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

Abstract

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/m2 (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, posttreatment 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 (83.3%, 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 of women with EC.

Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer

“…There have been two other reported preoperative window studies of metformin in newly diagnosed endometrial cancer patients . As with the data presented here, endometrial cancer patients in both of these studies were treated with short‐term metformin prior to hysterectomy and surgical staging .…”

Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions

“…In one study on endometrial cancer patients, it also increased plasmatic ketone body concentration by about 5-fold (130), and has been proposed to reduce IGF-1 levels (131). Metformin can therefore potentially target different metabolic pathways that are associated with cancer progression and proliferation, mimicking fasting/FMD; however, different from fasting, most of metformin-induced effects are likely restricted to hyperglycemic/diabetic patients.…”

Effect of Metformin on Different Non-Diabetes Related Conditions, a Special Focus on Malignant Conditions: Review of Literature

“…However, the drawback of the study was the end point as it was death due to any cause, not specifically due to the endometrium cancer [67]. Thus many studies have pointed towards the improvement in survival might be because of the patient’s overall health improvement rather than the regression/resolution of endometrial cancer per se [68-70]. …”

“…However, only 20 patients continued the trial, which calls for further elaboration on metformin’s benefits by using a bigger sample size [68]. …”