A Phase III Randomized Trial of Metformin vs Placebo in Early Stage Breast Cancer

A Phase III Randomized Trial of Metformin Versus Placebo on Recurrence and Survival in Early Stage Breast Cancer

This study is looking at whether Metformin, an agent that is commonly used to treat diabetes, can decrease or affect the ability of breast cancer cells to grow and whether Metformin will work with other therapies to keep cancer from recurring. Health Canada has not approved the sale or use of Metformin to treat breast cancer, although they have approved its use in this clinical trial. Although Metformin is approved by the FDA for the treatment of diabetes, its use in breast cancer is considered investigational.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Other: placebo; Drug: metformin hydrochloride

Detailed Description

This is a multicenter study. Patients are stratified according to hormone-receptor status (estrogen receptor- and/or progesterone receptor- positive vs both receptors negative), body mass index (≤ 30 vs > 30 kg/m²), HER2 status (positive vs negative), and prior chemotherapy (any vs none). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral metformin hydrochloride twice daily (once daily in weeks 1-4). Treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oral placebo twice daily (once daily in weeks 1-4). Treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity.

Blood and tumor samples are collected periodically for correlative studies.

Patients may complete quality-of-life, physical activity, and diet questionnaires at baseline and at 6, 12, 24, 36, 48, and 60 months. (Sub-set of patients).

After completion of study treatment, patients are followed annually.

