Predictive biomarkers for bevacizumab response in recurrent glioblastoma patients

BACKGROUND: Bevacizumab (BEV) plus chemotherapy has shown high response rates in recurrent glioblastoma (GBM) and patients who achieve response have an improved overall survival as well as quality of life. Recent retrospective analysis of the randomized phase III trial, AVAglio, indicate that patients with the proneural GBM subtype have a survival benefit when treated with BEV in combination with standard treatment. However, no validated biomarkers able to predict BEV response have been identified and the biology reflecting a clinical BEV response is poorly understood. The primary objective of this study was to evaluate the predictive and prognostic value of GBM subtypes in recurrent GBM patients treated with BEV therapy. The secondary objective was to identify biomarkers able to predict response to BEV therapy in recurrent GBM patients. METHODS: A total of 90 recurrent GBM patients treated with BEV combination treatment according to a previously published treatment protocol were included. Inclusion criteria: BEV plus irinotecan treatment in the period between May 2005-2011; available GBM tissue (according to WHO); response evaluable (RANO). RNA from tumor tissue was analyzed by the NanoString platform covering 800 genes. Raw data was assigned to molecular subtypes for each of the samples using the PAMR classifier model, previously trained on the AVAglio dataset. In order to identify novel candidate biomarkers able to predict response, differentially expressed genes (fold-change difference > 1.5) between patients responding versus progressing on BEV were identified using a t-test. Biomarkers significantly (P<0.05) associated with response in multivariate logistic regression analysis adjusted for recently validated clinical prognostic factors were selected for the final predictive model. RESULTS: Molecular subtypes were not associated with response or overall survival. However, two novel independent predictive biomarkers (gene1 down-regulated and gene2 up-regulated in responders) of BEV response and overall survival were identified. Results will be presented.