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Fluorescence In situ Hybridization Analysis of CirculatingTumor Cells in Metastatic Prostate Cancer

Purpose: To assess the feasibility of characterizing gene copy number alteration by fluorescence in situ hybridization (FISH) of circulating tumor cells (CTC) isolated using the CellSearch system in patients with progressive castration-resistant metastatic prostate cancer. Experimental Design: We used probe combinations that included the androgen receptor (AR )a ndMYC genes for FISH analysis of CTC samples collected from 77 men with castration- resistant metastatic prostate cancer. Results: High-level chromosomal amplification of AR was detected in 38% and relative gain of MYC in 56% of samples analyzed. No such abnormalities were detected in samples with CTC counts of <10, reflecting ascertainment difficulty in these lower count samples. Conclusion: The CTC isolated from our patient cohort present a very similar molecular cytoge- netic profile to that reported for late-stage tumors and show that FISH analysis of CTC can be a valuable, noninvasive surrogate for routine tumor profiling. That as many as 50% of these patients have substantial amplification of the AR locus indicates that androgen signaling continues to play an important role in late-stage prostate cancer. The therapeutic options for men with progressive castration- resistant prostate cancer are limited. Management is compli- cated by the uncertainty of predicting the prognosis of individual patients based on clinical variables alone. Because most advanced tumors are inherently unstable and heteroge- neous, robust methods to correlate specific tumor character- istics to clinical outcomes are urgently needed. Functional analyses of tumor genomics and cell biology have led to a new generation of antitumor agents. However, because many are directed toward specific targets or pathways, tumors lacking these targets will not respond. To expedite the introduction of new therapies into clinical practice, biomarkers are needed to define prognosis more precisely and to guide treatment selection based on the biological profile of an individual patient's tumor. This is particularly important with the clinical activity recently shown with two agents targeting the androgen receptor (AR) signaling axis: abiraterone acetate, an irreversible inhibitor of CYP17A that blocks androgen synthesis (1), and MDV3100, a potent AR antagonist selected for clinical development based on antitumor effects in preclinical prostate cancer models with overexpressed AR (2).