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

Abstract

Purpose: Endometrioid endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumor growth in vitro. Presurgical window studies allow rapid in vivo 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 in vivo using a robust window study design.Patients and Methods: 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.

Results: Eighty-eight women received metformin (n = 45) or placebo (n = 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%; P = 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.

Conclusions: 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.

Figure 1

PREMIUM CONSORT diagram.

Figure 2

Effect of metformin treatment on Ki-67 expression. A, Pre- and posttreatment Ki-67 expression in endometrial cancers from individual participants. B, Mean Ki-67 expression pre- and posttreatment with metformin or placebo. There was no significant difference in overall posttreatment Ki-67 expression between the metformin and placebo arms after adjusting for baseline Ki-67 expression. In the metformin arm, mean Ki-67 expression decreased from 39.8% (35.7%–43.9%) at baseline to 32.8% (95% CI, 28.0%–37.6%) following treatment, whereas in the placebo arm, mean Ki-67 expression decreased from 39.5% (95% CI, 34.5%–44.5%) to 33.9% (95% CI, 28.2%–39.7%). The mean difference in posttreatment Ki-67 expression between the metformin and placebo arms was −0.57% (95% CI, −7.57%–6.42%; P = 0.87), after adjusting for baseline Ki-67 expression.