Simvastatin in Preventing a New Breast Cancer in Women at High Risk for a New Breast Cancer
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Simvastatin Simvastatin 40 mg for 24-28 weeks |
Drug: simvastatin
24-28 weeks of simvastatin
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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
- Prevalence of Breast Gene (Estrogen Receptor [ER]-α and ER-β, Cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) Hypermethylation [Change from Baseline to week 24]
Median change in gene promotor methylation (%M) in the contralateral breast of women with breast cancer after six months of therapy
- Prevalence of Akt and p-Akt Activation by Contralateral Core Breast Biopsies [Baseline and week 24]
Eligibility Criteria
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
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore | Maryland | United States | 21231-2410 |
| 2 | Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute | Boston | Massachusetts | United States | 02115-6084 |
Sponsors and Collaborators
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Vered Stearns, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Documents (Full-Text)
None provided.More Information
Publications
- J0485
- P50CA088843
- P30CA006973
- JHOC-J0485
- SKCCC-J0485
- CDR0000477214
- NA_00041153
Study Results
Participant Flow
| Recruitment Details | Participants were required to have good performance status, intact contralateral breast, and be at least 3 months from planned local and systemic adjuvant treatment. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Simvastatin |
|---|---|
| Arm/Group Description | Simvastatin 40 mg for 24-28 weeks |
| Period Title: Overall Study | |
| STARTED | 50 |
| COMPLETED | 45 |
| NOT COMPLETED | 5 |
Baseline Characteristics
| Arm/Group Title | Simvastatin |
|---|---|
| Arm/Group Description | Simvastatin 40 mg for 24-28 weeks |
| Overall Participants | 50 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
53
|
| Sex: Female, Male (Count of Participants) | |
| Female |
50
100%
|
| Male |
0
0%
|
| Race/Ethnicity, Customized (Count of Participants) | |
| White |
47
94%
|
| African American |
1
2%
|
| Other |
2
4%
|
| Region of Enrollment (Count of Participants) | |
| United States |
50
100%
|
Outcome Measures
| Title | Change in a Panel of Biomarkers (High-sensitivity C-reactive Protein [hsCRP], Lipid Profile, and Circulating Estrogens) From Baseline |
|---|---|
| Description | |
| Time Frame | Baseline and week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Paired baseline and post-simvastatin treatment fasting lipid samples were available for 47 participants, including 45 women who completed the study and from two who discontinued the drug prior to the completion of the 24-28 weeks of drug, and are integrated in the intention-to-treat analyses |
| Arm/Group Title | Simvastatin |
|---|---|
| Arm/Group Description | Simvastatin 40 mg for 24-28 weeks |
| Measure Participants | 47 |
| hsCRP |
-0.15
|
| Total cholesterol |
-54
|
| High-density lipoprotein cholesterol (HDL) |
-1
|
| Estrogen (estrone sulfate) |
-81.5
|
| Title | Change in a Panel of Biomarkers (Contralateral Breast Density) From Baseline |
|---|---|
| Description | |
| Time Frame | Baseline and week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Paired baseline and post-simvastatin treatment mammograms for evaluation of breast density were available for 43 participants. |
| Arm/Group Title | Simvastatin |
|---|---|
| Arm/Group Description | Simvastatin 40 mg for 24-28 weeks |
| Measure Participants | 43 |
| Median (95% Confidence Interval) [percentage of change] |
-0.78
|
| Title | Prevalence of Breast Gene (Estrogen Receptor [ER]-α and ER-β, Cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) Hypermethylation |
|---|---|
| Description | Median change in gene promotor methylation (%M) in the contralateral breast of women with breast cancer after six months of therapy |
| Time Frame | Change from Baseline to week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Methylation values at both time points were only evaluable in 17 participants. |
| Arm/Group Title | Simvastatin |
|---|---|
| Arm/Group Description | Simvastatin 40 mg for 24-28 weeks |
| Measure Participants | 17 |
| CyclinD2 (CCND2) |
0.5
|
| SCGB3A1 |
0
|
| TWIST1 |
0.21
|
| RASSF1 |
0
|
| RARB |
-0.08
|
| APC |
0.01
|
| CMI |
-0.42
|
| Title | Prevalence of Akt and p-Akt Activation by Contralateral Core Breast Biopsies |
|---|---|
| Description | |
| Time Frame | Baseline and week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Enough tissue was not collected to assess this outcome measure. |
| Arm/Group Title | Simvastatin |
|---|---|
| Arm/Group Description | Simvastatin 40 mg for 24-28 weeks simvastatin: 24-28 weeks of simvastatin |
| Measure Participants | 0 |
Adverse Events
| Time Frame | up to 28 weeks | |
|---|---|---|
| Adverse Event Reporting Description | Adverse events data were collected during 24-28 weeks of simvastatin administration | |
| Arm/Group Title | Simvastatin | |
| Arm/Group Description | Simvastatin 40 mg for 24-28 weeks | |
All Cause Mortality |
||
| Simvastatin | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Simvastatin | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/50 (0%) | |
Other (Not Including Serious) Adverse Events |
||
| Simvastatin | ||
| Affected / at Risk (%) | # Events | |
| Total | 17/50 (34%) | |
| Gastrointestinal disorders | ||
| Constipation | 7/50 (14%) | 7 |
| Musculoskeletal and connective tissue disorders | ||
| Muscle weakness | 5/50 (10%) | 5 |
| Myalgia | 5/50 (10%) | 5 |
| Nervous system disorders | ||
| Headache | 4/50 (8%) | 4 |
| Skin and subcutaneous tissue disorders | ||
| Rash maculo-papular | 1/50 (2%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Vered Stearns |
|---|---|
| Organization | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins |
| Phone | 4432876489 |
| vstearn1@jhmi.edu |
- J0485
- P50CA088843
- P30CA006973
- JHOC-J0485
- SKCCC-J0485
- CDR0000477214
- NA_00041153