title: Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castration-resistant prostate cancer: A report from the PETRUS prospective study.
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.
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Department of Medicine, F-94805, Villejuif, France.|INSERM, U981 "Identification of Molecular Predictors and New Targets for Cancer Treatment", F-94805, Villejuif, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Massard
authors.affiliation: INSERM, U981 "Identification of Molecular Predictors and New Targets for Cancer Treatment", F-94805, Villejuif, France.|Gustave Roussy, Université Paris-Saclay, "Circulating Tumor Cells" Translational Platform, AMMICA CNRS UMS3655 - INSERM US23, F-94805, Villejuif, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Oulhen
authors.affiliation: Hôpital d'Instruction des Armées du Val de Grâce, Department of Oncology, F-75005, Paris, France.
authors.forename: Sylvestre
authors.initials: S
authors.lastname: Le Moulec
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Department of Biopathology, F-94805, Villejuif, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Auger
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Department of Biostatistics and Epidemiology, F-94805, Villejuif, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Foulon
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Department of Medicine, F-94805, Villejuif, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Abou-Lovergne
authors.affiliation: INSERM, U981 "Identification of Molecular Predictors and New Targets for Cancer Treatment", F-94805, Villejuif, France.|Gustave Roussy, Université Paris-Saclay, "Circulating Tumor Cells" Translational Platform, AMMICA CNRS UMS3655 - INSERM US23, F-94805, Villejuif, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Billiot
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Department of Biopathology, F-94805, Villejuif, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Valent
authors.affiliation: Gustave Roussy, Université Paris-Saclay, "Histo Cytopathology" Translational Platform, AMMICA CNRS UMS3655 - INSERM US23, F-94805, Villejuif, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Marty
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Department of Medicine, F-94805, Villejuif, France.|INSERM, U981 "Identification of Molecular Predictors and New Targets for Cancer Treatment", F-94805, Villejuif, France.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Loriot
authors.affiliation: Gustave Roussy, Université Paris-Saclay, Department of Medicine, F-94805, Villejuif, France.|INSERM, U981 "Identification of Molecular Predictors and New Targets for Cancer Treatment", F-94805, Villejuif, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: INSERM, U981 "Identification of Molecular Predictors and New Targets for Cancer Treatment", F-94805, Villejuif, France.|Gustave Roussy, Université Paris-Saclay, "Circulating Tumor Cells" Translational Platform, AMMICA CNRS UMS3655 - INSERM US23, F-94805, Villejuif, France.|Gustave Roussy, Université Paris-Saclay, Department of Biopathology, F-94805, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vielh
authors.affiliation: INSERM, U981 "Identification of Molecular Predictors and New Targets for Cancer Treatment", F-94805, Villejuif, France.|Gustave Roussy, Université Paris-Saclay, "Circulating Tumor Cells" Translational Platform, AMMICA CNRS UMS3655 - INSERM US23, F-94805, Villejuif, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Farace
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001706:Biopsy; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011446:Prospective Studies; D011467:Prostate / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D058028:Research Report
chemical_list: D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; D011944:Receptors, Androgen; C515553:TMPRSS2-ERG fusion protein, human
keywords: TMPRSS2-ERG translocation; androgen receptor; biopsy; circulating tumor cells; prostate cancer