Table 3.

Clinical trials of metformin in endometrial cancer.

References	Design	Assessment	Treatment	No MFM	MFM	Results
(110) (Iran)	Non-blinded randomized controlled trial	Endometrial histology after metformin vs. progesterone treatment for dysfunctional uterine bleeding	Metformin 500 mg twice daily or megestrol 40 mg daily for 3 months	21	22	Metformin induced endometrial atrophy in 95.5% (21/22) of patients (including 2 with low grade EEC) compared to 61.9% (13/21) receiving megestrol
(111) (Canada)	Single arm	Effect of metformin on serum and tumor biomarkers during window from biopsy-proven EC diagnosis to resection in non-diabetic patients	Metformin 500 mg three times daily from enrollment to surgery (21–50 days, mean 36.6 days, median 38 days)	10 (banked tissues)	11 (8 EEC, 3 NEEC)	Metformin reduced plasma insulin, IGF-1 and IGFBP-7 and decreased tumor Ki-67 and phospho-rpS6. Metformin treatment led to non-significant increase in plasma IGFBP-1
(112) (Japan)	Single arm	Effect of metformin on serum and tumor biomarkers during window from biopsy-proven EC diagnosis to surgical resection in non-diabetic patients	Metformin starting dose 750 mg daily, increased weekly as tolerated to 1,500–2,250 mg daily (divided) from enrollment to surgery (4–6 weeks)	10 (banked tissues)	31	Metformin reduced tumor topoisomerase IIα, Ki-67, phospho-rpS6, and phospho-ERK1/2 and increased tumor phospho-AMPK Metformin decreased serum insulin, glucose, and IGF-1 metformin decreased ability of sera to stimulate DNA synthesis in cultured cells
(113) (China)	Single arm	Effect of metformin plus estrogen/progesterone combination on early stage EC (Ia) in women with PCOS	Cyproterone acetate 2 mg daily, ethinyl estradiol 35 μg daily, and metformin 1,000 mg daily for 6 months	N/A	5	Estrogen/progesterone treatment combined with metformin led to reversion to normal endometrial epithelium in all patients
(114) (USA)	Single arm	Effect of metformin on tumor biomarkers during window from biopsy-proven EEC diagnosis to surgical resection in obese women	Metformin 850 mg daily from enrollment to surgery (7–28 days, mean 14.65 days)	N/A	20	Metformin decreased tumor Ki-67, phospho-AMPK, phospho-Akt, phospho-rpS6, phospho-4E-BP-1 and ER but did not change PR level Responders had increased serum free fatty acids and tumor staining for markers of fatty acid oxidation and glycogen synthesis
(115) (UK)	Non-randomized controlled trial	Effect of metformin on tumor biomarkers during window from biopsy-proven diagnosis of AEH or EEC to surgical resection	Metformin 850 mg twice daily from enrollment to surgery (7–34 days, median 20 days) vs. no treatment	12 (2 AEH, 10 EEC)	28 (0 AEH, 28 EEC)	Metformin decreased tumor Ki-67 and phospho-4E-BP1 but did not change levels of phospho-Akt, phospho-ACC, phospho-rpS6, ER, PR, or caspase-3
(116) (China)	Non-randomized controlled trial	Effect of metformin on serum and tumor biomarkers during window from biopsy-proven diagnosis of EC and surgical resection in non-diabetic women	Metformin 500 mg three times daily from enrollment to surgery (3–4 weeks) vs. no treatment	30	30	EC patients had higher serum IGF-1, lower tumor phospho-AMPK, and higher tumor phospho-mTOR at baseline than non-EC patients Metformin led to lower serum IGF-1, higher tumor phospho-AMPK and lower tumor phospho-mTOR in EC patients
(117) (USA)	Single arm	Effect of metformin on serum and tumor biomarkers during window from biopsy-proven diagnosis of EC to surgical resection	Metformin 850 mg daily from enrollment to surgery (7–24 days, median 9.5 days)	N/A	20	Metformin decreased serum IGF-1, omentin, insulin, C-peptide, and leptin Metformin decreased tumor phospho-Akt, phospho-rpS6, phospho-ERK1/2 but did not change levels of Ki-67, phospho-ACC or caspase-3
(118) (Japan)	Single arm	Efficacy of metformin in preventing recurrence after progestin therapy for AEH or early stage EC (stage Ia)	Metformin starting dose 750 mg daily, increased weekly as tolerated to 2,250 mg daily (divided, concurrent with medroxyprogesterone acetate-based protocol for 24–36 weeks, continued alone in complete responders until conception or recurrence)	N/A	16 AEH, 13 EC	Metformin maintenance associated with 3-year recurrence-free survival of 89%, compared to expected baseline of 52% recurrence-free survival at 2 years
(119) (China)	Non-randomized controlled trial	Effect of metformin on tumor biomarkers during window from biopsy-proven diagnosis of EC to surgical resection	Metformin 500 mg three times daily for 3–4 weeks	32	33	EC patients had higher tumor Ki-67, PI3K, phospho-Akt, phospho-S6K1, and phospho-4E-BP1 at baseline than non-EC patients Metformin decreased tumor Ki-67, PI3K, phospho-Akt, phospho-S6K1, and phospho-4E-BP1 in EC patients

MFM, metformin; EC, endometrial cancer; EEC, endometrioid endometrial cancer; NEEC, non-endometrioid endometrial cancer; IGF-1, insulin-like growth factor-1; IGFBP-1/7, insulin-like growth factor binding protein-1/7; rpS6, ribosomal protein S6; ERK1/2, extracellular signal-regulated kinase-1/2; AMPK, AMP-activated kinase; PCOS, polycystic ovary syndrome; Akt, protein kinase B; 4E-BP1, eukaryotic initiation factor 4E-binding protein-1; ER, estrogen receptor; PR, progesterone receptor; AEH, atypical endometrial hyperplasia; ACC, acetyl-CoA carboxylase; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; S6K1, S6 kinase 1.