Tumor Microvessel Density as a Potential Predictive Marker for Bevacizumab Benefit: GOG-0218 Biomarker Analyses

• Published in: JNCI : Journal of the National Cancer Institute Vol. 109; no. 11
• Main Authors: Bais, Carlos, Mueller, Barbara, Brady, Mark F, Mannel, Robert S, Burger, Robert A, Wei, Wei, Marien, Koen M, Kockx, Mark M, Husain, Amreen, Birrer, Michael J
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.11.2017
• Subjects: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab - therapeutic use; Biomarkers, Tumor - analysis; Biomarkers, Tumor - metabolism; Carboplatin - administration & dosage; Confidence Intervals; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Female; Humans; Intention to Treat Analysis; Microvessels; Middle Aged; Neuropilin-1 - metabolism; Ovarian Neoplasms - blood supply; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Paclitaxel - administration & dosage; Platelet Endothelial Cell Adhesion Molecule-1 - analysis; Proto-Oncogene Proteins c-met - metabolism; Retrospective Studies; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djx066

Combining 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. Patients 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. The 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. These 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.