• Study Type: Interventional
• Enrollment (Actual): 3649
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • British Columbia
    • Abbotsford, British Columbia, Canada, V2S 0C2
      • BCCA - Abbotsford Centre
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • BCCA - Cancer Centre for the Southern Interior
    • Surrey, British Columbia, Canada, V3V 1Z2
      • BCCA - Fraser Valley Cancer Centre
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BCCA - Vancouver Cancer Centre
    • Victoria, British Columbia, Canada, V8R 6V5
      • BCCA - Vancouver Island Cancer Centre
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1C 6Z8
      • The Moncton Hospital
    • Moncton, New Brunswick, Canada, E1C 8X3
      • The Vitalite Health Network - Dr. Leon Richard
    • Saint John, New Brunswick, Canada, E2L 4L2
      • Atlantic Health Sciences Corporation
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, AIB 3V6
      • Dr. H. Bliss Murphy Cancer Centre
  • Ontario
    • Cambridge, Ontario, Canada, N1R 3G2
      • Cambridge Memorial Hospital
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre at Hamilton Health Sciences
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario at Kingston
    • Kitchener, Ontario, Canada, N2G 1G3
      • Grand River Regional Cancer Centre
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program
    • Mississauga, Ontario, Canada, L5M 2N1
      • Credit Valley Hospital
    • Newmarket, Ontario, Canada, L3Y 2P9
      • Stronach Regional Health Centre at Southlake
    • Oshawa, Ontario, Canada, L1G 2B9
      • Lakeridge Health Oshawa
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Health Research Institute - General Division
    • Sault Ste. Marie, Ontario, Canada, P6B 0A8
      • Algoma District Cancer Program
    • St. Catharines, Ontario, Canada, L2R 7C6
      • Niagara Health System
    • Sudbury, Ontario, Canada, P3E 5J1
      • Northeast Cancer Center Health Sciences
    • Thunder Bay, Ontario, Canada, P7B 6V4
      • Thunder Bay Regional Health Science Centre
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M4C 3E7
      • Toronto East General Hospital
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Odette Cancer Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Univ. Health Network-Princess Margaret Hospital
    • Toronto, Ontario, Canada, M9C 1A5
      • Trillium Health Centre - West Toronto
    • Windsor, Ontario, Canada, N8W 2X3
      • Windsor Regional Cancer Centre
  • Prince Edward Island
    • Charlottetown, Prince Edward Island, Canada, C1A 8T5
      • PEI Cancer Treatment Centre,Queen Elizabeth Hospital
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
      • Hopital Charles LeMoyne
    • Laval, Quebec, Canada, H7M 3L9
      • Hopital de la Cite-de-la-Sante
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill University - Dept. Oncology
    • Montreal, Quebec, Canada, H1T 2M4
      • Hôpital Maisonneuve-Rosemont
    • Montreal, Quebec, Canada, H2W 1T8
      • CHUM - Hotel Dieu du Montreal
    • Quebec City, Quebec, Canada, G1R 2J6
      • CHUQ-Pavillon Hotel-Dieu de Quebec
    • Quebec City, Quebec, Canada, G1S 4L8
      • CHA-Hopital Du St-Sacrement
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre
• Switzerland
  • Chur, Switzerland, 7000
    • Switzerland-Chur (Ratisches Kantons- und Regionalspital)
  • Frauenfeld, Switzerland, 8501
    • Brustzentrum Thurgau, Spital Thurgau AG
  • Locarno, Switzerland, 6600
    • Fondazione Oncologia Lago Maggiore, FOLM
  • Luzern 16, Switzerland, 6000
    • Switzerland-Luzern (Kantonsspital Luzern)
  • Mendrisio, Switzerland, 6850
    • Switzerland - Oncology Institute of Southern Switzerland (IOSI)
  • Olten, Switzerland, 4600
    • Switzerland - Olten (Kantonsspital) affiliate-3101
  • St. Gallen, Switzerland, 9006
    • Switzerland - ZeTup St.Gallen
  • Zurich, Switzerland, 8005
    • Switzerland - Brust-Zentrum, Zurich
• United Kingdom
  • Birmingham, United Kingdom, B187QH
    • Sandwell and West Birmingham Hospitals NHS Trust
  • Birmingham
    • Edgbaston, Birmingham, United Kingdom, B15-2WB
      • University Hospital Birmingham NHS Foundation Trust
  • Crewe Road South
    • Edinburgh, Crewe Road South, United Kingdom, EH4 2XU
      • Edinburgh Cancer Centre, Western General Hospital
  • East Sussex
    • Brighton, East Sussex, United Kingdom, BN2 5BE
      • Brighton and Sussex University Hospitals NHS Trust
  • Kent
    • Gillingham, Kent, United Kingdom, ME75NY
      • Medway Nhs Foundation Trust
    • Maidstone, Kent, United Kingdom, ME16 9QQ
      • Kent Centre for Oncology
  • Marton Road
    • Middlesborough, Marton Road, United Kingdom, TS4 3BW
      • South Tees Hospitals NHS Foundation Trust
  • Pembrokeshire
    • Haverfordwest, Pembrokeshire, United Kingdom, SA61 2PZ
      • Withybush General Hospital
  • Rickmansworth Road
    • Middlesex, Rickmansworth Road, United Kingdom, HA6 2RN
      • East and North Hertfordshire NHS Trust
  • Sketty Lane
    • Swansea, Sketty Lane, United Kingdom, SA2 8QA
      • Singleton Hospital
  • Southmead
    • Bristol, Southmead, United Kingdom, BS10 5NB
      • North Bristol NHS Trust
  • Tooting
    • London, Tooting, United Kingdom, SW17 0QT
      • St George's Healthcare NHS Trust
  • University Of Dundee
    • Dundee, University Of Dundee, United Kingdom, DD1 9SY
      • Ninewells Hospital
  • Whitchurch
    • Cardiff, Whitchurch, United Kingdom, CF14 2TL
      • Velindre Cancer Centre
  • Withington
    • Manchester, Withington, United Kingdom, M20-4BX
      • The Christie NHS Foundation Trust
• United States
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Providence Alaska Medical Center
    • Fairbanks, Alaska, United States, 99701
      • Fairbanks Memorial Hospital
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
    • Scottsdale, Arizona, United States, 85258
      • Pinnacle Oncology Associates
    • Tucson, Arizona, United States, 85719
      • Arizona Cancer Center at University Medical Center North
    • Tucson, Arizona, United States, 85724
      • University of Arizona Health Sciences Center
  • California
    • Antioch, California, United States, 94531
      • Kaiser Permanente-Deer Valley Medical Center
    • Berkeley, California, United States, 94704
      • Alta Bates Summit Medical Center-Herrick Campus
    • Chico, California, United States, 95926
      • Enloe Medical Center
    • Glendale, California, United States, 91204
      • Glendale Memorial Hospital and Health Center
    • Hayward, California, United States, 94545
      • Kaiser Permanente, Hayward
    • La Jolla, California, United States, 92093
      • Moores University of California San Diego Cancer Center
    • Long Beach, California, United States, 90806
      • Long Beach Memorial Medical Center-Todd Cancer Institute
    • Los Angeles, California, United States, 90033-0804
      • University of Southern California
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles (UCLA )
