Tumor Microvessel Density as a Potential Predictive Marker for Bevacizumab Benefit: GOG-0218 Biomarker Analyses
Tumor Microvessel Density as a Potential Predictive Marker for Bevacizumab Benefit: GOG-0218 Biomarker Analyses
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DOI：
10.1093/jnci/djx066
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发表时间：
2017-11-01
影响因子：
10.3
通讯作者：
Birrer, Michael J.
中科院分区：
文献类型：
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作者：
Bais, Carlos;Mueller, Barbara;Birrer, Michael J.
背景：在 III 期 GOG-0218 试验中，贝伐珠单抗与一线化疗相结合在统计学上显着改善了无进展生存期 (PFS)，但未改善总生存期 (OS)。候选生物标志物的评估是一个探索性目标。方法：III期（不完全切除）或IV期卵巢癌患者被随机分配接受六个化疗周期的安慰剂或贝伐单抗，随后接受单药安慰剂或贝伐单抗。通过免疫组织化学评估了五种候选肿瘤生物标志物。使用中位数和四分位数截止值将生物标志物可评估人群分为高或低生物标志物表达亚组。分析了生物标志物表达和功效之间的关联。所有统计检验都是双向的。 结果：包含 78.5% 意向治疗人群的生物标志物可评估人群 (n-980) 具有代表性的基线特征和疗效结果。血管内皮生长因子 (VEGF) 受体 2、神经毡蛋白 1 或 MET 均未发现预后或预测相关性。较高的微血管密度（MVD；通过 CD31 测量）显示出对 PFS 的预测价值（贝伐单抗与安慰剂的风险比 [HR] - 0.40，95% 置信区间 [Cl] - 0.29 至 0.54，而高 MVD 与低 MVD 分别为 0.80，95% CI = 0.59 至 1.07 -P-交互=.003）和 OS（HR = 0.67，95% CI - 0.51 至 0.88，对比 1.10，95% CI = 0.84 至 1.44，P 交互作用 = 0.02)。肿瘤 VEGF-A 不能预测 PFS，但使用 VEGF-A 高表达的第三四分位数截止值显示出对 OS 的潜在预测价值。 结论：这些回顾性肿瘤生物标志物分析表明，血管内皮细胞（表达 VEGF 受体的主要细胞类型）密度与肿瘤 VEGF-A 水平以及贝伐珠单抗在卵巢癌中的作用强度之间呈正相关。 MVD (CD31) 和肿瘤 VEGF-A 的潜在预测价值与 VEGF-A 信号传导阻断驱动的作用机制一致。
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 [Cl] - 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% Cl = 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.