A Phase I Prevention Study of Atorvastatin in Women at Increased Risk for Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the minimum biological effective dose (MBED) of atorvastatin required to
induce modulation in the proliferation marker, Ki-67, in breast tissue of women who are at
high risk to develop breast cancer. We will evaluate pre- and post atorvastatin treatment (4
dose levels) expression of Ki-67 in samples obtained via FNA from breast tissue of women at
high risk for breast cancer. This specific aim tests the hypothesis that treatment with
atorvastatin will induce a decrease in Ki-67.

SECONDARY OBJECTIVES:

I. To evaluate atorvastatin induced modulation of breast cancer biomarkers markers (EGFR,
P-EGFR, ER, p21, p27, bcl-2, CC3, cytology) and drug related markers (LXR, total
cholesterol, LDL, HDL, CRP) in women who are at high risk to develop breast cancer.

II. To determine plasma and tissue levels of atorvastatin and two of its hydroxylated
metabolites (ohydroxyatorvastatin and p-hydroxyatorvastatin) in women who are treated with
atorvastatin and to correlate these levels with Ki-67 levels. III. To correlate changes in
Ki-67 and the above-described panel of biomarkers with HMG-CoA reductase genotype.

OUTLINE: Participants are randomized to 1 of 4 arms.

ARM I: Participants receive oral atorvastatin once daily for 3 months.

ARM II: Participants receive oral atorvastatin (at a higher dose than in arm I) once daily
for 3 months.

ARM III: Participants receive oral atorvastatin (at a higher dose than in arm II) once daily
for 3 months.

ARM IV: Participants do not receive treatment. Participants undergo blood sample collection
and fine needle aspiration of breast tissue at baseline and at 3 months for correlative
biomarker studies.

Inclusion Criteria:

- Women at increased risk for breast cancer, defined by one of the following:

- 5 year projected Gail risk of greater than 1.67%

- Previous diagnosis of atypical hyperplasia (AH) or lobular carcinoma in situ
(LCIS) (per participating institution's pathology review), or ductal carcinoma
in situ (participants could have received any type of surgery and radiation as
long as they have an intact opposite breast)

- The participant must have been properly informed of the study and must sign an
informed consent to be able to be enrolled in the study; the informed consent
document must be signed, witnessed, and dated prior to start of the study

- Normal physical exam and bilateral mammogram that shows no evidence of suspicious,
malignant disease, or uncharacterized lesions within last 12 months and no evidence
of any active other cancer

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky greater
than or equal to 70%)

- Leukocytes greater than 3,000/uL

- Platelets greater than 100,000/uL

- Total bilirubin within normal institutional limits

- AST (SGOT)or /ALT (SGPT) =< 1.5 X institutional ULN

- Creatinine within normal institutional limits

- CPK, PTT, PT within normal institutional limits (up to 1 month prior to
randomization)

- The effects of atorvastatin on the developing human fetus at the recommended
therapeutic dose are unknown; for this reason, women of child-bearing potential must
agree to use adequate contraception (barrier method of birth control (IUD);
abstinence) prior to study entry and for the duration of study participation; should
a woman become pregnant or suspect she is pregnant while participating in this study,
she should inform her study physician immediately

Exclusion Criteria:

- Any type of active invasive cancer

- Bilateral mastectomy

- Use of oral contraceptives; androgens; luteinizing-hormone-releasing-hormone (LHRH)
analogs, prolactin inhibitors, antiandrogens, tamoxifen, raloxifen, or aromatase
inhibitors; women who discontinue these drugs at least 3 months prior to study
enrollment will be eligible

- Chronic medical condition that requires regular use of statins or steroids (unless
participants have discontinued these drugs 1 month prior to enrollment)

- Participants may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to atorvastatin

- Psychiatric condition, including history of clinical depression, or addictive
disorder that would preclude obtaining informed consent or would interfere with
compliance; uncontrolled intercurrent illness including, but not limited to, ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements

- Pregnant women are excluded from this study because atorvastatin is a Class X agent
with the potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with atorvastatin breast feeding should be discontinued if
the mother is treated with atorvastatin