    • Marysville, California, United States, 95901
      • Fremont - Rideout Cancer Center
    • Oakland, California, United States, 94611
      • Kaiser Permanente-Oakland
    • Oakland, California, United States, 94609
      • Bay Area Tumor Institution CCOP
    • Orange, California, United States, 92868
      • University of California Medical Center At Irvine-Orange Campus
    • Pomona, California, United States, 91767
      • Pomona Valley Hospital Medical Center
    • Redwood City, California, United States, 94063
      • Kaiser Permanente-Redwood City
    • Richmond, California, United States, 94801
      • Kaiser Permanente-Richmond
    • Roseville, California, United States, 95661
      • Kaiser Permanente-Roseville
    • Sacramento, California, United States, 95823
      • Kaiser Permanente-South Sacramento
    • Sacramento, California, United States, 95825
      • Kaiser Permanente - Sacramento
    • Sacramento, California, United States, 95817
      • University of California Davis-Cancer Center
    • San Diego, California, United States, 92108
      • Kaiser Permanente-Mission
    • San Diego, California, United States, 92108
      • Kaiser Permanente
    • San Francisco, California, United States, 94115
      • Kaiser Permanente-San Francisco
    • San Francisco, California, United States, 94115
      • University of California San Francisco Medical Center-Mount Zion
    • San Jose, California, United States, 95119
      • Kaiser Permanente-Santa Teresa-San Jose
    • San Rafael, California, United States, 94903
      • Kaiser Permanente-San Rafael
    • Santa Clara, California, United States, 95051
      • Kaiser Permanente Medical Center - Santa Clara
    • Santa Rosa, California, United States, 95403
      • Kaiser Permanente-Santa Rosa
    • South San Francisco, California, United States, 94080
      • Kaiser Permanente-South San Francisco
    • Stanford, California, United States, 94305
      • Stanford University
    • Stockton, California, United States, 95210
      • Kaiser Permanente-Stockton
    • Truckee, California, United States, 96161
      • Tahoe Forest Cancer Center
    • Vacaville, California, United States, 95688
      • Kaiser Permanente Medical Center-Vacaville
    • Vallejo, California, United States, 94589
      • Kaiser Permanente-Vallejo
    • Walnut Creek, California, United States, 94596
      • Kaiser Permanente-Walnut Creek
    • Walnut Creek, California, United States, 94598
      • John Muir Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center - Anschutz Cancer Pavilion
    • Colorado Springs, Colorado, United States, 80909
      • Memorial Hospital Colorado Springs
    • Denver, Colorado, United States, 80205
      • Kaiser Permanente-Franklin
    • Fort Collins, Colorado, United States, 80524
      • Poudre Valley Hospital
    • Fort Collins, Colorado, United States, 80528
      • Front Range Cancer Specialists
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • University of Connecticut
    • Greenwich, Connecticut, United States, 06830
      • Greenwich Hospital
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
    • New Haven, Connecticut, United States, 06520-8032
      • Yale University
    • Stamford, Connecticut, United States, 06904
      • Stamford Hospital
    • Torrington, Connecticut, United States, 06790
      • Connecticut Oncology and Hematology LLP
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Hospital Center
    • Washington, District of Columbia, United States, 20016
      • Sibley Memorial Hospital
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Hospital
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Boca Raton Regional Hospital
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic in Florida
    • Lakeland, Florida, United States, 33805
      • The Watson Clinic
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Medical Center CCOP
    • Orlando, Florida, United States, 32803
      • Florida Hospital
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center and Research Institute
  • Georgia
    • Albany, Georgia, United States, 31701
      • Phoebe Putney Memorial Hospital
    • Gainesville, Georgia, United States, 30501
      • Northeast Georgia Medical Center
    • Valdosta, Georgia, United States, 31602
      • South Georgia Medical Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96819
      • Kaiser Permanente Moanalua Medical Center
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii
  • Illinois
    • Aurora, Illinois, United States, 60504
      • Rush - Copley Medical Center
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago
    • Chicago, Illinois, United States, 60608
      • Mount Sinai Hospital Medical Center
    • Chicago, Illinois, United States, 60625
      • Swedish Covenant Hospital
    • Chicago, Illinois, United States, 60631
      • Resurrection Healthcare
    • Chicago, Illinois, United States, 60612-3785
      • John H Stroger Jr Hospital of Cook County
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
    • Elmhurst, Illinois, United States, 60126
      • Elmhurst Memorial Hospital
    • Evanston, Illinois, United States, 60202
      • Saint Francis Hospital
    • Evanston, Illinois, United States, 60201
      • Evanston CCOP-NorthShore University HealthSystem
    • Harvey, Illinois, United States, 60426
      • Ingalls Memorial Hospital
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Moline, Illinois, United States, 61265
      • Trinity Medical Center
    • Peoria, Illinois, United States, 61615
      • Illinois CancerCare-Peoria
    • Peoria, Illinois, United States, 61615
      • Illinois Oncology Research Association CCOP
    • Springfield, Illinois, United States, 62781-0001
      • Memorial Medical Center
    • Urbana, Illinois, United States, 61801
      • Carle Foundation - Carle Cancer Center
  • Indiana
    • Elkhart, Indiana, United States, 46514
      • Michiana Hematology Oncology PC-Elkhart
    • Elkhart, Indiana, United States, 46514-2098
      • Elkhart Clinic
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Hospital/Melvin and Bren Simon Cancer Center
    • Kokomo, Indiana, United States, 46904
      • Howard Regional Healthcare System
    • Michigan City, Indiana, United States, 46360
      • Saint Anthony Memorial Health Center
    • Mishawaka, Indiana, United States, 46545-1470
      • Michiana Hematology Oncology PC-Mishawaka
    • Plymouth, Indiana, United States, 46563
      • Michiana Hematology Oncology PC-Plymouth
    • South Bend, Indiana, United States, 46601
      • Michiana Hematology Oncology PC-South Bend
    • Westville, Indiana, United States, 46391
      • Michiana Hematology Oncology-PC Westville
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic
    • Cedar Rapids, Iowa, United States, 52403
      • Oncology Associates at Mercy Medical Center
    • Council Bluffs, Iowa, United States, 51503
      • Heartland Oncology and Hematology LLP
    • Ottumwa, Iowa, United States, 52501
