Study of the Effect of Chemotherapy on Methylation Patterns in Breast Tumor Tissue and Paired Plasma Samples and Correlation With Clinical Response and Outcomes
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..
Sing Huang Tan, MBBS, MRCP
National University Hospital, Singapore
Singapore: Domain Specific Review Boards