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// Christophe Massard 1, 2, * , Marianne Oulhen 2, 3, * , Sylvestre Le Moulec 4 , Nathalie Auger 5 , Stephanie Foulon 6 , Aurelie Abou-Lovergne 1 , Fanny Billiot 2, 3 , Alexander Valent 5 , Virginie Marty 7 , Yohann Loriot 1, 2 , Karim Fizazi 1, 2 , Philippe Vielh 2, 3, 5, # , Francoise Farace 2, 3, # 1 Gustave Roussy, Universite Paris-Saclay, Department of Medicine, F-94805, Villejuif, France 2 INSERM, U981 “Identification of Molecular Predictors and New Targets for Cancer Treatment”, F-94805, Villejuif, France 3 Gustave Roussy, Universite Paris-Saclay, “Circulating Tumor Cells” Translational Platform, AMMICA CNRS UMS3655 – INSERM US23, F-94805, Villejuif, France 4 Hopital d’Instruction des Armees du Val de Grâce, Department of Oncology, F-75005, Paris, France 5 Gustave Roussy, Universite Paris-Saclay, Department of Biopathology, F-94805, Villejuif, France 6 Gustave Roussy, Universite Paris-Saclay, Department of Biostatistics and Epidemiology, F-94805, Villejuif, France 7 Gustave Roussy, Universite Paris-Saclay, “Histo Cytopathology” Translational Platform, AMMICA CNRS UMS3655 – INSERM US23, F-94805, Villejuif, France * These authors contributed equally to the study # These authors contributed equally to the study Correspondence to: Francoise Farace, email: francoise.farace@gustaveroussy.fr Keywords: prostate cancer, biopsy, circulating tumor cells, androgen receptor, TMPRSS2-ERG translocation Received: March 24, 2016 Accepted: June 17, 2016 Published: July 04, 2016 ABSTRACT Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer (mCRPC) patients. We reported the results of prospective PETRUS study of biomarker assessment in paired primary prostatic tumors, metastatic biopsies and circulating tumor cells (CTCs). Among 54 mCRPC patients enrolled, 38 (70%) had biopsies containing more than 50% tumour cells. 28 (52%) patients were analyzed for both tissue samples and CTCs. FISH for AR -amplification and TMPRSS2-ERG translocation were successful in 54% and 32% in metastatic biopsies and primary tumors, respectively. By comparing CellSearch and filtration (ISET)-enrichment combined to four color immunofluorescent staining, we showed that CellSearch and ISET isolated distinct subpopulations of CTCs: CTCs undergoing epithelial-to-mesenchymal transition, CTC clusters and large CTCs with cytomorphological characteristics but no detectable markers were isolated using ISET. Epithelial CTCs detected by the CellSearch were mostly lost during the ISET-filtration. AR -amplification was detected in CellSearch-captured CTCs, but not in ISET-enriched CTCs which harbor exclusively AR gain of copies. Eighty-eight percent concordance for ERG -rearrangement was observed between metastatic biopsies and CTCs even if additional ERG -alteration patterns were detected in ISET-enriched CTCs indicating a higher heterogeneity in CTCs. Molecular screening of metastatic biopsies is achievable in a multicenter context. Our data indicate that CTCs detected by the CellSearch and the ISET-filtration systems are not only phenotypically but also genetically different. Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients.