Genome wide analysis of Circulating Tumor Cells from Patients with Metastatic Prostate Cancer Reveals Clinically Relevant Aberrations Associated with Castration Resistance

The number of circulating tumor cells (CTCs) in metastatic prostate cancer patients provides prognostic and predictive information. However, it is the molecular characterization of CTCs that offers insight into the biology of these tumor cells in the context of personalized treatment. We performed a pilot study to evaluate the feasibility of isolation and genomic profiling of CTCs in castration-resistant prostate cancer. CTCs in 7.5 mLs of blood in 20 castration-resistant metastatic prostate cancer patients were enumerated using CellSearch. Additional 10-20 mLs of blood from 12 patients positive for CTCs were subjected to immunomagnetic enrichment and fluorescence activated cell sorting (IE/FACS) to isolate pools of ~20 CTCs. Genomic DNA of CTCs was subjected to whole genome amplification followed by gene copy number analysis via array comparative genomic hybridization (aCGH). Archival primary tumor biopsy samples available from 2 patients were also subjected to aCGH. Enumeration of CTCs revealed 15 patients with >=5 CTCs per 7.5 mLs. Of these, 12 samples were subjected to IE/FACS for CTC isolation, and 9 (75%) were successfully analyzed for copy number aberrations. Genomic profiling of CTCs revealed numerous copy number aberrations commonly observed in primary prostate tumors including gains in 8q and losses in 8p. High level copy number gains at the androgen receptor (AR) locus were observed in 7 (78%) of cases. Comparison of genomic profiles between CTCs and their matched tumors revealed a common lineage. Consistent with previous observations high-level gains in the AR were only observed in CTCs but not in the matched primary tumors. This is consistent with CTCs representing progressive disease that has adapted to hormone therapy.