Simvastatin in Preventing a New Breast Cancer in Women at High Risk for a New Breast Cancer
Simvastatin in Preventing a New Breast Cancer in Women at High Risk for a New Breast Cancer
RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming, growing,
 or coming back. The use of simvastatin may keep cancer from coming back in women who are at
 high risk for a new breast cancer after undergoing surgery for ductal carcinoma in situ or
 stage I, stage II, or stage III breast cancer.

 PURPOSE: This phase II trial is studying how well simvastatin works in preventing a new
 breast cancer in women at high risk for a new breast cancer after undergoing surgery for
 ductal carcinoma in situ or stage I, stage II, or stage III breast cancer.
OBJECTIVES:

 Primary

 -  Describe changes from baseline in a panel of biomarkers (high-sensitivity C-reactive
 protein [hsCRP], lipid profile, circulating estrogens, and contralateral breast density)
 in women at high risk of developing new breast cancer who have undergone surgical
 resection for history of ductal carcinoma in situ or stage I-III invasive breast cancer
 treated with simvastatin.

 Secondary

 -  Correlate changes in the panel of biomarkers with wild-type versus polymorphic
 3-hydroxyl-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase in women treated with
 simvastatin.

 Tertiary

 -  Evaluate methylation status across a panel of genes that are known to be frequently and
 specifically hypermethylated in ductal carcinoma in situ (DCIS) and invasive breast
 cancer (estrogen receptor [ER]-α and ER-β, cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1)
 and correlate change in cumulative methylation with change in hsCRP, lipid profile,
 contralateral breast density, estrogen concentrations, and pharmacogenetics.

 -  Measure changes in the phosphoinositide 3'-kinase (PI3K)/protein kinase B (Akt)
 signaling pathway (Akt and p-Akt) before and after treatment with simvastatin.

 OUTLINE: This is a multicenter study. Patients are stratified according to menopausal status
 (pre- vs post-menopausal).

 Patients receive oral simvastatin once daily for 24-28 weeks in the absence of disease
 progression or unacceptable toxicity.

 Patients undergo blood collection at baseline and at the end of study treatment for
 pharmacogenetic and biomarker correlative studies. Patients undergo mammography and
 measurement of breast density of the contralateral breast at baseline and at the end of study
 treatment.

 Quality of life is assessed at baseline and at the end of study treatment.

 PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.
DISEASE CHARACTERISTICS:

 -  History of histologically confirmed breast cancer, meeting 1 of the following staging
 criteria:

 -  Ductal carcinoma in situ

 -  Stage I-III invasive breast cancer

 -  At least 3 months since completion of all intended local and systemic therapy,
 including mastectomy or lumpectomy with or without radiotherapy, adjuvant
 chemotherapy, and/or endocrine therapy

 -  May have declined recommended treatment provided all treatment intended/agreed
 upon by the patient and treating physician was completed ≥ 3 months ago

 -  At least 1 healthy intact breast

 -  No prior radiotherapy or mastectomy

 -  Prior biopsies allowed

 -  Any hormone-receptor status

 PATIENT CHARACTERISTICS:

 -  Female

 -  Pre- or post-menopausal

 -  ECOG performance status 0-2

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective nonhormonal contraception

 -  No active liver disease

 -  AST and ALT ≤ 3 times upper limit of normal

 -  Creatinine clearance ≥ 30 mL/min

 -  No prior hypersensitivity to any 3-hydroxyl-3-methylglutaryl-Coenzyme A (HMG-CoA)
 reductase inhibitor or any of its components

 -  No other concurrent infectious, inflammatory, or autoimmune diseases (at the
 discretion of principal investigator)

 PRIOR CONCURRENT THERAPY:

 -  See Disease Characteristics

 -  No daily alcohol use > 3 standard drinks per day

 -  Standard drink defined as 10 grams of alcohol, which is equivalent to 285 mL of
 beer, 530 mL of light beer, 100 mL of wine, or 30 mL of liquor

 -  No selective estrogen receptor modulator or aromatase inhibitor within the past 3
 months

 -  No hormone replacement therapy (HRT) within the past 3 months

 -  No prior estrogen and/or progesterone HRT ≥ 5 years in duration

 -  Vaginal estrogen preparations allowed

 -  No concurrent HRT

 -  No other cholesterol-lowering drug, including a statin, within the past 3 months

 -  No concurrent itraconazole, ketoconazole, nefazodone, cyclosporine, HIV protease
 inhibitors, clarithromycin, erythromycin, mibefradil, carbamazepine, bosentan,
 chaparral, amiodarone, or verapamil

 -  No concurrent daily grapefruit juice consumption > 8 ounces per day

 -  No other concurrent agents or therapies intended to treat or prevent in situ or
 invasive breast cancer