Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer

Abstract

Background: Metformin has been associated with reduced cancer risk. The mechanisms underlying this cancer protective effect remain unknown.

Methods: "Window of opportunity" study of metformin in women with operable endometrial cancer (EC). Eleven newly diagnosed, untreated, non-diabetic patients with EC received metformin 500 mg tid from diagnostic biopsy to surgery. Fasting plasma insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 1 (IGFBP-1) and insulin-like growth factor binding protein 7 (IGFBP-7) measurements were taken before and after metformin treatment. Ki-67, pAMPK, and pS6 immunohistochemistry staining was performed on the endometrial cancer before and after metformin treatment and was compared to a control group of 10 women with EC who did not receive metformin.

Results: Metformin was administered for a mean of 36.6 days. None of the patients suffered side effects requiring withdrawal from the study. The study group comprised 8 patients with endometrioid EC, and 3 non-endometrioid EC, with a mean follow-up time of 57 months. Mean plasma insulin (p=0.0005), IGF-1 (p=0.001), and IGFBP-7 (p=0.0098) were significantly reduced after metformin treatment. A clear reduction in ki-67 and pS6 expression was observed by both conventional light microscope analysis and digital image analysis with a significant mean reduction in percentage of cells staining for ki-67 (9.7%, P=0.02) and pS6 (31%, P=0.03). In the non-treated control group expression was similar between the biopsy and the surgical specimens.

Conclusions: This pilot trial presents biological evidence consistent with anti-proliferative effects of metformin in women with EC in the clinical setting.

Keywords: AMPK; Endometrial cancer; Insulin growth factor; Metformin; ki-67; pS6.