Pre-surgical metformin In uterine malignancy (PREMIUM): a multi-center, randomized double-blind, placebo-controlled phase 3 trial
Kitson, S Maskell, Z Sivalingam, Vanitha Allen, J Ali, S Burns, S Gilmour, K Latheef, R Slade, Richard J Pemberton, P
Kitson, S
Maskell, Z
Sivalingam, Vanitha
Allen, J
Ali, S
Burns, S
Gilmour, K
Latheef, R
Slade, Richard J
Pemberton, P
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Abstract
Purpose 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.
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Date
2018
Publisher
Collections
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Type
Article
Citation
Kitson 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.