      • Ottumwa Regional Health Center
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology Oncology Associates
  • Kansas
    • Prairie Village, Kansas, United States, 66208
      • Kansas City CCOP
    • Wichita, Kansas, United States, 67214
      • Wichita CCOP
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Central Baptist Hospital
    • Owensboro, Kentucky, United States, 42303
      • Owensboro Mercy Medical Center
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Mary Bird Perkins Cancer Center
  • Maine
    • Bangor, Maine, United States, 04401
      • Eastern Maine Medical Center
    • York, Maine, United States, 03909
      • York Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
    • Baltimore, Maryland, United States, 21287-8936
      • Johns Hopkins University
    • Baltimore, Maryland, United States, 21201-1595
      • University of Maryland Greenebaum Cancer Center
    • Bethesda, Maryland, United States, 20814
      • Suburban Hospital
    • Frederick, Maryland, United States, 21701
      • Frederick Memorial Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic Medical Center
    • Gloucester, Massachusetts, United States, 01930
      • Addison Gilbert Hospital
    • Lowell, Massachusetts, United States, 01854
      • Lowell General Hospital
    • Worcester, Massachusetts, United States, 01608
      • Saint Vincent Hospital - Fallon Clinic
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System-Cancer Center
    • Battle Creek, Michigan, United States, 49017
      • Battle Creek Health System
    • Detroit, Michigan, United States, 48202
      • Wayne State University
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health at Butterworth Campus
    • Grand Rapids, Michigan, United States, 49503
      • Grand Rapids Clinical Oncology Program
    • Grand Rapids, Michigan, United States, 49503
      • Saint Mary's Health Care
    • Kalamazoo, Michigan, United States, 49007
      • West Michigan Cancer Center
    • Muskegon, Michigan, United States, 49444
      • Mercy Health Partners-Mercy Campus
    • Niles, Michigan, United States, 49120
      • Michiana Hematology Oncology PC-Niles
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital
    • Saint Joseph, Michigan, United States, 49085
      • Marie Yeager Cancer Center
    • Traverse City, Michigan, United States, 49684
      • Munson Medical Center
    • Wyoming, Michigan, United States, 49519
      • Metro Health Hospital
  • Minnesota
    • Coon Rapids, Minnesota, United States, 55433
      • Mercy Hospital
    • Duluth, Minnesota, United States, 55805
      • Duluth Clinic CCOP
    • Edina, Minnesota, United States, 55435
      • Fairview-Southdale Hospital
    • Fridley, Minnesota, United States, 55432
      • Unity Hospital
    • Maplewood, Minnesota, United States, 55109
      • Saint John's Hospital - Healtheast
    • Maplewood, Minnesota, United States, 55109
      • Minnesota Oncology Hematology PA-Maplewood
    • Minneapolis, Minnesota, United States, 55407
      • Abbott-Northwestern Hospital
    • Robbinsdale, Minnesota, United States, 55422
      • North Memorial Medical Health Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
    • Saint Cloud, Minnesota, United States, 56303
      • CentraCare Clinic
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Clinic - Saint Louis Park
    • Saint Louis Park, Minnesota, United States, 55416
      • Metro-Minnesota CCOP
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Willmar, Minnesota, United States, 56201
      • Rice Memorial Hospital
    • Woodbury, Minnesota, United States, 55125
      • Minnesota Oncology and Hematology PA-Woodbury
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
    • Pascagoula, Mississippi, United States, 39581
      • Singing River Hospital
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • Saint Luke's Hospital
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63131
      • Missouri Baptist Medical Center
    • Saint Louis, Missouri, United States, 63141
      • Saint John's Mercy Medical Center
    • Saint Louis, Missouri, United States, 63141
      • Saint Louis-Cape Girardeau CCOP
    • Springfield, Missouri, United States, 65807
      • Cox Medical Center
    • Springfield, Missouri, United States, 65804
      • Saint John's Hospital
  • Nebraska
    • Kearney, Nebraska, United States, 68847
      • Good Samaritan Hospital
    • Lincoln, Nebraska, United States, 68510
      • Lincoln Medical Education Foundation Cancer Resource Center
    • Omaha, Nebraska, United States, 68114
      • Methodist Estabrook Cancer Center
    • Omaha, Nebraska, United States, 68106
      • Missouri Valley Cancer Consortium CCOP
  • New Hampshire
    • Concord, New Hampshire, United States, 03301
      • New Hampshire Oncology-Hematology PA
    • Hooksett, New Hampshire, United States, 03106
      • New Hampshire Oncology Hematology Associates
    • Laconia, New Hampshire, United States, 03246
      • LRGHealthcare-Lakes Region General Hospital
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
    • Londonderry, New Hampshire, United States, 03053
      • The Dana-Farber Cancer Institute at Londonderry
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center
    • Mount Holly, New Jersey, United States, 08060
      • Fox Chase Cancer Center at Virtua Memorial Hospital of Burlington County
    • Ridgewood, New Jersey, United States, 07450
      • Valley Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico
    • Albuquerque, New Mexico, United States, 87110
      • Presbyterian Kaseman Hospital
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein College of Medicine
    • Bronx, New York, United States, 10467-2490
      • Montefiore Medical Center
    • Bronx, New York, United States, 10466
      • The North Division of Montefiore Medical Center
    • Brooklyn, New York, United States, 11219
      • Maimonides Medical Center
    • Brooklyn, New York, United States, 11235
      • Coney Island Hospital
    • Brooklyn, New York, United States, 11203
      • State University of New York Downstate Medical Center
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • East Syracuse, New York, United States, 13057
      • Hematology Oncology Associates of Central New York PC
    • Lake Success, New York, United States, 11042
      • Monter Cancer Center
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital CCOP
    • Mount Kisco, New York, United States, 10549
      • Mount Kisco Medical Group
    • Mount Kisco, New York, United States, 10549-3417
      • Mount Kisco Medical Group at Northern Westchester Hospital
    • New Hyde Park, New York, United States, 11040
      • Long Island Jewish Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
    • New York, New York, United States, 10025
      • Saint Luke's Roosevelt Hospital Center - Saint Luke's Division
    • Rochester, New York, United States, 14621
      • Rochester General Hospital
