Whole Genomic Copy Number Alterations in Circulating Tumor Cells from Men with Abiraterone or Enzalutamide-Resistant Metastatic Castration-Resistant Prostate Cancer.
Purpose: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.Experimental Design: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.Results: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 inAR, FOXA1, ABL1, MET, ERG, CDK12, BRD4, andZFHX3, while common genomic losses involvedPTEN, ZFHX3, PDE4DIP, RAF1, andGATA2Analysis of aCGH in a sample with sequential enzalutamide-resistant visceral progression showed acquired loss ofARamplification concurrent with gain ofMYCN, consistent with evolution toward a neuroendocrine-like, AR-independent clone.Conclusions:Genomic analysis of pooled CTCs in men with mCRPC suggests a reproducible, but highly complex molecular profile that includes common aberrations inAR, ERG, c-MET, and PI3K signaling during mCRPC progression, which may be useful for predictive biomarker development.Clin Cancer Res; 23(5); 1346-57. ©2016 AACR.
Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.|Duke Molecular Physiology Institute, Duke University, Durham, North Carolina.
Santosh
S
Gupta
Wake Forest School of Medicine, Winston Salem, North Carolina.
Jing
J
Li
Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
Gabor
G
Kemeny
Wake Forest School of Medicine, Winston Salem, North Carolina.
Rhonda L
RL
Bitting
Duke Molecular Physiology Institute, Duke University, Durham, North Carolina.
Joshua
J
Beaver
Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
Jason A
JA
Somarelli
Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
Kathryn E
KE
Ware
Duke Molecular Physiology Institute, Duke University, Durham, North Carolina.
Simon
S
Gregory
Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina. andrew.armstrong@duke.edu.
Andrew J
AJ
Armstrong
D000736:Androstenes / Q000008:administration & dosage / Q000009:adverse effects; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000097:blood*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000097:blood* / Q000235:genetics; D009360:Neoplastic Cells, Circulating; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology
D000736:Androstenes; D001549:Benzamides; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide; C089740:abiraterone