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

PRIMARY OBJECTIVES:

I. To determine the changes in the signal pathway profiling of breast tissue using reverse
phase proteomics in tissue biopsy of overweight or obese women at elevated risk for breast
cancer treated with metformin (metformin hydrochloride) (850mg orally twice a day) for 12
cycles.

SECONDARY OBJECTIVES:

I. To determine the effect of metformin on breast tissue density of overweight or obese women
at elevated risk for breast cancer using qualitative mammographic fat density criteria.

II. To determine the effect of metformin on the insulin axis in serum of overweight or obese
women at elevated risk for breast cancer treated with metformin (850mg orally twice a day)
for 12 cycles.

III. To determine the toxicities associated with metformin.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive metformin hydrochloride by mouth once daily on days 1-30 in course 1
and twice daily on days 1-30 thereafter. Treatment repeats every 30 days for 12 courses in
the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo by mouth once daily on days 1-30 in course 1 and twice daily
on days 1-30 thereafter. Treatment repeats every 30 days for 12 courses in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 5
years.

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