Breast Tumor Tissue Clinical Trial
Official title:
Study of the Effect of Chemotherapy on Methylation Patterns in Breast Tumor Tissue and Paired Plasma Samples and Correlation With Clinical Response and Outcomes
Primary Objectives
1. To identify hypermethylated genes in paired pretreatment breast tumor tissue and plasma
samples from locally advanced and metastatic breast cancer patients using a known gene
panel which includes APC1, Cyclin D2, RARB, RASSF1A, Twist, Hin1 and GSTP1.
Rationale: We and others have determined the optimal panel of genes that are able to
detect free DNA in plasma and serum. We will determine if the same panel of genes is
effective for detecting tumor DNA in the plasma of locally advanced and metastatic
breast cancer patients. Further, to determine if the methylation profile of the plasma
DNA for these genes is the same or different from the primary tumor at presentation, we
will analyze the primary tumor DNA from fresh frozen samples.
2. To identify methylation pattern changes in the same subset of patients' plasma samples
at 24 hours after completion of cycle 1 of chemotherapy and within 24 hours before
cycle 2.
Rationale: The optimal timing of sampling for methylation analysis that is reflective of the
tumors response to chemotherapy is not known. How soon methylation changes are observed,
whether they are high within 24 hours, as that tumor responds to chemotherapy, or whether
changes can be observed only some time after one cycle of chemotherapy will be studied. (3)
To also identify methylation pattern changes in breast tumor tissue after one cycle of
chemotherapy.
Rationale: To look for a correlation with plasma methylation patterns
Secondary Objectives
(1) To correlate our observed patterns of methylation pre- and post-treatment with clinical
parameters such as clinical and/or radiological response and patient outcome.
In advanced breast cancer, it is often difficult to predict which patients will respond
favorably to systemic therapy to decide on treatment duration or options while minimizing
exposure to toxic effects. Our goal is to examine using locally advanced and metastatic
breast cancer tumor tissue and plasma, the methylation profile patterns pre- and post
chemotherapy of a panel of biomarkers most commonly expressed in breast cancer and correlate
them with tumor response and patient outcome.
Our hypothesis is that DNA methylation pattern changes at baseline and early into a course
of systemic therapy can predict disease response or progression as well as survival. In the
long term, this could prove clinically useful in limiting exposure to ineffective regimens
and allowing earlier identification of more effective systemic therapy.
Core biopsies of breast tumor tissue are taken at baseline and after cycle 1 of
docetaxel/ketoconazole. Plasma samples are drawn at baseline, 24 hours after cycle 1
chemotherapy and 24 hours before cycle 2. Thirty patients' specimens (60 core biopsies and
90 plasma samples) will be utilized. Quantitative multiplex methylation-specific PCR will be
used for analyses of several tumor suppressor genes including APC1, Cyclin D2, RARB,
RASSF1A, Twist, Hin1 and GSTP1. From this data, we will identify a preliminary gene panel
associated with breast cancer which undergoes the most changes in methylation following
systemic therapy. Thirty paraffin-embedded healthy tissue samples from mastectomy specimens
and blood samples from unaffected individuals will serve as normal controls.
This preliminary study can be used to determine the clinical utility of DNA methylation in
breast tumor tissue and plasma as a predictive marker for response to chemotherapy and a
prognostic marker for patient outcome. If a relationship is found, we can then further study
if the change in methylation pattern has clinical utility in influencing therapeutic
decision-making which may be further expanded to the adjuvant setting..
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