title: Prospective evaluation of the molecular effects of metformin on the endometrium in women with newly diagnosed endometrial cancer: A window of opportunity study.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States. Electronic address: psoliman@mdanderson.org.
authors.forename: Pamela T
authors.initials: PT
authors.lastname: Soliman
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Westin
authors.affiliation: Department of Obstetrics and Gynecology, Carilion Clinic Gynecologic Oncology Roanoke, VA, United States.
authors.forename: David
authors.initials: D
authors.lastname: Iglesias
authors.affiliation: Division of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Munsell
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Schmandt
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Melinda
authors.initials: M
authors.lastname: Yates
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Lois
authors.initials: L
authors.lastname: Ramondetta
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018269:Carcinoma, Endometrioid / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000187:drug effects / Q000378:metabolism; D019394:Ki-67 Antigen / Q000187:drug effects / Q000378:metabolism; D037102:Lectins / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D011446:Prospective Studies; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; D058851:GPI-Linked Proteins; D007004:Hypoglycemic Agents; C432397:ITLN1 protein, human; D007328:Insulin; D019394:Ki-67 Antigen; D037102:Lectins; D020738:Leptin; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; D055372:AMP-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: Endometrial cancer; Inhibition; Metformin; Window of opportunity; mTOR