Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Simvastatin in Preventing a New Breast Cancer 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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Biomarker/Laboratory analysis, Prevention	Active	18 and over	NCI	JHOC-J0485 J0485, JHOC-SKCCC-J0485, JHOC-04100404, NCT00334542

Special Category: NCI Avon award trial

Objectives

Primary

1. 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

1. 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

1. 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.
2. Measure changes in the phosphoinositide 3’-kinase (PI3K)/protein kinase B (Akt) signaling pathway (Akt and p-Akt) before and after treatment with simvastatin.

Entry Criteria

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

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

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)

Expected Enrollment

A total of 50 patients will be accrued for this study.

Outcomes

Change in a panel of biomarkers (high-sensitivity C-reactive protein [hsCRP], lipid profile, circulating estrogens, and contralateral breast density) from baseline

Prevalence of breast gene (estrogen receptor [ER]-α and ER-β, cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) hypermethylation
Prevalence of Akt and p-Akt activation by contralateral core breast biopsies

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.

Trial Contact Information

Trial Lead Organizations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Vered Stearns, MD, Principal investigator		Ph: 443-287-6489

U.S.A.
Maryland
	Baltimore
	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
		Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Center at John Hopkins	Ph:  410-955-8804
			Email: jhcccro@jhmi.edu
Massachusetts
	Boston
	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
		Judy Garber, MD	Ph:  617-632-2282 866-790-4500
			Email: judy_garber@dfci.harvard.edu

Registry Information
Official Title		A Phase II Study of Simvastatin in Women at High Risk for a New Breast Cancer
Trial Start Date		2006-03-29
Trial Completion Date		2009-06-30 (estimated)
Registered in ClinicalTrials.gov		NCT00334542
Date Submitted to PDQ		2006-03-29
Information Last Verified		2009-07-05
NCI Grant/Contract Number		CA06973, CA88843

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