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospitals Inc
    • Charlotte, North Carolina, United States, 28204
      • Presbyterian Hospital
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital
    • Hendersonville, North Carolina, United States, 28791
      • Margaret R Pardee Memorial Hospital
    • High Point, North Carolina, United States, 27261
      • High Point Regional Hospital
    • Kinston, North Carolina, United States, 28501
      • Kinston Medical Specialists PA
    • Pinehurst, North Carolina, United States, 28374
      • FirstHealth of the Carolinas-Moore Regional Hosiptal
    • Raleigh, North Carolina, United States, 27607
      • Rex Cancer Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
    • Winston-Salem, North Carolina, United States, 27103
      • Forsyth Memorial Hospital
  • North Dakota
    • Bismarck, North Dakota, United States, 58501
      • Mid Dakota Clinic
    • Bismarck, North Dakota, United States, 58501
      • Medcenter One Health Systems
    • Fargo, North Dakota, United States, 58102
      • Sanford Clinic North-Fargo
    • Fargo, North Dakota, United States, 58122
      • Sanford Medical Center-Fargo
    • Grand Forks, North Dakota, United States, 58201
      • Altru Cancer Center
    • Minot, North Dakota, United States, 58701
      • Trinity Cancer Care Center
  • Ohio
    • Akron, Ohio, United States, 44307
      • Akron General Medical Center
    • Akron, Ohio, United States, 44304
      • Akron City Hospital
    • Canton, Ohio, United States, 44710
      • Aultman Health Foundation
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center
    • Kettering, Ohio, United States, 45429
      • Kettering Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97210
      • Legacy Good Samaritan Hospital and Medical Center
    • Portland, Oregon, United States, 97227
      • Kaiser Permanente
    • Portland, Oregon, United States, 97225
      • Columbia River Oncology Program
  • Pennsylvania
    • Bryn Mawr, Pennsylvania, United States, 19010
      • Bryn Mawr Hospital
    • Danville, Pennsylvania, United States, 17822-2001
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Milton S Hershey Medical Center
    • Lancaster, Pennsylvania, United States, 17604
      • Lancaster General Hospital
    • Paoli, Pennsylvania, United States, 19301
      • Paoli Memorial Hospital
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Pennsylvania Hospital
    • Phoenixville, Pennsylvania, United States, 19460
      • Phoenixville Hospital
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh
    • Reading, Pennsylvania, United States, 19605
      • Saint Joseph Medical Center
    • State College, Pennsylvania, United States, 16803
      • Mount Nittany Medical Center
    • West Chester, Pennsylvania, United States, 19380
      • Chester County Hospital
    • Wynnewood, Pennsylvania, United States, 19096
      • Lankenau Hospital
  • Rhode Island
    • Pawtucket, Rhode Island, United States, 02860
      • Memorial Hospital of Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
    • Providence, Rhode Island, United States, 02905
      • Women and Infants Hospital
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • AnMed Health Cancer Center
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Florence, South Carolina, United States, 29506
      • McLeod Regional Medical Center
    • Spartanburg, South Carolina, United States, 29303
      • Spartanburg Regional Medical Center
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Rapid City Regional Hospital
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Cancer Institute
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Clinic
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee - Knoxville
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
    • Nashville, Tennessee, United States, 37204
      • Vanderbilt Breast Center at One Hundred Oaks
  • Texas
    • Austin, Texas, United States, 78701
      • University Medical Center Brackenridge
    • Laredo, Texas, United States, 78045
      • Doctor's Hospital of Laredo
    • San Antonio, Texas, United States, 78229-3900
      • University of Texas Health Science Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute/University of Utah
  • Vermont
    • Berlin, Vermont, United States, 05602
      • Mountainview Medical
    • Burlington, Vermont, United States, 05401
      • University of Vermont
  • Virginia
    • Charlottesville, Virginia, United States, 22901
      • Martha Jefferson Hospital
    • Lynchburg, Virginia, United States, 24501
      • Lynchburg Hematology-Oncology Clinic
  • Washington
    • Longview, Washington, United States, 98632
      • Saint John Medical Center
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
    • Seattle, Washington, United States, 98122-4307
      • Swedish Medical Center-First Hill
    • Seattle, Washington, United States, 98112
      • Group Health Cooperative
    • Seattle, Washington, United States, 98104
      • Pacific Medical Center-First Hill
    • Seattle, Washington, United States, 98101
      • Virginia Mason CCOP
    • Spokane, Washington, United States, 99220
      • Rockwood Clinic
    • Tacoma, Washington, United States, 98405
      • Northwest CCOP
    • Walla Walla, Washington, United States, 99362
      • Providence Saint Mary Regional Cancer Center
    • Wenatchee, Washington, United States, 98801
      • Wenatchee Valley Medical Center
    • Yakima, Washington, United States, 98902
      • North Star Lodge Cancer Center at Yakima Valley Memorial Hospital
  • West Virginia
    • Huntington, West Virginia, United States, 25701
      • Edwards Comprehensive Cancer Center
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University
    • Wheeling, West Virginia, United States, 26003
      • Wheeling Hospital
  • Wisconsin
    • Eau Claire, Wisconsin, United States, 54701
      • Marshfield Clinic Cancer Care at Regional Cancer Center
    • Fond Du Lac, Wisconsin, United States, 54935
      • Central Wisconsin Cancer Program
    • Green Bay, Wisconsin, United States, 54301
      • Saint Vincent Hospital
    • Green Bay, Wisconsin, United States, 54311-6519
      • Aurora BayCare Medical Center
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Health System/CCOP
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic
    • Mequon, Wisconsin, United States, 53097
      • Columbia Saint Mary's Hospital - Ozaukee
    • Milwaukee, Wisconsin, United States, 53210
      • Wheaton Franciscan Healthcare - Saint Joseph
    • Milwaukee, Wisconsin, United States, 53211
      • Columbia Saint Mary's Water Tower Medical Commons
    • Minocqua, Wisconsin, United States, 54548
      • Marshfield Clinic-Minocqua Center
    • Summit, Wisconsin, United States, 53066
      • Aurora Medical Center in Summit
    • Weston, Wisconsin, United States, 54476
      • Marshfield Clinic - Weston Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Eligibility Criteria:

