Abstract
Patients with recurrent glioblastoma achieving response to bevacizumab combined with chemotherapy have clinical improvement and prolonged survival. High gene expression of angiotensinogen (AGT) is associated with a poor bevacizumab response. Because AGT expression is epigenetically regulated, we aimed to investigate whether AGT promoter methylation in tumor tissue predicts response to bevacizumab combination therapy in patients with recurrent glioblastoma. The study included 159 patients with recurrent glioblastoma, treated with bevacizumab combination treatment (training cohort, n = 77; validation cohort, n = 82). All patients could be evaluated for treatment response and biomarkers. DNA methylation of 4 CpG sites in the AGT promoter was measured using pyrosequencing. A model for nonresponse was established using logistic regression analysis. In the training cohort, lower methylation of each of the four CpG sites in the AGT promoter was significantly associated with nonresponse (all P < 0.05). Moreover, the mean methylation level of all four CpG sites was associated with an increased likelihood of not achieving response to bevacizumab combination therapy (twofold decrease: odds ratio = 3.01; 95% confidence interval: 1.41–6.44; P = 0.004). We developed a model for nonresponse in the training cohort, where a threshold of mean AGT promoter methylation levels was set to below 12%. The model could predict bevacizumab nonresponse with 96% specificity. Importantly, this predictor was also significantly associated with nonresponse in the validation cohort (P = 0.037). Taken together, our findings suggest that low AGT promoter methylation in tumor tissue predicts nonresponse to bevacizumab combination treatment in patients with recurrent glioblastoma. We have, thus, established and successfully validated a predictor for nonresponse that can be used to identify patients who will not benefit from bevacizumab combination therapy.
Highlights
Glioblastoma almost inevitable progress following standard treatment, comprising surgery, radiotherapy plus concomitant and adjuvant temozolomide (Stupp et al, 2005)
In this study of 77 recurrent glioblastoma patients, a low methylation of the CCAAT/ enhancer-binding protein (CEBP) binding region in the angiotensinogen gene (AGT) promoter was found significantly associated with a lack of response to bevacizumab combination treatment
A clinically useful model able to predict whether a patient is likely or not to achieve response to bevacizumab combination therapy was established and validated successfully in a cohort of 82 recurrent glioblastoma patients
Summary
Glioblastoma almost inevitable progress following standard treatment, comprising surgery, radiotherapy plus concomitant and adjuvant temozolomide (Stupp et al, 2005). For the prognostic favorable group of recurrent glioblastoma patients (defined as baseline ECOG performance status ≤ 1, prednisolone ≤ 25 mg, and unifocal disease) we have based on retrospective data (Urup et al, 2016a) observed an impressive difference in median overall survival (OS) of 10 months between responding and nonresponding patients. This highlights the importance of identifying patients benefitting from bevacizumab combination treatment based on prognostic factors and predictive biomarkers for bevacizumab efficacy. To date no validated predictive tumor biomarkers for bevacizumab efficacy have been identified
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