Preventing Anthracycline Cardiovascular Toxicity With Statins (PREVENT)

PRIMARY OBJECTIVES:

Specific Aim 1:

To determine if Atorvastatin(Lipitor) administration preserves LVEF 24 months after
initiation of Anthracycline-based adjuvant therapy for adjuvant treatment of breast cancer.

Specific Aim 2:

To determine if baseline to 6-month differences in LVEF predict baseline to 24-month
differences in LVEF after Anthracycline-based adjuvant therapy and concomitant atorvastatin
therapy.

To achieve these aims, we will perform a double-blind, placebo-controlled, randomized
clinical trial of 0 or 40 mg of atorvastatin/day in 250 women scheduled to receive
Anthracycline-based adjuvant therapy for treatment of adjuvant breast cancer. We will use
innovative noninvasive magnetic resonance imaging (MRI) procedures to accurately measure
LVEF. In addition, we will measure LV volumes, myocardial strain, fibrosis, aortic pulse wave
velocity (PWV) and wall thickness, all factors that can influence LVEF by altering LV
pre-load, after-load, and contractility.19,20 Advanced serum biomarkers will be measured that
assess for the presence of oxidative/nitrosative stress, systemic inflammation and
circulating neurohormones that also may influence LVEF.

This study will test a new clinical paradigm to manage breast cancer: primary prevention of
Anthracycline-based adjuvant therapy-related LV dysfunction using pre-treatment with low-cost
statins. In addition, this trial will be the first systematic collection of data regarding
the mechanism(s) and time course by which LV dysfunction and subsequent CHF evolve in women
given Anthracycline-based adjuvant therapy for adjuvant breast cancer. These data will be
useful to physicians trying to determine the optimal cardiac protection strategies when
administering adjuvant chemotherapeutic regimens to their breast cancer patients. The
objective of this research is to use inexpensive medications to preserve CV health and
thereby improve overall survival in the growing number of breast cancer patients.

SECONDARY OBJECTIVES

Specific Aim 1:

To document the effect of Atorvastatin (Lipitor) on cognitive function using a battery of
neurocognitive tests (HVLT, Rey-Osterreith Figure, COWA, Trail-making Parts A and B, Digit
Span and Grooved Pegboard) in breast cancer patients receiving an anthracycline.

Specific Aim 2:

To document the effect of Atorvastatin(Lipitor) on self-reported quality of life using
validated questionnaires (PROMIS including: General form, Cog Concerns, Cog Abilities,
Fatigue, Pain intensity and interference, Sleep Disturbance, Physical Functioning and Social
Functioning) in breast cancer patients receiving an anthracycline.

Inclusion Criteria:

- Newly diagnosed Stage I-III female breast cancer (including inflammatory breast
cancer)

- Scheduled to receive adjuvant chemotherapy with an Anthracycline (doxorubicin and
epirubicin)

- 30 to 80 years of age

- LVEF > 50% (Most recent within the last 5 years)

- Prior chemotherapy regimen not containing anthracyclines is allowed

- Able to hold breath for 15 seconds

- Prior cancers allowed if no evidence of disease in last 5 years

- ECOG 0 or 1

Exclusion Criteria:

- Prior use of lipid-lowering therapy within the last 6 months

- Current postmenopausal hormone-replacement therapy

- Uncontrolled hypertension (systolic blood pressure >190 mm Hg or diastolic blood
pressure >100 mm Hg)

- Scheduled to receive neoadjuvant chemotherapy with an anthracycline

- No active liver disease allowed

- Uncontrolled hypothyroidism

- Recent history (within past 3 years) of alcohol or drug abuse, inflammatory conditions
such as lupus or inflammatory bowel disease, use of immunosuppressant agents, or
another medical condition that might compromise safety or the successful completion of
the study.

- Patients with ferromagnetic cerebral aneurysm clips or other intraorbital/intracranial
metal;pacemakers, defibrillators, functioning neurostimulator devices or other
implanted electronic devices.

- Unstable angina; significant ventricular arrhythmias (>20 PVCs/min due to gating
difficulty) atrial fibrillation with uncontrolled ventricular response; coronary
artery disease; acute myocardial infarction within 28 days

- Current use of CYP 3A4 inhibitors. These include Clarithromycin, HIV protease
inhibitors, Itraconazole, grapefruit juice, Cyclosporine, Rifampin or Digoxin

- Current or history of hepatic dysfunction

- Unable to provide informed consent

- Claustrophobia

- Planning to move within 24 months of trial enrollment

- Pregnant or breast-feeding