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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Figure 1.

Trial profile. IHC = immunohistochemistry.

Figure 2.

Overview of candidate biomarkers for (A) progression-free survival and (B) overall survival. *Cox model including treatment, biomarker (dichotomized at median), interaction of treatment by biomarker, International Federation of Gynecology and Obstetrics (FIGO) stage and debulking status, and baseline performance status as covariates. The two-sided interaction test was performed using the Wald test. †Stratified analysis (using the two stratification factors used for patient random assignment: FIGO stage and debulking status, and baseline performance status). BEV = bevacizumab; CD = cluster of differentiation; CI = confidence interval; CT = chemotherapy; HR = hazard ratio; MVD = microvessel density; OS = overall survival; PFS = progression-free survival; PLA = placebo; tVEGF = tumor vascular endothelial growth factor; tVEGFR = tumor vascular endothelial growth factor receptor.

Figure 3.

Relationship between microvessel density and outcome (median cutoff). A) Progression-free survival and (B) overall survival are shown. The two-sided interaction test was performed using the Wald test. BEV = bevacizumab; CD = cluster of differentiation; CT = chemotherapy; MVD = microvessel density; OS = overall survival; PFS = progression-free survival; PLA = placebo.

Figure 4.

Microvessel density (MVD) analyses by quartile. A) Progression-free survival (PFS) by CD31 MVD quartile. B) Overall survival (OS) by MVD quartile. C) PFS and OS by MVD using Q3 as the cutoff. The two-sided interaction test was performed using the Wald test. *Cox model including treatment, biomarker (dichotomized at quartile 1, median, or quartile 3), interaction of treatment by biomarker, International Federation of Gynecology and Obstetrics (FIGO) stage and debulking status, and baseline performance status as covariates. †Stratified analyses (using the two stratification factors used for patient random assignment: FIGO stage and debulking status, and baseline performance status). BEI = biomarker-evaluable immunohistochemistry; BEV = bevacizumab; CD = cluster of differentiation; CI = confidence interval; CT = chemotherapy; HR = hazard ratio; OS = overall survival; PFS = progression-free survival; PLA = placebo; Q = quartile.

Figure 5.

Bevacizumab treatment effect by tumor vascular endothelial growth factor–A quartile. A) Progression-free survival. B) Overall survival. The two-sided interaction test was performed using the Wald test. *Cox model including treatment, biomarker (dichotomized at quartile 1, median, or quartile 3), interaction of treatment by biomarker, International Federation of Gynecology and Obstetrics (FIGO) stage and debulking status, and baseline performance status as covariates. †Stratified analysis (using the two stratification factors used for patient random assignment: FIGO stage and debulking status, and baseline performance status). BEI = biomarker-evaluable immunohistochemistry; BEV = bevacizumab; CI = confidence interval; CT = chemotherapy; HR = hazard ratio; NR = not reached; OS = overall survival; PFS = progression-free survival; PLA = placebo; Q = quartile.