c-peptide and Carcinoma--Endometrioid

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.. 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.. 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.. 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.

Topics: 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