Metformin Hydrochloride vs. Placebo in Overweight or Obese Patients at Elevated Risk for Breast Cancer

Inclusion Criteria:

• Patients must be post-menopausal women; post-menopausal women are defined as: (1) those >= 50 years of age who had not menstruated during the preceding 12 months or who had castrate follicle-stimulating hormone levels (> 40 IU/L), (2) those who had undergone a bilateral oophorectomy

• Patients must be at elevated risk for breast cancer based on strong family history or a history of breast biopsy documenting atypical hyperplasia anytime in the past; for this study strong family history is defined as having:

  • 1 first-degree (parent, offspring, sibling) relative =< 50 years old when diagnosed with breast cancer, or
  • >= 2 first-degree relatives of any age when diagnosed with breast cancer, or
  • >= 2 second-degree (aunts, uncles, grandparents, grandchildren, nieces, nephews, or half-siblings) maternal or paternal relatives diagnosed with breast cancer and at least 1 diagnosed at =< 50 years of age

• Patients must have a body mass index (BMI) >= 25.0 as calculated by the formula: weight in pounds / height squared x 703 = BMI; a BMI of:

  • 18.5-24.9 is considered normal;
  • 25.0-29.9 is considered overweight;
  • 30.0+ is regarded as obese
• Patients must be willing to complete a bilateral mammogram at baseline with repeat exam after 12 cycles of protocol therapy; patients who have had a mammogram within 1 month prior to registration to protocol therapy will not need to repeat the exam
• Patients must be willing to provide a core tissue biopsy at baseline and with repeat tissue collection after 12 cycles of protocol therapy
• White blood cell (WBC) >= 3.0 x 109/L
• Granulocytes (polymorphs + bands) >= 1.5 x 109/L
• Platelets >= 100 x 109/L
• Hemoglobin >= 110 g/L
• Aspartate aminotransferase (AST) =< 1.8 X upper limit of normal (ULN)
• Alanine aminotransferase (ALT) =< 1.8 X ULN
• Alkaline phosphatase =< 2 X ULN
• Serum creatinine =< 115 umol/L (1.3mg/dL)
• Serum bilirubin =< institution ULN (except for subjects with Gilbert's Disease who are eligible despite elevated serum bilirubin level)
• 12 hour fasting glucose level < 7.0 mmol/L
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1 within 28 days of registration
• Life expectancy of >= 5 years
• Subjects must be accessible for treatment, adverse event tracking and follow-up as determined by the treating physician
• Subject consent and authorization for the release of health information must be obtained according to local institutional guidelines

Exclusion Criteria:

• No history of any malignancy except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for >= 5 years
• No known diabetes (type 1 or 2) or baseline fasting glucose >= 7.0 mmol/L
• No known hypersensitivity or intolerance to metformin
• No 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, history of acidosis of any type; habitual intake of 3 or more alcoholic beverages per day)
• No current treatment with metformin, sulfonylureas, thiazolidinediones or insulin for any reason
• No breastfeeding
• No concurrent or planned participation in randomized trials of weight loss or exercise interventions or trials targeting insulin, insulin-like growth factor 1 (IGF-1) or their receptors