Phase II Study of Metformin for Reduction of Obesity-Associated Breast Cancer Risk

High adiposity is a major risk factor for a number of chronic diseases, including type 2
diabetes, cardiovascular diseases, and certain types of cancer, including postmenopausal
breast cancer. The increased postmenopausal breast cancer risk in women with high adiposity
is likely to be attributed to multiple metabolic disturbances including altered circulating
sex steroid hormones, hyperinsulinemic insulin resistance, altered expression and secretion
of adipokines from adipose tissue, increased production of pro-inflammatory cytokines, and
increased oxidative stress.

Metformin, a widely used antidiabetic drug, exerts favorable effects on multiple metabolic
disturbances which may lead to reduction of breast cancer risk in women with high adiposity.
In addition, metformin may exert a direct effect in mammary tissue through the activation of
the AMP-activated protein kinase signaling pathway, leading to an antiproliferative effect
and induction of apoptosis. Recent case control and cohort studies found that treatment with
metformin appears to substantially reduce the risk for development of cancer in diabetics,
including breast cancer. There are a number of ongoing clinical trials of metformin in breast
cancer patients. However, applicability of these trials to at risk healthy women requires
further research and the concurrent or prior cancer treatments in these trials hinder the
evaluation of metformin as a single agent for breast cancer risk reduction. In addition,
recent clinical and animal studies suggest that metformin may only exert tumor suppressive
effects in metabolic phenotypes of high adiposity and metabolic disturbances.

A Phase II randomized, double-blind, placebo-controlled trial of metformin in
overweight/obese premenopausal women who have metabolic syndrome will be conducted. This
study population is at increased risk for postmenopausal breast cancer and has a high
prevalence of metabolic disturbances. The overall objective of this study is to determine its
potential effects on reduction of obesity-associated breast cancer risk.

Inclusion Criteria:

- Premenopausal women

- 21-54 years of age

- Have a BMI of 25 kg/m2 or greater

- No change in menstrual patterns for the past 6 months preceding the time of
registration

- Waist circumference ≥ 35 inches or ≥ 31 inches for Asian Americans, individuals with
polycystic ovary syndrome, or individuals with non-alcoholic fatty liver disease.

- Have at least one other component of metabolic syndrome (103) reported below:

- Elevated triglycerides (≥ 150 mg/dL (1.7 mmol/L) or on drug treatment for
elevated triglycerides

- Reduced HDL-C (< 50 mg/dL (1.3 mmol/L) or on drug treatment for reduced HDL-C

- Elevated blood pressure (≥ 130 Hg systolic blood pressure or ≥85 mm Hg diastolic
blood pressure or on antihypertensive drug treatment in a patient with a history
of hypertension

- Elevated fasting glucose (≥100 mg/dL)

- Mammogram negative for breast cancer within the 12 months preceding the time of
registration for women ≥ 50 years of age

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Postmenopausal women

- Amenorrhea for at least 12 months (preceding the time of registration), or

- History of hysterectomy and bilateral salpingo-oophorectomy, or

- At least 55 years of age with prior hysterectomy with or without oophorectomy, or

- Age 35 to 54 with a prior hysterectomy without oophorectomy OR with a status of
ovaries unknown with documented follicle-stimulating hormone level demonstrating
elevation in postmenopausal range

- Women who are pregnant, planning pregnancy within the next year, or breastfeeding

- On treatment with any drug for diabetes

- Have uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or any illness that would limit compliance with study requirements

- Have received chemotherapy and/or radiation for any malignancy (excluding non-melanoma
skin cancer and cancers confined to organs with removal as only treatment) in the past
5 years (preceding the time of registration)

- Have received other investigational agents within the past 3 months (preceding the
time of registration)

- Have a history of lactic acidosis or risk factors for lactic acidosis

- Have significant renal disease or dysfunction (creatinine ≥ 1.4 mg/dL)

- Have significant hepatic dysfunction (bilirubin ≥ 1.5 x ULN unless with Gilberts
syndrome or AST/ALT ≥ 3 x ULN)

- Have a history of alcoholism or high alcohol consumption (average of > 3 standard
drinks/day)

- Have a history of allergic reactions to metformin or similar drugs

- Have a history of severe claustrophobia

- Have electrically, magnetically, or mechanically activated implants including cardiac
pacemaker, cochlear implants, magnetic surgical clips or prostheses

- Have breast implants