VEGF isoforms as outcome biomarker for anti-angiogenic therapy in recurrent glioblastoma.

The disappointing results from phase III trials evaluating bevacizumab on unselected patients with newly diagnosed glioblastoma (GBM) highlight the need of predictive biomarkers for response to anti-angiogenic treatment, particularly in the setting of recurrrent tumor. In a previous study, we prospectively selected patients for bevacizumab therapy based on the immunohistochemical overexpression of VEGF. To further address this issue, we have determined the expression levels of total VEGF and of its freely diffusible isoform VEGF-121 in 25 recurrent GBM patients treated with bevacizumab using real-time RT-PCR. We have found an inverse relationship between either VEGF-121 levels or the ratio VEGF-121/total VEGF and progression-free survival (PFS). Patients with total VEGF levels higher than the median value did not show any sustained response, i.e. a response with PFS > 12 mos. Moreover, all patients showing both total VEGF and the ratio VEGF-121/total VEGF lower than the median value had a sustained response. Therefore, low levels of total VEGF and of VEGF-121 are predictive of better response to bevacizumab. It is likely that the heavier isoforms of VEGF may the most relevant target of anti-angiogenic therapies and that the lightest VEGF-121 isoform may interfere with bevacizumab efficacy. The analysis of total VEGF and of its isoforms is a promising useful tool in selecting GBM patients for anti-angiogenic treatment and deserves prospective validation in larger cohorts.