A Double Blind Prospective Study of Metformin vs. Placebo in Overweight or Obese Post-menopausal Women 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