Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizurnab in metastatic colorectal cancer
Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizurnab in metastatic colorectal cancer
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DOI：
10.1200/jco.2005.01.5388
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发表时间：
2006-01-10
影响因子：
45.3
通讯作者：
Koeppen, H
中科院分区：
文献类型：
--
作者：
Jubb, AM;Hurwitz, HI;Koeppen, H
目的贝伐单抗（Bevacizumab）是抗血管内皮生长因子A（VEGF）的单克隆抗体。在转移性结直肠癌（mCRC）的关键试验中，贝伐单抗与一线伊立替康、氟尿嘧啶和亚叶酸（IFL）联合治疗显著延长了中位生存期。这些回顾性亚组分析的目的是评估VEGF，血小板反应蛋白-2（THBS-2），微血管密度（MVD）作为预后因素和/或预测因子的bevacizumab.Patients和方法在关键试验中，813例未经治疗的mCRC患者被随机分配接受IFL加贝伐单抗或安慰剂。在收集的312份组织样本中（285份原发灶，27份转移灶），278份（贝伐珠单抗153份，安慰剂125份）的结局数据可用。通过原位杂交（ISH）和免疫组织化学对组织芯片和全切片上的上皮和间质VEGF表达进行评估。通过ISH在组织微阵列上检测基质THBS-2表达。通过Chalkley计数定量VIVID。在回顾性亚组analysis.Results中，无论VEGF或THBS-2表达或MVD水平如何，贝伐珠单抗治疗患者的死亡风险估计风险比（HR）均< 1。高THBS-2评分的患者在贝伐单抗治疗后的生存率无显著改善（HR = 0.11; 95%CI，0.02至0.51）与评分较低的患者相比（HR = 0.65; 95% CI，0.41 - 1.02）;交互作用分析P = 0.22，VEGF或THBS-2表达和VIVID不是显著的预后因素。结论这些探索性分析表明，在mCRC患者中，贝伐单抗加IFL可改善与VEGF或THBS-2表达水平或MVD无关。
Purpose Bevacizumab is a monoclonal antibody to vascular endothelial growth factor-A (VEGF). In the pivotal trial in metastatic colorectal cancer (mCRC), addition of bevacizumab to first-line irinotecan, fluorouracil, and leucovorin (IFL) significantly prolonged median survival. The aim of these retrospective subset analyses was to evaluate VEGF, thrombospondin-2 (THBS-2), and microvessel density (MVD) as prognostic factors and/or predictors of benefit from bevacizumab.Patients and Methods In the pivotal trial, 813 patients with untreated mCRC were randomly assigned to receive IFL plus bevacizumab or placebo. Of 312 tissue samples collected (285 primaries, 27 metastases), outcome data were available for 278 (153 bevacizurnab, 125 placebo). Epithelial and stromal VEGF expression were assessed by in situ hybridization (ISH) and immunohistochemistry on tissue microarrays and whole sections. Stromal THBS-2 expression was examined by ISH on tissue microarrays. VIVID was quantified by Chalkley count. Overall survival was associated with these variables in retrospective subset analyses.Results In all subgroups, estimated hazard ratios (HRs) for risk of death were < 1 for bevacizumab-treated patients regardless of the level of VEGF or THBS-2 expression or MVD. Patients with a high THBS-2 score showed a nonsignificant improvement in survival following bevacizumab treatment (HR = 0.11; 95% CI, 0.02 to 0.51) compared to patients with a low score (HR = 0.65; 95% CI, 0.41 to 1.02); interaction analysis P = .22, VEGF or THBS-2 expression and VIVID were not significant prognostic factors.Conclusion These exploratory analyses suggest that in patients with mCRC addition of bevacizumab to IFL improves survival regardless of the level of VEGF or THBS-2 expression, or MVD.