title: Measuring the biological effect of presurgical metformin treatment in endometrial cancer.
abstract: BACKGROUND
  Preclinical studies in endometrial cancer (EC) show that metformin reduces cellular proliferation by PI3K-AKT-mTOR inhibition. We tested the hypothesis that short-term presurgical metformin reduces cellular proliferation in atypical endometrial hyperplasia (AEH) and endometrioid EC, and assessed the feasibility of using phosphorylated PI3K-AKT-mTOR proteins as tissue end points.
  
  
  METHODS
  Women with AEH or EC received metformin 850 mg twice a day or no drug in the presurgical window between diagnosis and hysterectomy. Before and after the window, tissue samples were obtained; serum markers of insulin resistance (e.g. homeostasis model of assessment of insulin resistance index) were determined; and anthropometrics measured (e.g. BMI). Cell proliferation (Ki-67) and PI3K-AKT-mTOR phosphostatus were assessed by immunohistochemistry and scored blinded to treatment.
  
  
  RESULTS
  Twenty-eight metformin-treated and 12 untreated patients, well matched for age and BMI, completed the study. Metformin treatment (median 20 days, range 7-34) was associated with a 17.2% reduction in tumour Ki-67 (95% CI -27.4, -7.0, P=0.002), in a dose-dependent manner. Tumour PI3K-AKT-mTOR protein phosphostatus varied but the effects were not significant after adjusting for changes in controls.
  
  
  CONCLUSIONS
  Short-term metformin was associated with reduced Ki-67 expression in EC. Changes in tumour PI3K-AKT-mTOR protein phosphostatus were seen in both groups. Future studies should address the variability attributed to different sampling techniques including devascularisation of the uterus at hysterectomy.
authors.affiliation: Gynaecological Oncology Research Group, Institute of Cancer Sciences, University of Manchester, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
authors.forename: V N
authors.initials: VN
authors.lastname: Sivalingam
authors.affiliation: Gynaecological Oncology Research Group, Institute of Cancer Sciences, University of Manchester, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
authors.forename: S
authors.initials: S
authors.lastname: Kitson
authors.affiliation: Department of Histopathology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: R
authors.initials: R
authors.lastname: McVey
authors.affiliation: Centre for Biostatistics, Institute of Population Health, University of Manchester, Manchester, UK.
authors.forename: C
authors.initials: C
authors.lastname: Roberts
authors.affiliation: Clinical Biochemistry Department, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: P
authors.initials: P
authors.lastname: Pemberton
authors.affiliation: Obstetrics and Gynaecology Department, Tameside General Hospital, Tameside, UK.
authors.forename: K
authors.initials: K
authors.lastname: Gilmour
authors.affiliation: Obstetrics and Gynaecology Department, The Royal Oldham Hospital, Pennine Acute Hospitals NHS Trust, Oldham, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ali
authors.affiliation: Cancer Studies and Surgery Research Group, Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Renehan
authors.affiliation: Gynaecological Oncology Research Group, Institute of Cancer Sciences, University of Manchester, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
authors.forename: H C
authors.initials: HC
authors.lastname: Kitchener
authors.affiliation: Gynaecological Oncology Research Group, Institute of Cancer Sciences, University of Manchester, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
authors.forename: E J
authors.initials: EJ
authors.lastname: Crosbie
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004714:Endometrial Hyperplasia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007044:Hysterectomy; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D019394:Ki-67 Antigen; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009215:Myometrium / Q000473:pathology; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011300:Preoperative Care; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D019394:Ki-67 Antigen; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human