EGAGenomicsYouri Hoogstratehttps://ega-archive.org/dacs/EGAC00001001686EGAEGA DAC EGAC00001001686EGAy.hoogstrate@erasmusmc.nlThe results from the randomized phase II BELOB trial provided evidence for a potential benefit of bevacizumab (beva), a humanized monoclonal antibody against circulating VEGF-A, when added to CCNU chemotherapy in patients with recurrent glioblastoma (GBM). In this study, we performed gene expression profiling (DASL and RNA-seq) of formalin-fixed, paraffin-embedded tumor material from participants of the BELOB trial to identify patients with recurrent GBM who benefitted most from beva+CCNU treatment. We demonstrate that tumors assigned to the IGS-18 or "classical" subtype and treated with beva+CCNU showed a significant benefit in progression-free survival and a trend toward benefit in overall survival, whereas other subtypes did not exhibit such benefit. In particular, expression of FMO4 and OSBPL3 was associated with treatment response. Importantly, the improved outcome in the beva+CCNU treatment arm was not explained by an uneven distribution of prognostically favorable subtypes as all molecular glioma subtypes were evenly distributed along the different study arms. The RNA-seq analysis also highlighted genetic alterations, including mutations, gene fusions, and copy number changes, within this well-defined cohort of tumors that may serve as useful predictive or prognostic biomarkers of patient outcome. Further validation of the identified molecular markers may enable the future stratification of recurrent GBM patients into appropriate treatment regimens.Identification of Patients with Recurrent Glioblastoma Who May Benefit from Combined Bevacizumab and CCNU Therapy: A Report from the BELOB Trial.Erdem-Eraslan Lale L, van den Bent Martin J MJ, Hoogstrate Youri Y, Naz-Khan Hina H, Stubbs Andrew A, van der Spek Peter P, Böttcher René R, Gao Ya Y, de Wit Maurice M, Taal Walter W, Oosterkamp Hendrika M HM, Walenkamp Annemiek A, Beerepoot Laurens V LV, Hanse Monique C J MC, Buter Jan J, Honkoop Aafke H AH, van der Holt Bronno B, Vernhout René M RM, Sillevis Smitt Peter A E PA, Kros Johan M JM, French Pim J PJWhole Transcriptome Shotgun Sequencing, RNA-seq.Therapy, grade IV adult astrocytic tumour, ccnu, NSC-79037, Ung2, Progress Reports, Giant Cell, Grade IV, Bevacizumab awwb, N-(2-chloroethyl)-N'-cyclohexyl-N-nitroso-, Astrocytomas, Client, adult glioblastoma multiforme, NSC79037, Investigative, NSC 79037, Investigative Report, primary glioblastoma multiforme, Summary Report, Research Reports, Avastin, Urea, ung2, glioblastoma, CCNU, Giant Cell Glioblastomas, Cecenu, E130318K11, Summary Reports, UDG2, glioblastoma multiforme, treatment, Glioblastoma, grade IV adult astrocytic tumor, Progress Report, spongioblastoma multiforme, udg2, Field, Glioblastomas, GBM, C86987, Ccnu, Giant Cell Glioblastoma, CILD29, Treatments, Bevacizumab-awwb, Astrocytoma, Progress, Glioblastoma Multiforme, Report, Field Reports, Grade IV Astrocytomas, Patient, Therapeutic, Reports, Clients, grade IV adult Astrocytic tumor, disease management, Therapies, Treatment, Grade IV Astrocytoma, CeeNU, Investigative Reports, Summary, Mvasi, Belustine, Field Report, Field.Glioma 1, l(1)G0410, Formol, beta-cat-arm, Biological Markers, Viral Marker, Materials, Surrogate Endpoints, ccnu, GLM, determination, NSC-79037, glial tumors, Laboratory, supply, 1200014M06Rik, Biochemical, Endpoint, Mixed Glioma, 6-tetrahydropyridine:oxygen N-oxidoreductase activity, 6720421I08Rik, Tumor, tumour of the neuroglia, Serum, Astrocytomas, beta-cat, Mutations, Transcript Expression Analysis, Laboratory Markers, D1Ertd532e, FMO activity, methionine S-oxidase, [M]Glioma NOS (morphologic abnormality), NSC 79037, Biological, Methanal, Parafilm, responsivity, tumor of the neuroglia, Gene Expression Monitorings, Urea, 2, A530055M08, 3, [M]Gliomas (morphologic abnormality), Analysis, Profilings, Event-Free Survival, Ziegler's enzyme, GD-VEGF, CCNU, ARM, Arm, beta-Cat, N-dimethylaniline, treatment, flavin-containing monooxygenase activity, dimethylaniline monooxygenase (N-oxide-forming) activity, glioma (morphologic abnormality), Analyses, TMAU, N, neuroglial tumour, Formaldehyd, Oxomethane, Neoplasm of the Neuroglia, Ccnu, Giant Cell Glioblastoma, Dm Arm, arm, Astrocytoma, Upper, genetic, Gene Expression Analysis, Immune, Markers, grade IV adult Astrocytic tumor, Viral Markers, disease management, tumour of neuroglia, Therapies, Gliomas (morphologic abnormality), Vascular Endothelial Growth Factor-A, Malignancies, FMOII, FAD-containing monooxygenase activity, flavin-containing monooxygenase, glioma, Mvasi, dimethylaniline N-oxidase activity, neoplasm of the neuroglia, Tumors, Therapy, Upper