Identification of Patients with Recurrent Glioblastoma Who May Benefit from Combined Bevacizumab and CCNU Therapy: A Report from the BELOB Trial

Lale Erdem-Eraslan, Martin J van den Bent, Youri Hoogstrate, Hina Naz-Khan, Andrew Stubbs, Peter van der Spek, René Böttcher, Ya Gao, Maurice de Wit, Walter Taal, Hendrika M Oosterkamp, Annemiek Walenkamp, Laurens V Beerepoot, Monique C J Hanse, Jan Buter, Aafke H Honkoop, Bronno van der Holt, René M Vernhout, Peter A E Sillevis Smitt, Johan M KrosPim J French

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)525-34
Number of pages10
JournalCancer Research
Volume76
Issue number3
DOIs
Publication statusPublished - 1 Feb 2016

Cite this

Erdem-Eraslan, L., van den Bent, M. J., Hoogstrate, Y., Naz-Khan, H., Stubbs, A., van der Spek, P., ... French, P. J. (2016). Identification of Patients with Recurrent Glioblastoma Who May Benefit from Combined Bevacizumab and CCNU Therapy: A Report from the BELOB Trial. Cancer Research, 76(3), 525-34. https://doi.org/10.1158/0008-5472.CAN-15-0776