  METHODS
  We compared the rate of complete response (CR) between diabetics who were treated with metformin (group MF+; n = 34) or not treated (group MF-; n = 21) and control nondiabetic patients (group C; n = 185). We also examined the effects of metformin on DTC cells in vitro.
  
  
  RESULTS
  The groups were comparable in terms of age, sex, body mass index, diabetes management, frequencies of multifocal tumor growth, extrathyroidal extension, and locoregional and distant metastases. Tumor size was significantly smaller in the MF+ group compared with the MF- and C groups (1.37 ± 0.97 vs 2.44 ± 1.49 vs 2.39 ± 1.73 cm, respectively; P = .026). A multivariate model revealed that extrathyroidal extension (P = .018), distant metastases (P < .0001), and lack of treatment with metformin of diabetics (P < .0001) decreased the likelihood of CR. A Cox hazards model revealed that age (P = .025), locoregional metastases (P = .022), distant metastases (P = .003), and lack of treatment with metformin of patients with diabetes (P = .014) are associated with increased risk for shortened progression-free survival. In vitro data revealed that metformin inhibited cancer cell growth, activated cAMP-inducible protein kinase (5'-AMP-activated protein kinase [AMPK]), and down-regulated p70S6K/pS6. Metformin potentiated H₂O₂-inducible activation of AMPK but attenuated pERK and p70S6K. Tumors from MF+ patients demonstrated a lower level of phospho-p70S6K compared with the MF- group.
  
  
  CONCLUSIONS
  Tumor size is smaller in patients treated with metformin, suggesting inhibition of tumor growth by the drug. Among diabetics, the absence of metformin therapy is an independent factor for decreased likelihood of CR and increased risk of shorter progression-free survival. In vitro data suggest that p70S6K/pS6 is likely a molecular target of metformin in DTC cells.
authors.affiliation: Department of Pediatrics, Uniformed Services University of Health Sciences, Bethesda, Maryland 20814-4712, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Klubo-Gwiezdzinska
authors.forename: John
authors.initials: J
authors.lastname: Costello
authors.forename: Aneeta
authors.initials: A
authors.lastname: Patel
authors.forename: Andrew
authors.initials: A
authors.lastname: Bauer
authors.forename: Kirk
authors.initials: K
authors.lastname: Jensen
authors.forename: Mihriye
authors.initials: M
authors.lastname: Mete
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Burman
authors.forename: Leonard
authors.initials: L
authors.lastname: Wartofsky
authors.forename: Vasyl
authors.initials: V
authors.lastname: Vasko
mesh_terms: D000328:Adult; D000368:Aged; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003920:Diabetes Mellitus / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D018384:Oxidative Stress; D016016:Proportional Hazards Models; D012074:Remission Induction; D013964:Thyroid Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin