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.

Original languageEnglish
Pages (from-to)281-289
Number of pages9
JournalBritish Journal of Cancer
Issue number3
Early online date21 Jan 2016
Publication statusPublished - 2 Feb 2016


  • Aged
  • Aged, 80 and over
  • Blood Glucose
  • C-Peptide
  • Carcinoma, Endometrioid
  • Endometrial Hyperplasia
  • Endometrial Neoplasms
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Hypoglycemic Agents
  • Hysterectomy
  • Immunohistochemistry
  • Insulin
  • Insulin Resistance
  • Ki-67 Antigen
  • Metformin
  • Middle Aged
  • Myometrium
  • Neoadjuvant Therapy
  • Neoplasm Grading
  • Neoplasm Invasiveness
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Preoperative Care
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Treatment Outcome
  • Clinical Trial
  • Journal Article
  • Research Support, Non-U.S. Gov't


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