Arms, Glioma (except Nasal glioma, Viral, DMA oxidase activity, Surrogate Endpoint, Monoclonal Antibody, familial, Monitorings, RNA-seq, obsolete_glioma, Malignant Glioma, Biochemical Markers, beta-catenin/Arm, Giant Cell, N-(2-chloroethyl)-N'-cyclohexyl-N-nitroso-, Biologic Marker, results, Glioma-Derived Vascular Endothelial Cell Growth Factor, Gene Expression, rhabdomyosarcoma alveolar, NSC79037, KU-MEL-1, Benign, Monoclonal Antibodies, Marker, VEGF-A, primary glioblastoma multiforme, rhabdomyosarcoma 2, Avastin, Chemotherapy, Genetic Materials, Amplification Refractory Mutation System, Gliomas, Glial Cell Tumor, fixed, Genetic Material, methylphenyltetrahydropyridine N-monooxygenase activity, l(1)G0234, Glioblastoma, Pharmacotherapy, End Points, spongioblastoma multiforme, VPF, Transcriptome Profilings, GBM, Benign Neoplasms, Tumor of Neuroglia, INSDC_feature:gene, Immunologic, Laboratory Marker, EG:86E4.6, Treatments, dJ127D3.1, Malignant Neoplasms, NS21, HLFMO3, Gene Expression Analyses, Grade IV Astrocytomas, Patient, FMO1, flavin-containing monooxygenase form 1, Brachiums, FMO2, betacat, t12687 ALR Dm, Material, Biochemical Marker, FMO3, Tumor of the Neuroglia, FMO4, FMO5, human liver flavin-containing monooxygenase form 3, ALDR1, glial tumour, not neoplastic), Cistron, Expression Analysis, IGS, Glioma, inherited genetic, CeeNU, DmelCG11579, glial neoplasm, dimethylaniline oxidase activity, Vascular Endothelial Growth Factor, malignant (morphologic abnormality), other neoplasm, Glioma Derived Vascular Endothelial Cell Growth Factor, Vasculotropin, Neoplasms of Neuroglia, vegfa, Belustine, Glioma NOS, Clinical Markers, Ung2, chemotherapy, Clinical Marker, Neoplasms, neuroglial tumor, Benign Neoplasm, number, Gene, flavin monooxygenase activity, pharmacotherapy, Neuroglial Tumor, Pharmacotherapies, Grade IV, Malignant, rhabdomyosarcoma, presence, Chemotherapies, Vascular Permeability Factor, Gene Expression Profilings, Surrogate End Points, ORP3, Surrogate Markers, Antibody, mRNA Differential Displays, Gene Expression Pattern Analysis, brachium, Vascular, Survival, ung2, Whole Transcriptome Shotgun Sequencing, glioblastoma, FMO5 enzyme, Vascular permeability factor, vegf-a, Cecenu, Giant Cell Glioblastomas, E130318K11, 1-methyl-4-phenyl-1, Mixed Gliomas, Drug Therapies, Upper Arm, VEGF164, OSBP3, Permeability Factor, study, N-dimethylaniline N-oxidase, reactivity, Biomarker, AW111792, grade IV adult astrocytic tumor, Genetic, Clinical, Malignancy, Glioma NOS (morphologic abnormality), udg2, ORP-3, distribution, Biological Marker, FAD-monooxygenase, flavin-containing monooxygenase 5, C86987, Transcriptomics, Brachium, Event-Free, Glial Neoplasm, Transcript Expression, Transcriptome Analysis, CILD29, Monitoring, neuroglial neoplasm, Neoplasias, NADPH:oxygen oxidoreductase (N-oxide-forming), Glioblastoma Multiforme, Immunologic Markers, glial tumor, Formalin, Event Free Survival, Clients, flavin-containing monooxygenase 4, flavin-containing monooxygenase 3, flavin-containing monooxygenase 2, FMO-II, Grade IV Astrocytoma, [M]Gliomas, Expression Analyses, constitutitional genetic, l(1)2Bv, Tumors of Neuroglia, alveolar, Immunologic Marker, Biologic, Cancer, grade IV adult astrocytic tumour, Profiling, Transcriptome, ALR, Malignant Neoplasm, ARMS, malignant, Serum Markers, End Point, Bevacizumab awwb, Monoclonal, Cistrons, Client, RMS2, HEL-S-6, Progression Free Survival, neoplasm of neuroglia, flavin mixed function oxidase activity, Immune Marker, l(1)arm, Differential Display, transcription profiling, adult glioblastoma multiforme, count in organism, disease management., Transcript Expression Analyses, Arms, Surrogate End Point, chemical analysis, Neoplasm, DD3, FORMALIN, Mixed, supply and distribution, [M]Glioma NOS, mRNA Differential Display, gene expression profiling, UDG2, Biologic Markers, Progression-Free, glioblastoma multiforme, Glial Tumor, Gene Expression Monitoring, NOS (except Nasal glioma, Serum Marker, Vegf, Exhibit, Neuroglial Neoplasm, Transcriptome Profiling, mRNA, Neuroglial Neoplasms, Surrogate, Glial Cell, Endpoints, Malignant glioma, Glioblastomas, mixed-function amine oxidase activity, patient, Differential Displays, Cancers, l(1)G0192, FMO-I, Transcriptome Analyses, Bevacizumab-awwb, Methylene oxide, Surrogate Marker, upper extremity, Drug, CG11579, tumor of neuroglia, Neoplasm of Neuroglia, VEGF, no ICD-O subtype, Oxomethylene, Therapeutic, cardinality, Glial Cell Tumors, Malignant Gliomas, Treatment, pharmacologic therapy, assay, response, vegf, hereditary, Neoplasia, Immune MarkersfalseBoard considering access to BELOB RNA-seq dataData Access Committee EGAC00001001686EGAC00001001686960626762204EGAS00001004570EGAD00001006329