Prospective evaluation of the molecular effects of metformin on the endometrium in women with newly diagnosed endometrial cancer: A window of opportunity study

Objective. Metformin reduces cancer incidence and improves overall survival in diabetic patients. In preclinical studies, metformin decreases endometrial cancer (EC) cell growth by activation of AMPK/mTOR inhibition. We sought to determine the effects of metformin on serum/tumor biomarkers in women with EC. Methods. In this prospective trial, newly diagnosed EC patients underwent pre-treatment blood draw/endometrial biopsy, were administered oral metformin 850 mg daily for >= 7 days, and underwent post-treatment blood draw/definitive surgery. Pre- and post- serum analyses were performed. Tumor samples were evaluated for changes in AMPK, PI3K/AKT pathway, proliferation, and apoptosis by immunohistochemistry. Results. Twenty patients completed the trial. Median age and BMI were 57 years (range: 27-67) and 34.5 kg/m(2) (range: 21.9-50.0). Median duration of metformin was 9.5 days (range: 7-24). A majority of women had endometrioid adenocarcinomas (90%) and were early stage (85%). After metformin, there were significant decreases in serum IGF-1 (p = 0.046), omentin (p = 0.007), insulin (p = 0.012), C-peptide (p = 0.018), and leptin (p = 0.0035). Compared to baseline, post-treatment tissue showed decreased phospho-AKT in 18/20 patients (90%, p = 0.0002), decreased phospho-S6rp in 14/20 patients (70%, p = 0.057), and decreased phospho-p44/42MAPK in 15/18 patients (833%, p = 0.0038). There was no difference in Ki67, phospho-ACC, or caspase 3. Changes did not correlate with BMI, grade, or KRAS mutation. Conclusion. In this prospective window of opportunity study, we demonstrated that relevant serum and molecular changes occur in patients with newly diagnosed EC after a short course of metformin. Ongoing clinical trials will help determine the appropriate role for metformin in the treatment cif women with EC (C) 2016 Elsevier Inc. All rights reserved.