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. 2016 Dec;143(3):466-471.
doi: 10.1016/j.ygyno.2016.10.011. Epub 2016 Oct 13.

Prospective evaluation of the molecular effects of metformin on the endometrium in women with newly diagnosed endometrial cancer: A window of opportunity study

Pamela T Soliman  1 , Qian Zhang  2 , Russell R Broaddus  3 , Shannon N Westin  2 , David Iglesias  4 , Mark F Munsell  5 , Rosemarie Schmandt  2 , Melinda Yates  2 , Lois Ramondetta  2 , Karen H Lu  2
Affiliations

Prospective evaluation of the molecular effects of metformin on the endometrium in women with newly diagnosed endometrial cancer: A window of opportunity study

Pamela T Soliman et al. Gynecol Oncol. 2016 Dec.

Abstract

Objective: Metformin reduces cancer incidence and improves overall survival in diabetic patients. In preclinical studies, metformin decreases endometrial cancer (EC) cell growth by activation of AMPK/mTOR inhibition. We sought to determine the effects of metformin on serum/tumor biomarkers in women with EC.

Methods: In this prospective trial, newly diagnosed EC patients underwent pre-treatment blood draw/endometrial biopsy, were administered oral metformin 850mg daily for ≥7days, and underwent post-treatment blood draw/definitive surgery. Pre- and post- serum analyses were performed. Tumor samples were evaluated for changes in AMPK, PI3K/AKT pathway, proliferation, and apoptosis by immunohistochemistry.

Results: Twenty patients completed the trial. Median age and BMI were 57years (range: 27-67) and 34.5kg/m2 (range: 21.9-50.0). Median duration of metformin was 9.5days (range: 7-24). A majority of women had endometrioid adenocarcinomas (90%) and were early stage (85%). After metformin, there were significant decreases in serum IGF-1 (p=0.046), omentin (p=0.007), insulin (p=0.012), C-peptide (p=0.018), and leptin (p=0.0035). Compared to baseline, post-treatment tissue showed decreased phospho-AKT in 18/20 patients (90%, p=0.0002), decreased phospho-S6rp in 14/20 patients (70%, p=0.057), and decreased phospho-p44/42MAPK in 15/18 patients (83.3%, p=0.0038). There was no difference in Ki67, phospho-ACC, or caspase 3. Changes did not correlate with BMI, grade, or KRAS mutation.

Conclusion: In this prospective window of opportunity study, we demonstrated that relevant serum and molecular changes occur in patients with newly diagnosed EC after a short course of metformin. Ongoing clinical trials will help determine the appropriate role for metformin in the treatment of women with EC.

Keywords: Endometrial cancer; Inhibition; Metformin; Window of opportunity; mTOR.

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Conflict of interest statement

None of the authors have a conflict of interest.

Figures

Figure 1
Figure 1
The direct and indirect downstream effects of metformin.
Figure 2
Figure 2
Examples of the immunohistochemical changes in p-S6p, phosphor-AKT and MAPK in pre- and post-treatment tissue samples.
See this image and copyright information in PMC

References

    1. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2009;52(1):17–30. - PubMed
    1. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ (Clinical research ed. 2005;330(7503):1304–1305. - PMC - PubMed
    1. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes care. 2009;32(9):1620–1625. - PMC - PubMed
    1. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137(2):482–488. - PMC - PubMed
    1. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27(20):3297–3302. - PMC - PubMed

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