• Carlos Bais, Barbara Mueller, Mark F Brady, Robert S Mannel, Robert A Burger, Wei Wei, Koen M Marien, Mark M Kockx, Amreen Husain, Michael J Birrer, and NRG Oncology/Gynecologic Oncology Group.
• Genentech Inc., South San Francisco, CA; F Hoffmann-La Roche Ltd, Basel, Switzerland; NRG Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; University of Oklahoma, Oklahoma City, OK; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Pennsylvania, Philadelphia, PA; Center for Cancer Research, Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; HistoGeneX NV, Antwerp, Belgium; Division of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
• J. Natl. Cancer Inst. 2017 Nov 1; 109 (11).

BackgroundCombining bevacizumab with frontline chemotherapy statistically significantly improved progression-free survival (PFS) but not overall survival (OS) in the phase III GOG-0218 trial. Evaluation of candidate biomarkers was an exploratory objective.MethodsPatients with stage III (incompletely resected) or IV ovarian cancer were randomly assigned to receive six chemotherapy cycles with placebo or bevacizumab followed by single-agent placebo or bevacizumab. Five candidate tumor biomarkers were assessed by immunohistochemistry. The biomarker-evaluable population was categorized into high or low biomarker-expressing subgroups using median and quartile cutoffs. Associations between biomarker expression and efficacy were analyzed. All statistical tests were two-sided.ResultsThe biomarker-evaluable population (n = 980) comprising 78.5% of the intent-to-treat population had representative baseline characteristics and efficacy outcomes. Neither prognostic nor predictive associations were seen for vascular endothelial growth factor (VEGF) receptor-2, neuropilin-1, or MET. Higher microvessel density (MVD; measured by CD31) showed predictive value for PFS (hazard ratio [HR] for bevacizumab vs placebo = 0.40, 95% confidence interval [CI] = 0.29 to 0.54, vs 0.80, 95% CI = 0.59 to 1.07, for high vs low MVD, respectively, P interaction = .003) and OS (HR = 0.67, 95% CI = 0.51 to 0.88, vs 1.10, 95% CI = 0.84 to 1.44, P interaction = .02). Tumor VEGF-A was not predictive for PFS but showed potential predictive value for OS using a third-quartile cutoff for high VEGF-A expression.ConclusionsThese retrospective tumor biomarker analyses suggest a positive association between density of vascular endothelial cells (the predominant cell type expressing VEGF receptors) and tumor VEGF-A levels and magnitude of bevacizumab effect in ovarian cancer. The potential predictive value of MVD (CD31) and tumor VEGF-A is consistent with a mechanism of action driven by VEGF-A signaling blockade.© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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