title: Phase II study of metformin for reduction of obesity-associated breast cancer risk: a randomized controlled trial protocol.
abstract: Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk.
  
  
  
  This is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n = 75) or placebo (n = 75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored.
  
  
  
  The study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases.
  
  
  
  ClinicalTrials.gov Identifier: NCT02028221 . Registered on January 2, 2014. Grant #: 1R01CA172444-01A1 awarded on Sept 11, 2013.
authors.affiliation: The University of Arizona Cancer Center, 1515 N Campbell Ave; Rm 2964B, Tucson, AZ, 85724, USA. jam1@email.arizona.edu.|Department of Nutritional Sciences, The University of Arizona, Tucson, AZ, USA. jam1@email.arizona.edu.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Martinez
authors.affiliation: The University of Arizona Cancer Center, 1515 N Campbell Ave; Rm 2964B, Tucson, AZ, 85724, USA.
authors.forename: Pavani
authors.initials: P
authors.lastname: Chalasani
authors.affiliation: The University of Arizona Cancer Center, 1515 N Campbell Ave; Rm 2964B, Tucson, AZ, 85724, USA.|Department of Epidemiology and Biostatistics, The University of Arizona, Tucson, AZ, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Thomson
authors.affiliation: The University of Arizona Cancer Center, 1515 N Campbell Ave; Rm 2964B, Tucson, AZ, 85724, USA.|Department of Epidemiology and Biostatistics, The University of Arizona, Tucson, AZ, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Roe
authors.affiliation: The University of Arizona Cancer Center, 1515 N Campbell Ave; Rm 2964B, Tucson, AZ, 85724, USA.|Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Altbach
authors.affiliation: The University of Arizona Cancer Center, 1515 N Campbell Ave; Rm 2964B, Tucson, AZ, 85724, USA.|Department of Medical Imaging, University of Arizona, Tucson, AZ, USA.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Galons
authors.affiliation: Department of Medical Hematology/ Oncology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Stopeck
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Thompson
authors.affiliation: The University of Arizona Cancer Center, 1515 N Campbell Ave; Rm 2964B, Tucson, AZ, 85724, USA.
authors.forename: Diana Evelyn
authors.initials: DE
authors.lastname: Villa-Guillen
authors.affiliation: The University of Arizona Cancer Center, 1515 N Campbell Ave; Rm 2964B, Tucson, AZ, 85724, USA.
authors.forename: H-H Sherry
authors.initials: HH
authors.lastname: Chow
mesh_terms: D052242:Adiponectin / Q000097:blood; D000328:Adult; D001835:Body Weight / Q000187:drug effects; D001940:Breast / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology; D001943:Breast Neoplasms / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004311:Double-Blind Method; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008279:Magnetic Resonance Imaging / Q000379:methods; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000150:complications*; D017063:Outcome Assessment, Health Care; D012307:Risk Factors; D013739:Testosterone / Q000097:blood; D055105:Waist Circumference / Q000187:drug effects
chemical_list: D052242:Adiponectin; D007004:Hypoglycemic Agents; C515497:IGFBP3 protein, human; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D020738:Leptin; D013739:Testosterone; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D008687:Metformin
keywords: Biomarkers; Breast cancer prevention; Breast density; Metabolic syndrome; Metabolomics; Metformin