Bevacizumab may differentially improve prognosis of advanced ovarian cancer patients with low expression of VEGF-A165b, an anti-angiogenic VEGF-A splice variant

Abstract Purpose: The identification of a robust immunohistochemical marker to predict the response to anti-angiogenic bevacizumab in ovarian cancer is of high clinical interest. VEGF-A, the molecular target of bevacizumab, is expressed as multiple isoforms with pro- or anti-angiogenic properties, of which VEGF-A165b is the most dominant anti-angiogenic isoform. The balance of VEGF-A isoforms is closely related to the angiogenic capacity of a tumor and may define its vulnerability to anti-angiogenic therapy. We investigated whether the expression of VEGF-A165b could be related to the effect of bevacizumab in advanced ovarian cancer patients. Experimental Design: Formalin-fixed paraffin-embedded (FFPE) tissues from 413 patients of the ICON7 multicenter phase III trial, treated with standard platinum-based chemotherapy with or without bevacizumab, were probed for VEGF-A165b expression by immunohistochemistry. Results: In patients with low VEGF-A165b expression, the addition of bevacizumab to standard platinum-based chemotherapy significantly improved progression-free (HR: 0.727, 95%CI=0.538 – 0.984; p=0.039) and overall survival (HR: 0.662, 95%CI=0.458 – 0.958; p=0.029). Multivariate analysis showed that the addition of bevacizumab in low VEGF-A165b expressing patients conferred significant improvements in progression-free survival (HR: 0.610, 95%CI=0.446 - 0.834; p=0.002) and overall survival (HR: 0.527, 95%CI=0.359 – 0.775; p=0.001), independently from established risk factors. Conclusions: We demonstrate for the first time that bevacizumab may differentially improve prognosis of advanced ovarian cancer patients with low expression of VEGF-A165b, an anti-angiogenic VEGF-A splice variant. We envision that this novel biomarker could be implemented into routine diagnostics and may have direct clinical implications for guiding bevacizumab-related treatment decisions in advanced ovarian cancer patients.