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Measuring the biological effect of presurgical metformin treatment in endometrial cancer
V N Sivalingam1, S Kitson1, R McVey2
1Gynaecological Oncology Research Group, Institute of Cancer Sciences, University of Manchester, St Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
Background:
Preclinical studies in endometrial cancer (EC) show that metformin reduces cellular proliferation by PI3K-AKT-mTOR inhibition. We tested the hypothesis that short-term presurgical metformin reduces cellular proliferation in atypical endometrial hyperplasia (AEH) and endometrioid EC, and assessed the feasibility of using phosphorylated PI3K-AKT-mTOR proteins as tissue end points.
Methods:
Women with AEH or EC received metformin 850 mg twice a day or no drug in the presurgical window between diagnosis and hysterectomy. Before and after the window, tissue samples were obtained; serum markers of insulin resistance (e.g. homeostasis model of assessment of insulin resistance index) were determined; and anthropometrics measured (e.g. BMI). Cell proliferation (Ki-67) and PI3K-AKT-mTOR phosphostatus were assessed by immunohistochemistry and scored blinded to treatment.
Results:
Twenty-eight metformin-treated and 12 untreated patients, well matched for age and BMI, completed the study. Metformin treatment (median 20 days, range 7-34) was associated with a 17.2% reduction in tumour Ki-67 (95% CI -27.4, -7.0, P=0.002), in a dose-dependent manner. Tumour PI3K-AKT-mTOR protein phosphostatus varied but the effects were not significant after adjusting for changes in controls.
Conclusions:
Short-term metformin was associated with reduced Ki-67 expression in EC. Changes in tumour PI3K-AKT-mTOR protein phosphostatus were seen in both groups. Future studies should address the variability attributed to different sampling techniques including devascularisation of the uterus at hysterectomy.
Insights
Short-term metformin treatment reduced cell proliferation marker Ki-67 in endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) patients. This study also assessed PI3K-AKT-mTOR pathway proteins as potential tissue biomarkers.
Area of Science:
- Gynecologic Oncology
- Pharmacology
- Molecular Biology
Background:
- Preclinical studies indicate metformin inhibits cellular proliferation in endometrial cancer (EC) via PI3K-AKT-mTOR pathway.
- Metformin's potential to reduce proliferation in atypical endometrial hyperplasia (AEH) and EC requires clinical investigation.
- Assessing PI3K-AKT-mTOR phosphoproteins as tissue biomarkers is crucial for treatment monitoring.
Purpose of the Study:
- To evaluate the efficacy of short-term presurgical metformin in reducing cellular proliferation in AEH and EC.
- To determine if PI3K-AKT-mTOR pathway phosphoproteins can serve as reliable tissue biomarkers.
- To assess the feasibility of using these markers in clinical settings.
Main Methods:
- A presurgical window study involving women with AEH or EC.
- Metformin (850 mg twice daily) or placebo administered between diagnosis and hysterectomy.
- Assessment of tumor cell proliferation (Ki-67) and PI3K-AKT-mTOR phosphostatus via immunohistochemistry on tissue samples.
Main Results:
- Metformin treatment (median 20 days) significantly reduced tumor Ki-67 expression by 17.2% (P=0.002) in a dose-dependent manner.
- While PI3K-AKT-mTOR phosphostatus showed variations, significant changes were not consistently observed after adjustments.
- Serum markers of insulin resistance and anthropometrics were also measured but not detailed in the abstract.
Conclusions:
- Short-term metformin administration is associated with decreased Ki-67 expression in EC.
- Tumor PI3K-AKT-mTOR protein phosphostatus changes occurred in both metformin-treated and control groups.
- Further research is needed to address variability in tissue sampling and its impact on biomarker assessment.
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