Simvastatin in Preventing a New Breast Cancer in Women at High Risk for a New Breast Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Study of Simvastatin in Women at High Risk for a New Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: simvastatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simvastatin<br>Simvastatin 40 mg for 24-28 weeks | Drug: simvastatin<br>* 24-28 weeks of simvastatin<br>* Other names: Zocor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in a Panel of Biomarkers (High-sensitivity C-reactive Protein [hsCRP], Lipid Profile, and Circulating Estrogens) From Baseline |  | Baseline and week 24 | 
| Change in a Panel of Biomarkers (Contralateral Breast Density) From Baseline |  | Baseline and week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of Breast Gene (Estrogen Receptor [ER]-α and ER-β, Cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) Hypermethylation | Median change in gene promotor methylation (%M) in the contralateral breast of women with breast cancer after six months of therapy | Change from Baseline to week 24 | 
| Prevalence of Akt and p-Akt Activation by Contralateral Core Breast Biopsies |  | Baseline and week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, ductal breast carcinoma in situ, breast cancer in situ, stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer