Angiotensinogen and HLA class II predict bevacizumab response in recurrent glioblastoma patients.
Bevacizumab combination therapy is among the most frequently used treatments in recurrent glioblastoma and patients who achieve response to bevacizumab have improved survival as well as quality of life. Accordingly, the aim of this study was to identify predictive biomarkers for bevacizumab response in recurrent glioblastoma patients.



The study included a total of 82 recurrent glioblastoma patients treated with bevacizumab combination therapy whom were both response and biomarker evaluable. Gene expression of tumor tissue was analyzed by using a customized NanoString platform covering 800 genes. Candidate gene predictors associated with response were analyzed by multivariate logistic and Cox regression analysis.



Two genes were independently associated with response: Low expression of angiotensinogen (2-fold decrease in AGT; OR = 2.44; 95% CI: 1.45-4.17; P = 0.0009) and high expression of a HLA class II gene (2-fold increase in HLA-DQA1; OR = 1.22; 95% CI: 1.01-1.47; P = 0.04). These two genes were included in a model that is able predict response to bevacizumab combination therapy in clinical practice. When stratified for a validated prognostic index, the predictive model for response was significantly associated with improved overall survival.



Two genes (low angiotensinogen and high HLA-class II expression) were predictive for bevacizumab response and were included in a predictive model for response. This model can be used in clinical practice to identify patients who will benefit from bevacizumab combination therapy.
Department of Radiation Biology, The Finsen Center, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: thomas.urup@regionh.dk.
Thomas
T
Urup
Department of Radiation Biology, The Finsen Center, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Signe Regner
SR
Michaelsen
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet, Building 208, DK-2800 Lyngby, Denmark; Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200, Denmark.
Lars Rønn
LR
Olsen
Department of Radiation Biology, The Finsen Center, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Anders
A
Toft
Department of Gastroenterology, Hvidovre Hospital, Kettegård Allé 30, DK-2650 Hvidovre, Denmark.
Ib Jarle
IJ
Christensen
Department of Radiation Biology, The Finsen Center, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Kirsten
K
Grunnet
Bioinformatics Centre, Department of Biology and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200, Denmark.
Ole
O
Winther
Department of Neuropathology, Center of Diagnostic Investigation, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Helle
H
Broholm
Department of Neurosurgery, The Neurocenter, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Michael
M
Kosteljanetz
Neuroinflammation Unit, BRIC, University of Copenhagen, DK-2100 Copenhagen, Denmark.
Shohreh
S
Issazadeh-Navikas
Department of Radiation Biology, The Finsen Center, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Department of Oncology, The Finsen Center, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Hans Skovgaard
HS
Poulsen
Department of Radiation Biology, The Finsen Center, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Department of Oncology, The Finsen Center, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Phase I Unit, Finsencenter, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Ulrik
U
Lassen
D000328:Adult; D000368:Aged; D000808:Angiotensinogen / Q000378:metabolism*; D000068258:Bevacizumab / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000145:classification / Q000188:drug therapy* / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D011379:Prognosis; D016896:Treatment Outcome; D055815:Young Adult
D014408:Biomarkers, Tumor; D000949:Histocompatibility Antigens Class II; D000808:Angiotensinogen; D000068258:Bevacizumab
Angiotensin; Anti-angiogenic treatment; Antigen presentation; Glioblastoma; Immune activation; Predictive model; Vascular normalization