Breast Cancer
Conditions
Keywords
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
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.
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.
Interventions
DRUGsimvastatin
24-28 weeks of simvastatin
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Simvastatin Simvastatin 40 mg for 24-28 weeks | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | New cancer diagnosis | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Simvastatin |
|---|---|
| Age, Continuous | 53 years |
| Race/Ethnicity, Customized African American | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Race/Ethnicity, Customized White | 47 Participants |
| Region of Enrollment United States | 50 Participants |
| Sex: Female, Male Female | 50 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 17 / 50 |
| serious Total, serious adverse events | 0 / 50 |
Outcome results
Primary
Change in a Panel of Biomarkers (Contralateral Breast Density) From Baseline
Time frame: Baseline and week 24
Population: Paired baseline and post-simvastatin treatment mammograms for evaluation of breast density were available for 43 participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Simvastatin | Change in a Panel of Biomarkers (Contralateral Breast Density) From Baseline | -0.78 percentage of change |
Primary
Change in a Panel of Biomarkers (High-sensitivity C-reactive Protein [hsCRP], Lipid Profile, and Circulating Estrogens) From Baseline
Time frame: Baseline and week 24
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Simvastatin | Change in a Panel of Biomarkers (High-sensitivity C-reactive Protein [hsCRP], Lipid Profile, and Circulating Estrogens) From Baseline | hsCRP | -0.15 mg/dl |
| Simvastatin | Change in a Panel of Biomarkers (High-sensitivity C-reactive Protein [hsCRP], Lipid Profile, and Circulating Estrogens) From Baseline | Total cholesterol | -54 mg/dl |
| Simvastatin | Change in a Panel of Biomarkers (High-sensitivity C-reactive Protein [hsCRP], Lipid Profile, and Circulating Estrogens) From Baseline | High-density lipoprotein cholesterol (HDL) | -1 mg/dl |
| Simvastatin | Change in a Panel of Biomarkers (High-sensitivity C-reactive Protein [hsCRP], Lipid Profile, and Circulating Estrogens) From Baseline | Estrogen (estrone sulfate) | -81.5 mg/dl |
Secondary
Prevalence of Akt and p-Akt Activation by Contralateral Core Breast Biopsies
Time frame: Baseline and week 24
Population: Enough tissue was not collected to assess this outcome measure.
Secondary
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
Time frame: Change from Baseline to week 24
Population: Methylation values at both time points were only evaluable in 17 participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Simvastatin | Prevalence of Breast Gene (Estrogen Receptor [ER]-α and ER-β, Cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) Hypermethylation | CyclinD2 (CCND2) | 0.5 percent methylation (%M) |
| Simvastatin | Prevalence of Breast Gene (Estrogen Receptor [ER]-α and ER-β, Cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) Hypermethylation | SCGB3A1 | 0 percent methylation (%M) |
| Simvastatin | Prevalence of Breast Gene (Estrogen Receptor [ER]-α and ER-β, Cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) Hypermethylation | TWIST1 | 0.21 percent methylation (%M) |
| Simvastatin | Prevalence of Breast Gene (Estrogen Receptor [ER]-α and ER-β, Cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) Hypermethylation | RASSF1 | 0 percent methylation (%M) |
| Simvastatin | Prevalence of Breast Gene (Estrogen Receptor [ER]-α and ER-β, Cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) Hypermethylation | RARB | -0.08 percent methylation (%M) |
| Simvastatin | Prevalence of Breast Gene (Estrogen Receptor [ER]-α and ER-β, Cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) Hypermethylation | APC | 0.01 percent methylation (%M) |
| Simvastatin | Prevalence of Breast Gene (Estrogen Receptor [ER]-α and ER-β, Cyclin D2, RAR-β, Twist, RASSF1A, and HIN-1) Hypermethylation | CMI | -0.42 percent methylation (%M) |