Measurement of circulating cell-free DNA in relation to 18F-fluorocholine PET/CT imaging in chemotherapy-treated advanced prostate cancer.

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.