Pre-surgical metformin In uterine malignancy (PREMIUM): a multi-center, randomized double-blind, placebo-controlled phase 3 trial
Slade, Richard J
AffiliationDivision of Cancer Sciences, University of Manchester
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AbstractPurpose Endometrioid endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumor growth in vitro. Pre-surgical window studies allow rapid in vivo assessment of anti-tumor 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 (850mg daily for three days, and twice daily thereafter) or placebo for 1-5 weeks until surgery. The primary outcome was post-treatment immunohistochemical 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 post-treatment 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.
CitationKitson S, Maskell Z, Sivalingam VN, Allen JL, Ali S, Burns S, et al. Pre-surgical metformin In uterine malignancy (PREMIUM): a multi-center, randomized double-blind, placebo-controlled phase 3 trial. Clin Cancer Res. 2018 Dec 18.
JournalClincal Cancer Research