The Effect of Simvastatin on Breast Cancer Cell Growth in Women With Stage I-II Breast Cancer

PRIMARY OBJECTIVES:

I. Evaluate the relationship between short-term use of oral simvastatin on change in
expression of Ki-67 as a candidate biomarker of breast tumor proliferation among women with
clinical stage 1 or 2- primary invasive breast cancer.

II. Evaluate the relationship between short-term use of oral simvastatin on changes in other
candidate predictive markers of breast tumor proliferation (cyclin D1 and P27), changes in a
marker of apoptosis (cleaved caspase-3 [CC3]), changes in a marker of inflammation
(c-reactive protein [CRP]) and as novel additional biomarkers changes in the composition of
the plasma membrane (lipid rafts) and changes in activation of signaling markers
(phosphorylation [p]Akt, pMAPK, pEGFR, PHER2).

III. To conduct exploratory analyses comparing the effect of statins on breast tumor
proliferation and apoptosis in groups defined by tumor expression of hydroxymethylglutaryl
co-enzyme A (CoA) reductase (HMG-CoA), estrogen receptor (ER)/progesterone receptor (PR)
status, HER2neu, and tumor grade.

OUTLINE:

Patients receive simvastatin orally (PO) daily for 2-4 weeks in the absence of disease
progression or unacceptable toxicity.

Inclusion Criteria:

- Provision of informed consent prior to any study specific procedures

- Histologic confirmation of invasive breast cancer with any measures of ER, PR and
HER2neu

- Clinical stage I or II breast cancer for which there will be at least a 2 week period
of time between diagnosis and definitive surgery

- Performance status (Eastern Cooperative Oncology Group [ECOG] 0-1)

- Not currently pregnant during the study; participants will be informed that the use of
contraceptive pills is contraindicated because it may interfere with the study drug
and it may be harmful to the woman who has been diagnosed with breast cancer

Exclusion Criteria:

- Plans for administration of neoadjuvant chemotherapy or hormonal therapy

- Insufficient tissue on diagnostic core breast biopsy for analysis

- Previous or concurrent malignancy (with the exception of non-melanomatous skin cancer)

- Severe gastrointestinal disorder

- Current use of statins or fibrates for any time during the 3 months prior to the study

- Proven hypersensitivity to statins

- White blood cell (WBC) < 3,500/mm^3

- Platelet (Plt) < 120,000/mm^3

- Hemoglobin (HgB) < 10 g/dL

- Aspartate aminotransferase (AST) > 45 U/L

- Alanine aminotransferase (ALT) > 45 U/L

- Creatinine > 1.5 mg/dL

- Bilirubin > 1.15 mg/dL

- Creatine kinase measurement (CPK) > or = 250 mg/dL

- Central nervous system (CNS) diseases and major psychiatric diseases or inability to
comply to the protocol procedures

- Active infections

- Cardiac failure, class I-IV

- Current anticoagulant or antiplatelet aggregation therapy

- Mitral and/or tricuspid valvopathy or valvular prosthesis; angina; severe arterial
hypertension; chronic and/or paroxysmal atrial fibrillation; previous myocardial
infarction

- Current lactation