Abstract
Purpose: To examine the effects of chemotherapy on circulating cell‐free DNA (cfDNA) composition in relation to investigational whole‐body measurement of tumor activity by fluorine‐18 fluorocholine (FCH) positron emission tomography/computed tomography (PET/CT) in hormone‐refractory prostate cancer (HRPC). Methods: Serial FCH PET/CT scans were performed in eight patients with HRPC receiving docetaxel‐based chemotherapy. Corresponding serial cfDNA samples were characterized by microfluidic electrophoresis, quantified by real‐time PCR, and compared with PET/CT results. Promoter methylation of two prostate cancer‐associated genes, GSTP1 and RARB2, was assessed by methylation‐specific PCR of bisulfite‐converted cfDNA. Results: Plasma cfDNA concentrations increased significantly from 13.3 ng/mL at baseline to 46.8 ng/mL and 50.9 ng/mL after one and three treatment cycles, respectively (p= 0.001). GSTP1 and/or RARB2 promoter methylation was identified in all pretreatment samples. The appearance of large (200 bp–10.4 kb) cfDNA fragments was noted in posttreatment samples along with loss of methylation at GSTP1 and/or RARB2. Tumor activity on PET/CT correlated with cfDNA concentration (r=−0.50, p= 0.01). Patients meeting criteria for PET tumor response had significantly lower pretreatment cfDNA levels than those who did not (8.0 vs. 16.4 ng/mL, p= 0.03). Conclusions: Chemotherapy is associated with significant changes in plasma cfDNA content and FCH PET/CT‐detected tumor activity. These interrelated measures are potential candidate markers of therapeutic response in HRPC. Clin Trans Sci 2012; Volume #: 1–6
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