• Subjects must have histologically confirmed invasive breast cancer and be enrolled in the trial within 12 months after the first histologic diagnosis of invasive breast cancer. A core biopsy interpreted as invasive cancer meets this criterion; otherwise, the date of first histologic diagnosis will be the date of first surgical procedure that identifies invasive cancer (biopsy, lumpectomy or mastectomy). Neoadjuvant subjects should have no evidence of clinical T4 disease prior to chemotherapy and surgery. Bilateral breast carcinoma is allowed provided diagnoses are synchronous - that is, within 3 months of one another - and at least one of the two breast carcinomas meet the eligibility criteria and neither violates the eligibility criteria.
• All subjects (both adjuvant and neo-adjuvant) must have sentinel lymph node biopsy and/or axillary lymph node dissection.

Sentinel lymph node biopsy alone is allowed in the following instances:

1. sentinel lymph node biopsy is negative: pN0
2. sentinel lymph node biopsy is positive for isolated tumour cells only: pN0 (i+)
3. * clinically node negative, T1-2 tumours with sentinel lymph node biopsy positive in ≤ 2 lymph nodes without extra-capsular extension or matted nodes and undergoing breast conserving surgery and tangential whole breast irradiation (* excludes subjects treated with neo-adjuvant systemic therapy)

Definitive surgery and/or chemotherapy have been completed at least 4 weeks prior to randomization. Surgical margins must be clear of invasive carcinoma. If there is microscopic residual ductal in situ disease present at lumpectomy or total mastectomy margins, further excision is highly recommended. If further excision is not undertaken, the subject may still be entered on study, provided that in addition to breast or chest wall irradiation, a boost to the tumour bed is delivered. In situ lobular disease at the margin is acceptable.

Adjuvant subjects with the following pT pN combinations are eligible:

• pT1c, pN0 AND negative estrogen and progesterone receptors AND HER2 negative OR
• pT2N0 and at least one of the following tumour characteristics: histologic grade 3, lymphovascular invasion, negative estrogen and progesterone receptors, HER2 positive, Oncotype Dx recurrence score ≥ 25 (or if Oncotype Dx recurrence score is not available, Ki67 > 14%) OR
• Subjects with pT3, pN0 OR
• Subjects with pT1-3, pN1-3

The eligibility of neo-adjuvant subjects is assessed on the basis of cTNM. The same eligible TNM combinations apply.

