VEGF-121 plasma level as biomarker for response to anti-angiogenetic therapy in recurrent glioblastoma

Maurizio Martini,Francesco Pierconti,Quintino Giorgio D’Alessandris,Hany El-Sayed Marei,Lucia Ricci-Vitiani,Luigi Maria Larocca,Vincenzo Fiorentino,Ivana De Pascalis,Roberto Pallini

doi:10.1186/s12885-018-4442-2

Abstract

BackgroundVascular endothelial growth factor (VEGF) isoforms, particularly the diffusible VEGF-121, could play a major role in the response of recurrent glioblastoma (GB) to anti-angiogenetic treatment with bevacizumab. We hypothesized that circulating VEGF-121 may reduce the amount of bevacizumab available to target the heavier isoforms of VEGF, which are the most clinically relevant.MethodsWe assessed the plasma level of VEGF-121 in a brain xenograft model, in human healthy controls, and in patients suffering from recurrent GB before and after bevacizumab treatment. Data were matched with patients’ clinical outcome.ResultsIn athymic rats with U87MG brain xenografts, the level of plasma VEGF-121 relates with tumor volume and it significantly decreases after iv infusion of bevacizumab. Patients with recurrent GB show higher plasma VEGF-121 than healthy controls (p = 0.0002) and treatment with bevacizumab remarkably reduced the expression of VEGF-121 in plasma of these patients (p = 0.0002). Higher plasma level of VEGF-121 was significantly associated to worse PFS and OS (p = 0.0295 and p = 0.0246, respectively).ConclusionsQuantitative analysis of VEGF-121 isoform in the plasma of patients with recurrent GB could be a promising predictor of response to anti-angiogenetic treatment.

Highlights

Vascular endothelial growth factor (VEGF) isoforms, the diffusible VEGF-121, could play a major role in the response of recurrent glioblastoma (GB) to anti-angiogenetic treatment with bevacizumab
Plasma VEGF-121 in rats with intracranial xenografts of human U87MG cells Recently, we found that GB produces different VEGF isoforms and that the clinical and radiological response to bevacizumab is associated with low expression of VEGF-121 mRNA by the tumor tissue [19]
When we compare recurrent GB patients with higher VEGF-121 plasma level before the bevacizumab treatment with patients with lower level of VEGF-121, we found a significant association between lower level of this VEGF isoform and a better prognosis (OS, p = 0.0246; HR 15.34; 95% CI from 1.418 to 166.0; Progression-free survival (PFS), p = 0.0295; HR 16.23; 95% CI from 1.320 to 199.6; Fig. 3)

Summary

Introduction

Vascular endothelial growth factor (VEGF) isoforms, the diffusible VEGF-121, could play a major role in the response of recurrent glioblastoma (GB) to anti-angiogenetic treatment with bevacizumab. As GBs are highly vascularized cancers with high levels of VEGF, therapies that target angiogenesis have generated substantial interest [6] In this regard, a humanized antiVEGF monoclonal antibody, called bevacizumab, has recently been approved for the therapy of recurrent GB [6,7,8,9]. The initial optimism generated by the therapeutic results in the recurrent setting was tempered by recent Phase III trials showing no efficacy for treating newly diagnosed GBs [6, 10, 11] This data, together with the clinical evidence that a significant percentage of GBs treated with bevacizumab for an extended period of time undergoes transformation to a more biologically aggressive tumor, leads to uncertainty about the appropriate indications for the use of bevacizumab in GB [12, 13].

Methods

Results

Discussion

Conclusion