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

A Phase II Study of Simvastatin 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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: simvastatin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney kimmel comprehensive cancer center at johns hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02115-6084
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Simvastatin; Simvastatin 40 mg for 24-28 weeks	Drug: simvastatin; 24-28 weeks of simvastatin; Other Names: Zocor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Fackler MJ, McVeigh M, Mehrotra J, Blum MA, Lange J, Lapides A, Garrett E, Argani P, Sukumar S. Quantitative multiplex methylation-specific PCR assay for the detection of promoter hypermethylation in multiple genes in breast cancer. Cancer Res. 2004 Jul 1;64(13):4442-52. doi: 10.1158/0008-5472.CAN-03-3341.
• Higgins MJ, Prowell TM, Blackford AL, Byrne C, Khouri NF, Slater SA, Jeter SC, Armstrong DK, Davidson NE, Emens LA, Fetting JH, Powers PP, Wolff AC, Green H, Thibert JN, Rae JM, Folkerd E, Dowsett M, Blumenthal RS, Garber JE, Stearns V. A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer. Breast Cancer Res Treat. 2012 Feb;131(3):915-24. doi: 10.1007/s10549-011-1858-7. Epub 2011 Nov 11.

Study record dates

Study Major Dates

• Study Start: March 1, 2006
• Primary Completion (Actual): June 1, 2009
• Study Completion (Actual): November 1, 2011

Study Registration Dates

• First Submitted: June 7, 2006
• First Submitted That Met QC Criteria: June 7, 2006
• First Posted (Estimate): June 8, 2006

Study Record Updates

• Last Update Posted (Actual): April 3, 2019
• Last Update Submitted That Met QC Criteria: March 26, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; breast cancer; stage II breast cancer; stage IIIC breast cancer; stage I breast cancer; breast cancer in situ; ductal breast carcinoma in situ
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: J0485; P30CA006973 (U.S. NIH Grant/Contract); P50CA088843 (U.S. NIH Grant/Contract); JHOC-J0485 (Other Identifier: SKCCC at Johns Hopkins); SKCCC-J0485 (Other Identifier: SKCCC at Johns Hopkins); CDR0000477214 (Registry Identifier: NCI PDQ); NA_00041153 (Other Identifier: JHM IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO