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. 2016 Oct;10(8):1160-8.
doi: 10.1016/j.molonc.2016.05.005. Epub 2016 May 26.

Angiotensinogen and HLA Class II Predict Bevacizumab Response in Recurrent Glioblastoma Patients

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Free PMC article

Angiotensinogen and HLA Class II Predict Bevacizumab Response in Recurrent Glioblastoma Patients

Thomas Urup et al. Mol Oncol. .
Free PMC article

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Angiotensin; Anti-angiogenic treatment; Antigen presentation; Glioblastoma; Immune activation; Predictive model; Vascular normalization.

Figures

Figure 1
Figure 1
Flowchart for identification of differentially expressed genes associated with bevacizumab response. The number of genes shown in the right dotted box denotes the number of genes identified according to analytical steps.
Figure 2
Figure 2
Predictive model for response to bevacizumab. The linear curve is the threshold for angiotensinogen and human leukocyte antigen complex class II DQ alpha 1 (DCA1) gene expression, separating responders from non‐responders with a sensitivity of 66% and a specificity of 80%. X‐ and Y‐axis represent gene expression count data for the two genes normalized to reference genes.
Figure 3
Figure 3
Immunohistochemistry of glioblastomas with low and high angiotensinogen expression. Overviews (×50) of angiotensinogen stains are shown for two low (A–B) and two high (C–D) angiotensinogen gene expressing tumors. Tumor blood vessels (×400) of corresponding angiotensinogen stains are shown below for low (E–F) and high (G–H) angiotensinogen expression. Serial sections of corresponding samples were stained for CD31 (I–L), Collagen IV (M–P) and smooth muscle actin (Q–T) and blood vessels (×400) are shown below for tumors with low (I‐J, M−N, Q‐R) and high (K‐L, OP, ST) angiotensinogen gene expression.

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