Bevacizumab May Differentially Improve Prognosis of Advanced Ovarian Cancer Patients with Low Expression of VEGF-A165b, an Antiangiogenic VEGF-A Splice Variant

Purpose: The identification of a robust IHC marker to predict the response to antiangiogenic bevacizumab in ovarian cancer is of high clinical interest. VEGF-A, the molecular target of bevacizumab, is expressed as multiple isoforms with pro-or antiangiogenic prop-erties, of which VEGF-A165b is the most dominant antiangiogenic isoform. The balance of VEGF-A isoforms is closely related to the angiogenic capacity of a tumor and may define its vulnerability to antiangiogenic 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 tis-sues from 413 patients of the ICON7 multicenter phase III trial, treated with standard platinum-based chemotherapy with or with-out bevacizumab, were probed for VEGF-A165b expression by IHC. Results: In patients with low VEGF-A165b expression, the addi-tion of bevacizumab to standard platinum-based chemotherapy significantly improved progression-free (HR: 0.727; 95% CI, 0.538- 0.984; P 1/4 0.039) and overall survival (HR: 0.662; 95% CI, 0.458- 0.958; P 1/4 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 1/4 0.002) and overall survival (HR: 0.527; 95% CI, 0.359-0.775; P 1/4 0.001), independently from established risk factors.Conclusions: We demonstrate for the first time that bevaci-zumab may differentially improve the prognosis of advanced ovarian cancer patients with low expression of VEGF-A165b, an antiangiogenic VEGF-A splice variant. We envision that this novel biomarker could be implemented into routine diag-nostics and may have direct clinical implications for guiding bevacizumab-related treatment decisions in advanced ovarian cancer patients.