Whole Genomic Copy Number Alterations in Circulating Tumor Cells from Men with Abiraterone or Enzalutamide-Resistant Metastatic Castration-Resistant Prostate Cancer.

Abstract

<b>Purpose:</b> Beyond enumeration, circulating tumor cells (CTCs) can provide genetic information from metastatic cancer that may facilitate a greater understanding of tumor biology and enable a precision medicine approach.<b>Experimental Design:</b> CTCs and paired leukocytes from men with metastatic castration-resistant prostate cancer (mCRPC) were isolated from blood through red cell lysis, CD45 depletion, and flow sorting based on EpCAM/CD45 expression. We next performed whole genomic copy number analysis of CTCs and matched patient leukocytes (germline) using array-based comparative genomic hybridization (aCGH) from 16 men with mCRPC, including longitudinal and sequential aCGH analyses of CTCs in the context of enzalutamide therapy.<b>Results:</b> All patients had mCRPC and primary or acquired resistance to abiraterone acetate or enzalutamide. We compiled copy gains and losses, with a particular focus on those genes highly implicated in mCRPC progression and previously validated as being aberrant in metastatic tissue samples and genomic studies of reference mCRPC datasets. Genomic gains in >25% of CTCs were observed in <i>AR, FOXA1, ABL1, MET, ERG, CDK12, BRD4</i>, and <i>ZFHX3</i>, while common genomic losses involved <i>PTEN, ZFHX3, PDE4DIP, RAF1</i>, and <i>GATA2</i> Analysis of aCGH in a sample with sequential enzalutamide-resistant visceral progression showed acquired loss of <i>AR</i> amplification concurrent with gain of <i>MYCN</i>, consistent with evolution toward a neuroendocrine-like, AR-independent clone.<b>Conclusions:</b> Genomic analysis of pooled CTCs in men with mCRPC suggests a reproducible, but highly complex molecular profile that includes common aberrations in <i>AR, ERG, c-MET</i>, and PI3K signaling during mCRPC progression, which may be useful for predictive biomarker development. <i>Clin Cancer Res; 23(5); 1346-57. ©2016 AACR</i>.