• HER2 status must be known. (Positive = 3+ over-expression by IHC in > 30% of invasive tumour cells OR HER2 gene amplification by FISH/CISH > 6 HER2 gene copies per nucleus, OR a FISH/CISH ratio: HER2 gene copies to chromosome 17 signals of ≥ 2.2. All other results will be considered negative).
• Patients must have had a bilateral mammogram within 12 months prior to randomization, unless the initial surgery was a total mastectomy, in which case only a mammogram of the remaining breast is required. (Subjects with bilateral total mastectomies and no mammogram within 12 months prior to randomization must, instead, have a physical examination of the chest wall to ensure there is no residual or recurrent disease at the time of randomization. The date of this examination is used in place of the mammogram date on the eligibility checklist.)

• Investigations, including chest X-ray or CT chest, bone scan (with radiographs of suspicious areas) and abdominal ultrasound or liver scan or CT abdomen have been performed between the first histologic diagnosis and the time of randomization.

  • Chest X-Ray, 2 view (or Chest CT) is mandatory
  • Bone scans (with x-rays of abnormal areas) are required only if there are signs or symptoms of metastatic disease
  • Abdominal imaging is required only if there are signs or symptoms of metastatic disease
• Hematology investigations (WBC, Granulocytes, Platelets, Hemoglobin) have been completed within 28 days prior to randomization and results are available.
• Biochemistry investigations have been completed within 28 days prior to randomization and values are within the parameters required by the protocol.

AST < 1.8 X ULN; ALT < 1.8 X ULN; Alkaline Phosphatase < 2 X ULN; Serum Creatinine < 115 μmol/L (1.3mg/dL) Serum Bilirubin < institution ULN (except for subjects with Gilbert's Disease who are eligible despite elevated serum bilirubin level)

• ECOG Performance Status of 0,1 or 2 (at baseline evaluation visit within 28 days prior to randomization).
• Age ≥ 18 and < 75 and life expectancy of at least 5 years (18 years of age was used as a cut-off due to the lack of data indicating that breast cancer is a health issue in the < 18 years age group and metformin safety in pediatric patients has not been confirmed. Age > 80 carries increased risk of lactic acidosis and study intervention is for 5 years).
• Subjects must be accessible for treatment and follow-up. Investigators must assure themselves the subjects randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
• In accordance with NCIC CTG policy, protocol treatment is to begin within 10 working days of patient randomization.
• Subject consent must be obtained according to local Institutional and/or University Human Experimentation Committee requirements. It will be the responsibility of the local participating investigators to obtain the necessary local clearance, and to indicate in writing to the NCIC CTG Study Coordinator that such clearance has been obtained, before the trial can commence in that centre. Because of differing requirements, a standard consent form for the trial will not be provided but a sample form is given. A copy of the initial full board REB approval and approved consent form must be sent to the central office. The patient must sign the consent form prior to randomization or registration. Please note that the consent form for this study must contain a statement which gives permission for the NCIC CTG and monitoring agencies to review patient records (see Section 16 for further details).

For the first 888 eligible English or French-speaking subjects only (sub-set enrollment completed 2011NOV04):

• Subject is able (i.e. sufficiently fluent) and willing to complete the Quality of Life (EORTC QLQ C-30 and Trial Specific Checklist) in English or French. The baseline assessment must already have been completed at the time of enrollment. Inability (illiteracy in English or French, loss of sight or other equivalent reason) to complete questionnaires will not make the patient ineligible for the study; however, ability but unwillingness to complete the questionnaires will make the patient ineligible. (Once the target number of 888 subjects is achieved, this criterion will no longer need to be fulfilled.) [See Appendix VI]. Sub-set enrollment completed 2011NOV04.
• English-speaking subjects who have completed the Quality of Life Questionnaire who are able (i.e. sufficiently fluent) and willing to complete Nurses Health Study II Physical Activity Questionnaire and Block Alive Screener in English. The baseline assessment must already have been completed at the time of enrollment. Inability (illiteracy in English, loss of sight or other equivalent reason) to complete questionnaires will not make the patient ineligible for the study; however, ability but unwillingness to complete the questionnaires will make the patient ineligible. (This component of the study will close at the same time as the Quality Of Life sub-study.) Closed to new patient enrollment as of 2011NOV04.

