PRE-surgical Metformin In Uterine Malignancy (PREMIUM): a Multi-Center, Randomized Double-Blind, Placebo-Controlled Phase III Trial.

Abstract

Endometrioid endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumor growth <i>in vitro</i>. Presurgical window studies allow rapid <i>in vivo</i> assessment of antitumor activity. Previous window studies found metformin reduced endometrial cancer proliferation but these lacked methodological rigor. PREMIUM measured the anti-proliferative effect of metformin <i>in vivo</i> using a robust window study design.<b>Patients and Methods:</b> A multicenter, double-blind, placebo-controlled trial randomized women with atypical hyperplasia or endometrioid endometrial cancer to receive metformin (850 mg daily for 3 days, and twice daily thereafter) or placebo for 1 to 5 weeks until surgery. The primary outcome was posttreatment IHC expression of Ki-67. Secondary outcomes investigated the effect of metformin on markers of the PI3K-Akt-mTOR and insulin signaling pathways and obesity. Eighty-eight women received metformin (<i>n</i> = 45) or placebo (<i>n</i> = 43) and completed treatment. There was no overall difference in posttreatment Ki-67 between the metformin and placebo arms, in an ANCOVA analysis adjusting for baseline Ki-67 expression (mean difference -0.57%; 95% CI, -7.57%-6.42%; <i>P</i> = 0.87). Metformin did not affect expression of markers of the PI3K-Akt-mTOR or insulin signaling pathways, and did not result in weight loss. Short-term treatment with standard diabetic doses of metformin does not reduce tumor proliferation in women with endometrioid endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings.