Statins and Breast Cancer Biomarkers

This project was designed to evaluate the effect of a specific statin (atorvastatin) on
several breast cancer biomarkers. One hundred women will be treated for one year with either
40 mg of atorvastatin or placebo. The primary aim of this project is to determine the effect
of atorvastatin on breast density, a known risk factor for breast cancer. In addition, the
affect of atorvastatin on serum biomarkers (IGF1) and tissue biomarkers (atypia and Ki67)
associated with risk is being evaluated.

Because of their tolerability and safety, statins have a great potential as a breast cancer
preventative agent. Should this pilot study show a significant decrease in breast density
and/or change in serum and tissue biomarkers in statin treated patients these data would
then be used to support a large randomized trial.

This is a multi-center, prospective, randomized placebo controlled clinical trial. Target
enrollment is 100 women, with 50 receiving atorvastatin and 50 receiving a similar appearing
placebo tablet. Eligible women must be at least 35 years old with regular menstrual cycles
and a Gail Model risk of greater than 1.66% over 5 years.

Inclusion Criteria:

- Women willing and able to give written informed consent

- Pre-menopausal women with regular menstrual cycles (4 cycles in the past 6 months)

- At least 35 years of age

- Women at increased risk of developing breast cancer, defined as at least one of the
following four criteria:

- Having had a biopsy demonstrating atypical hyperplasia or lobular neoplasia/LCIS

- A germline mutation in BRCA1/2 in themselves or their family.

- A Gail Model Risk of > 1.67% over 5 years

- A strong family history of breast and/or ovarian cancer which is defined as at
least one of the following:

- One first-degree relative with breast cancer before the age of 50 years

- One first degree relative with bilateral breast cancer

- Two or more first-degree relatives with breast cancer

- One first degree relative and two or more second or third degree relatives
with breast cancer

- One first-degree relative with breast cancer and one or more relatives with
ovarian cancer

- Two second or third degree relatives with either breast cancer and one or
more with ovarian cancer

- One second or third degree relative with breast cancer and two or more with
ovarian cancer

- Three or more second or third degree relatives with breast cancer

- A prior history of breast cancer, including DCIS and stage 0-IIIb, and are at
least one year off of all therapy (including radiation, biologic, hormonal
and/or chemotherapy)

Exclusion Criteria:

- Women with a prior history of stage IV breast cancer or ovarian cancer

- Women already taking statins. Women previously on statins may participate if they
have not taken any statins in the six months prior to study entry

- Women concurrently participating in another breast cancer chemoprevention trial

- Women taking hormone replacement therapy (estrogen and progesterone; topical estrogen
will be allowed)

- Women taking tamoxifen, raloxifene, or an aromatase inhibitor

- Women taking drugs that increase risk of statin induced myopathy or rhabdomyolysis
(i.e., Niacin, protease inhibitors, verapamil, gemfibrozil, cyclosporine,
clofibrate/fenofibrate or any CYP3A4 inhibitor)

- Women with underlying liver disease or abnormal liver studies including:

- alkaline phosphatase, ALT, AST and Bilirubin (greater than 1.5 times normal)

- Women who have had hypersensitivity to atorvastatin or any component of the
formulation

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