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.

Endometrial Cancer as a Metabolic Disease with Dysregulated PI3K Signaling: Shedding Light on Novel Therapeutic Strategies

“…Nevertheless, a meta-analysis of the above studies supports a greater overall survival in metformin users compared to nonusers [ 133 ], although the low number of studies and the lack of randomized studies compromise the evidence level of the meta-analysis. Clinical trials using metformin for atypical endometrial hyperplasia (AEH) or EC have recently accumulated evidence for its efficacy [ 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 ]. Most studies used the presurgical window approach, in which patients diagnosed by endometrial biopsy were treated with metformin during the period prior to hysterectomy, and some studies targeted patients who underwent fertility-sparing treatments in combination with progestins.…”

Targeting endometrial cancer stem cell activity with metformin is inhibited by patient-derived adipocyte-secreted factors

“…Despite widespread interest in metformin in other aspects of the management of endometrial cancer, the effect of the drug on endometrial cancer stem cells has not previously been studied, although there is limited observational data to suggest that it may act as a chemosensitiser (36)(37)(38). Whilst our own randomised controlled pre-surgical window study did not demonstrate reduced endometrial cancer cell proliferation in response to metformin exposure, as measured by immunohistochemical expression of Ki-67, this does not preclude a specific effect of the drug on endometrial cancer stem cells (39).…”

“…Tissue microarrays (TMAs) were constructed from endometrial tumours sampled by prior to and following treatment with metformin or placebo as part of the PREMIUM study [full study details published elsewhere (39)]. Immunohistochemistry was performed using the Leica Bond Max and Refine Detection Kit.…”

“…In order to determine whether these in vitro findings were of relevance to patients, we compared the immunohistochemical expression of ALDH and CD133 in endometrial cancers from patients receiving metformin or a matched placebo prior to surgery within the context of the PREMIUM randomised controlled trial (39). Pre-and post-treatment endometrial biopsies were available for 69 patients, 33 of whom received metformin for 1-5 weeks and 35 patients were given placebo.…”

New therapeutic approaches for the fertility‐sparing treatment of endometrial cancer

“…However, the effect of oral metformin administration in EC treatment in vivo has been controversial. For example, the most recent randomized study using placebo control revealed no significant reduction in Ki‐67 index in the metformin‐treated group relative to the placebo group, suggesting that the reduction in Ki‐67 index observed in other studies was influenced by hysterectomy‐induced hypoxia. Nevertheless, the overall therapeutic effect cannot be overlooked for clinical doses of metformin in EC patients.…”