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Metformin and endometrial cancer survival: a quantitative synthesis of observational studies.

ABSTRACT: Metformin has been reported to have anticancer effect and can affect patient survival in several malignancies. However, the results are inconclusive for endometrial cancer. Hence, we conducted a systematic review and meta-analysis to investigate the prognostic role of metformin in patients with endometrial cancer. Studies were identified from Pubmed and Embase database through March 2017. Observational studies reporting hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) were selected. Data were abstracted and summarised using random-effects models. From 250 unique citations, we identified ten studies including 6242 patients with nine studies examining OS and five studies examining PFS. Meta-analysis demonstrated that metformin users had better OS (HR, 0.58; 95% CI, 0.45 to 0.76; P = 0.207, I2 = 26.6%) and PFS (HR, 0.61; 95% CI, 0.49 to 0.76; P =0.768, I2 = 0%) than non-users for endometrial cancer patients. Similar findings were observed using sensitivity analysis adjusted by trim and filled methods (HR, 0.47; 95% CI, 0.37 to 0.58) and subgroup analyses. Based on the current evidence, we find that metformin use is associated with better OS and PFS in patients with endometrial cancer. However, further large-scale prospective studies are needed to establish its validity.

SUBMITTER: Guo J

PROVIDER: S-EPMC5630401 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Metformin and endometrial cancer survival: a quantitative synthesis of observational studies.

Guo Jianfeng J Xu Kai K An Min M Zhao Yingchao Y

Oncotarget 20170802 39

Metformin has been reported to have anticancer effect and can affect patient survival in several malignancies. However, the results are inconclusive for endometrial cancer. Hence, we conducted a systematic review and meta-analysis to investigate the prognostic role of metformin in patients with endometrial cancer. Studies were identified from Pubmed and Embase database through March 2017. Observational studies reporting hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival ...[more]

PMID: 29029501

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Project description:BACKGROUND:Obesity and diabetes are associated with increased risk and worse outcomes for endometrial cancer. Metformin is a widely prescribed generic drug for the treatment of type II diabetes and metabolic syndrome and may also have anti-tumorigenic effects. Thus, we assessed the metabolic anti-tumorigenic effects of metformin in (1) human endometrial cancer cell lines under varying glucose concentrations, and (2) a novel genetically engineered mouse model of endometrioid endometrial cancer under obese and lean conditions. METHODS:The effects of metformin on cytotoxicity, apoptosis, cell cycle progression, and the AMPK/mTOR/S6 and MAPK pathways were assessed in ECC-1 and Ishikawa cells under low, normal and high glucose conditions. The impact of metformin treatment on tumor growth under obese and lean conditions was evaluated using a novel LKB1fl/fl p53fl/fl mouse model of endometrial cancer. Global, untargeted metabolomics was used to identify (1) obesity-associated differences between endometrial tumors and (2) the obesity-dependent effects of metformin in the endometrial tumors. RESULTS:Hypoglycemic conditions significantly enhanced the sensitivity of the cells to metformin in regards to its anti-proliferative and apoptotic effects, as compared to hyperglycemic and normal glucose conditions. Metformin inhibited tumor growth in both the obese and lean mice, which metformin-induced inhibition of tumor progression in obese mice was significantly greater than in lean mice. Metabolomic profiling in endometrial cancer tissues revealed significant differences between obese- and lean-mice. Enhanced energy metabolism was seen in obese- versus lean-mice as evidenced by increases in glycolytic and oxidative phosphorylation intermediates. In addition, dramatic increases in lipid biosynthesis and lipid peroxidation were found in the obese- versus lean-mice, whereas metformin obviously reversed the obesity-driven upregulation of lipid and protein biosynthesis in the obese mice. CONCLUSIONS:The obese state promoted tumor aggressiveness in the LKB1fl/fl p53fl/fl mouse model, accompanied by increases in energy metabolism, lipid biosynthesis, and markers of lipid peroxidation. Metformin had increased efficacy against endometrial cancer in obese versus lean mice and reversed the detrimental metabolic effects of obesity in the endometrial tumors. Taken together, it is likely that the unique metabolic milieu underlies metformin's improved efficacy in treating endometrial cancer which develop in an obese host environment.

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Metformin and endometrial cancer survival: a quantitative synthesis of observational studies.

Publications

Metformin and endometrial cancer survival: a quantitative synthesis of observational studies.

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