Ineligibility Criteria:

• Subjects with a history of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years.
• Subjects with locally recurrent or metastatic breast carcinoma. (Subjects with prior invasive breast cancer at any time are not eligible. Subjects with prior DCIS only in either breast are eligible provided the DCIS has been curatively treated including surgery, radiotherapy and/or Tamoxifen).
• Subjects whose axillary node status is unknown.
• Known diabetes (type 1 or 2) or baseline fasting glucose > 7.0 mmol/L (126 mg/dL). (Sampled and assayed according to local institution's procedures.)
• Known hypersensitivity or intolerance to metformin.
• Any condition associated with increased risk of metformin-associated lactic acidosis (e.g. congestive heart failure defined as New York Heart Association {NYHA} Class III or IV functional status [see Appendix IX], history of acidosis of any type; habitual * Currently taking metformin, sulfonylureas, thiazolidinediones or insulin for any reason.
• Current or planned pregnancy or lactation in women of child-bearing potential. Men should not father a child. (An effective method of birth control should be used while on study treatment which could include abstinence, IUD, condoms or other barrier methods of birth control because the safety of metformin in pregnancy or in male fertility has not been established).
• Concurrent or planned participation in randomized trials of weight loss or exercise interventions or trials targeting insulin, IGF-1 or their receptors, or involving P13K inhibitors (at the time of randomization)*.
• These interventions would interfere with the primary endpoint. (Also, in general, double randomizations in breast cancer trials for MA.32 patients are permitted only if the patient meets all the eligibility criteria for MA.32 and the sponsor of the previous trial has no objection to the patient also being enrolled in MA.32).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I; Patients receive oral metformin hydrochloride twice daily (once daily in weeks 1-4). Treatment continues for up to 5 years in receptor positive (ER and/or PgR positive) subjects in the absence of disease progression or unacceptable toxicity.	Drug: metformin hydrochloride; Given orally
Placebo Comparator: Arm II; Patients receive oral placebo twice daily (once daily in weeks 1-4). Treatment continues for up to 5 years in receptor positive (ER and/or PgR positive) subjects in the absence of disease progression or unacceptable toxicity.	Other: placebo; Given orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Invasive Disease-free Survival in Hormone Receptor (ER and PgR) Positive Sub-groups	Invasive disease-free survival (IDFS) is defined as percentage of patients without documented development of ipsilateral and contralateral invasive breast tumour, local/regional invasive recurrence, distant recurrence, death from any causes. If a subject has not had invasive disease or died at the time of data cut-off for this final analysis, IDFS was censored on the date of last follow-up.	5 years
Invasive Disease-free Survival	Invasive disease-free survival (IDFS) is defined as the percent of patients without documented development of ipsilateral and contralateral invasive breast tumour, local/regional invasive recurrence, distant recurrence, death from any causes. If a subject has not had invasive disease or died at the time of data cut-off for this final analysis, IDFS was censored on the date of last follow-up.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Number of patients who died from any causes.	10 years
Distant Relapse-free Survival	Distant Relapse Free Survival (DRFS) is defined as the percentage of patients without any documented distant recurrence, death from breast cancer, death from a non breast cancer cause or death from an unknown cause. If a subject has not had distant DRFS event nor died at the time of data cut-off for this analysis, DRFS will be censored on the date of last disease assessment.	5 years
Breast Cancer-specific Mortality	Patients who died from breast cancer	10 years

Collaborators and Investigators

• Sponsor: Canadian Cancer Trials Group
• Collaborators: National Cancer Institute (NCI); ETOP IBCSG Partners Foundation; ICR-CTSU
• Investigators: Principal Investigator: Pamela J. Goodwin, MD, Mount Sinai Hospital, Canada

Publications and helpful links

General Publications

• Goodwin PJ, Parulekar WR, Gelmon KA, Shepherd LE, Ligibel JA, Hershman DL, Rastogi P, Mayer IA, Hobday TJ, Lemieux J, Thompson AM, Pritchard KI, Whelan TJ, Mukherjee SD, Chalchal HI, Oja CD, Tonkin KS, Bernstein V, Chen BE, Stambolic V. Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst. 2015 Mar 4;107(3):djv006. doi: 10.1093/jnci/djv006. Print 2015 Mar.
• Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, Lemieux J, Ligibel JA, Hershman DL, Mayer IA, Hobday TJ, Bliss JM, Rastogi P, Rabaglio-Poretti M, Mukherjee SD, Mackey JR, Abramson VG, Oja C, Wesolowski R, Thompson AM, Rea DW, Stos PM, Shepherd LE, Stambolic V, Parulekar WR. Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial. JAMA. 2022 May 24;327(20):1963-1973. doi: 10.1001/jama.2022.6147.

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2010
• Primary Completion (Actual): September 21, 2021
• Study Completion (Actual): August 18, 2023

Study Registration Dates

• First Submitted: April 9, 2010
• First Submitted That Met QC Criteria: April 9, 2010
• First Posted (Estimated): April 12, 2010

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: August 18, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; male breast cancer; stage II breast cancer; stage IIIC breast cancer; HER2-positive breast cancer; stage I breast cancer; estrogen receptor-positive breast cancer; progesterone receptor-positive breast cancer; HER2-negative breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: MA32; U10CA077202 (U.S. NIH Grant/Contract); CAN-NCIC-MA.32 (Other Identifier: PDQ Identifier); CDR0000669788 (Other Identifier: PDQ)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No