title: A pilot 'window of opportunity' neoadjuvant study of metformin in localised prostate cancer.
abstract: BACKGROUND
  Metformin is an inhibitor of complex 1 in the respiratory chain, and is widely used to reduce insulin resistance. It has also been described to have pleotropic effects including via AMPK on inhibiting the mTOR kinase. Pre-clinical and epidemiological studies suggest an ability to modulate disease evolution in prostate cancer. In this study, we aimed to (i) demonstrate safety and tolerability of neoadjuvant metformin administration and (ii) document changes in proliferative (Ki67) and AMPK-related signalling indices between matching biopsies and prostatectomies
  
  
  METHODS
  Men were treated in a single-arm 'window of opportunity' study between their decision to undergo radical prostatectomy and the operation itself. Forty patients were planned but only 24 patients were enrolled owing to slow accrual. Twenty-one patients were evaluable for pathological outcomes and 22 for serum metabolic indices. Metformin was given at doses to 500 mg t.i.d. Ki67 index was calculated using the Aperio-positive pixel count algorithm, whereas immunohistochemical measurements were by consensus H-Score. Comparative statistics were analysed by students t-tests and/or Wilcoxon matched pairs signed rank test.
  
  
  RESULTS
  Baseline characteristics included median PSA 6 ng ml(-1) (3.22-36.11 ng ml(-1)). Median duration of drug treatment was 41 days (18-81). Treatment was well tolerated with only three patients developing G3/4 toxicities. In a per patient and per tumour analyses, metformin reduced the Ki67 index by relative amounts of 29.5 and 28.6 % (P=0.0064 and P=0.0042) respectively. There was also a significant decrease in P-4EBP1 staining (P<0.001) but no change in P-AMPK or P-ACC. There were no correlations between any metabolic, morphometric or cancer-related serum indices. There was a trend towards PSA reduction (P=0.08). The study is limited by small patient numbers and tumour heterogeneity.
  
  
  CONCLUSIONS
  Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Joshua
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: V E
authors.initials: VE
authors.lastname: Zannella
authors.affiliation: 1] Princess Margaret Cancer Centre, Toronto, ON, Canada [2] Department of Pathology, University Health Network, Toronto, ON, Canada.
authors.forename: M R
authors.initials: MR
authors.lastname: Downes
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Bowes
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Hersey
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Koritzinsky
authors.affiliation: 1] Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tübingen, Stuttgart, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schwab
authors.affiliation: 1] Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tübingen, Stuttgart, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Hofmann
authors.affiliation: 1] Princess Margaret Cancer Centre, Toronto, ON, Canada [2] Department of Pathology, University Health Network, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Evans
authors.affiliation: 1] Princess Margaret Cancer Centre, Toronto, ON, Canada [2] Department of Pathology, University Health Network, Toronto, ON, Canada.
authors.forename: T
authors.initials: T
authors.lastname: van der Kwast
authors.affiliation: 1] Princess Margaret Cancer Centre, Toronto, ON, Canada [2] Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany [3] University of Tübingen, Stuttgart, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Trachtenberg
authors.affiliation: 1] Princess Margaret Cancer Centre, Toronto, ON, Canada [2] Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany [3] University of Tübingen, Stuttgart, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Finelli
authors.affiliation: 1] Princess Margaret Cancer Centre, Toronto, ON, Canada [2] Division of Urology, Department of Surgery, University Health Network, Toronto, ON, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Fleshner
authors.affiliation: 1] Princess Margaret Cancer Centre, Toronto, ON, Canada [2] Department of Pathology, University Health Network, Toronto, ON, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Sweet
authors.affiliation: Jewish General Hospital, Montreal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Pollak
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D001706:Biopsy; D006801:Humans; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010865:Pilot Projects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D008687:Metformin