title: Identification of Patients with Recurrent Glioblastoma Who May Benefit from Combined Bevacizumab and CCNU Therapy: A Report from the BELOB Trial.
abstract: The 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.
authors.affiliation: Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Lale
authors.initials: L
authors.lastname: Erdem-Eraslan
authors.affiliation: Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. Bioinformatics, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Youri
authors.initials: Y
authors.lastname: Hoogstrate
authors.affiliation: Bioinformatics, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Hina
authors.initials: H
authors.lastname: Naz-Khan
authors.affiliation: Bioinformatics, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stubbs
authors.affiliation: Bioinformatics, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van der Spek
authors.affiliation: Department of Urology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Böttcher
authors.affiliation: Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Ya
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Maurice
authors.initials: M
authors.lastname: de Wit
authors.affiliation: Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Walter
authors.initials: W
authors.lastname: Taal
authors.affiliation: Department of Medical Oncology, Medical Center Haaglanden, The Hague, the Netherlands.
authors.forename: Hendrika M
authors.initials: HM
authors.lastname: Oosterkamp
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Annemiek
authors.initials: A
authors.lastname: Walenkamp
authors.affiliation: Department of Oncology, St Elisabeth Ziekenhuis, Tilburg, the Netherlands.
authors.forename: Laurens V
authors.initials: LV
authors.lastname: Beerepoot
authors.affiliation: Department of Neurology, Catharina Hospital Eindhoven, the Netherlands.
authors.forename: Monique C J
authors.initials: MC
authors.lastname: Hanse
authors.affiliation: Department of Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Buter
authors.affiliation: Department of Internal Medicine, Isala Kliniek, Zwolle, the Netherlands.
authors.forename: Aafke H
authors.initials: AH
authors.lastname: Honkoop
authors.affiliation: Clinical Trial Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Bronno
authors.initials: B
authors.lastname: van der Holt
authors.affiliation: Clinical Trial Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: René M
authors.initials: RM
authors.lastname: Vernhout
authors.affiliation: Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Peter A E
authors.initials: PA
authors.lastname: Sillevis Smitt
authors.affiliation: Pathology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.affiliation: Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. p.french@erasmusmc.nl.
authors.forename: Pim J
authors.initials: PJ
authors.lastname: French
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008130:Lomustine / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D008130:Lomustine