Phase II Study of Simvastatin in Primary Breast Cancer; Test of Its Potential Selectivity on Basal Subtype Breast Cancer
Primary Objectives
1. Evaluate the biological response (proliferation and apoptosis) of Simvastatin in primary
breast cancer.
2. Evaluate the cell type specificity of Simvastatin effect on basal subtype breast cancer,
especially cells with CD44+/CD24- immunophenotype in the primary tumor. Secondary objectives
1. To study cellular response to Simvastatin in transriptome.
2. To obtain gene expression signature that predict Simvastatin biological effects.
3. To identify genetic polymorphisms that may influence Simvastatin pharmacokinetics
and/or biological effects on breast cancer.
4. To correlate tumor and plasma proteomics with tumor gene expression changes, and to
identify tumor and/or serum protein markers that predict Simvastatin biological
effects.
5. To correlate peripheral blood mononuclear cell gene expression changes with tumor gene
expression changes, and to identify blood gene markers that may predict Simvastatin
biological effects. VI. Abstract of Research Proposal In no more than 300 words,
describe concisely the specific aims, hypotheses, methodology and approach of the
application, indicating where appropriate the application's importance to science or
medicine. The abstract must be self-contained so that it can serve as a succinct and
accurate description of the application when separated from it. Please use lay terms.
If this not possible, the technical and medical terms should be explained in simple
language. We hypothesize that Simvastatin administration would result in selective
killing of the basal subtype of breast cancer, in particular, CD44+/CD24- breast cancer
cells in primary tumor. We further hypothesize that tumor genomic changes would
correlate with tumor response to Simvastatin. We are also looking to correlate
Simvastatin biological effects with the expression pattern of initial status of primary
tumor. In addition, we hypothesize that Simvastatin-induced tumor gene expression
changes may correlate with tumor and plasma proteomics, peripheral blood mononuclear
cell gene expression changes, and pharmacogenetics, and that these analyses may further
refine the selection of patients most likely to benefit from Simvastatin. This is a
single-centre, open-label, phase II study of Simvastatin in resectable primary breast
cancer.
A total of 100 patients with measurable, resectable, primary breast tumor will be enrolled
to receive 10-21 days of Simvastatin at a dose of 20 mg daily before definitive breast
cancer surgery. Pre-treatment tumor biopsy will be obtained from each subject before
starting Simvastatin. Subjects will take Simvastatin at a dose of 20 mg daily for 10-21
days, prior to definitive breast cancer surgery. The post-treatment tumor biopsy will be
obtained at surgery. At each tumor biopsy, 3-4 tumor samples will be obtained through the
same needle track. One tumor core at each time point will be fixed in formalin for
histological examination and immunohistochemical studies. The remaining tumor cores will be
stored in liquid nitrogen for subsequent RNA and protein extraction for gene expression and
proteomics studies. Blood samples will be obtained before and after 10-21 days of
Simvastatin treatment for Simvastatin pharmacokinetic analysis, plasma proteomics and
peripheral mononuclear cell gene expression analysis. 10 ml blood will be taken from each
participant for genotyping studies.
Interventional
Primary Purpose: Treatment
Soo Chin Lee, MBBS, MRCP
Principal Investigator
National University Hospital, Singapore
Singapore: Domain Specific Review Boards
BR04/18/08
NCT00807950
March 2008
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