Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma.
Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma.
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DOI：
10.18632/oncotarget.10898
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发表时间：
2016-10-25
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影响因子：
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通讯作者：
Ghiringhelli F
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作者：
Bertaut A;Truntzer C;Madkouri R;Kaderbhai CG;Derangère V;Vincent J;Chauffert B;Aubriot-Lorton MH;Farah W;Mourier KL;Boidot R;Ghiringhelli F
贝伐单抗用于治疗胶质母细胞瘤;然而，目前没有生物标志物预测其疗效。我们使用了一个探索性队列的患者接受放化疗，然后贝伐单抗或化疗复发（N = 265）。贝伐单抗的使用增加了中位总生存期（OS）18.7 vs 11.3个月，p = 0.0014）。在多变量分析中，年龄、初次手术、中性粒细胞计数、Karnofsky状态>70%和贝伐单抗给药是生存的独立预后因素。我们发现贝伐单抗的使用和基线中性粒细胞计数之间存在相互作用。中性粒细胞计数的临界值设定为6000/mm 3。只有中性粒细胞计数高的患者从贝伐单抗治疗中获益（17.3 vs 8.8个月p < 0.0001）。我们使用TEMAVIR试验的数据验证了这一结果，该试验测试了新辅助贝伐单抗联合伊立替康与放射化疗在胶质母细胞瘤一线治疗中的疗效。来自TCGA的转录组学数据强调了CSF 3表达，编码G-CSF的基因，中性粒细胞的生长因子，与VEGF-A依赖性血管生成相关。在另一个独立队列（BELOB试验）中，比较了洛莫司汀与洛莫司汀加贝伐珠单抗在复发时的效果，贝伐珠单抗仅使肿瘤中CSF 3高表达的患者受益。这些数据表明，只有贝伐珠单抗治疗前外周中性粒细胞计数较高的患者才能从这种治疗中受益。
Bevacizumab is used to treat glioblastoma; however, no current biomarker predicts its efficacy. We used an exploratory cohort of patients treated with the radiochemotherapy then bevacizumab or chemotherapy at recurrence (N = 265). Bevacizumab use increased median overall survival (OS) 18.7 vs 11.3 months, p = 0.0014). In multivariate analysis, age, initial surgery, neutrophil count, Karnofsky status >70% and bevacizumab administration were independent prognostic factors of survival. We found an interaction between bevacizumab use and baseline neutrophil count. The cut-off value for the neutrophil count was set at 6000/mm3. Only patients with a high neutrophil count benefited from the bevacizumab treatment (17.3 vs 8.8 months p < 0.0001). We validated this result using data from the TEMAVIR trial, which tested the efficacy of neoadjuvant bevacizumab plus irinotecan versus radiochemotherapy in the first-line treatment of glioblastoma. Transcriptomic data from TCGA underlined that CSF3 expression, the gene encoding G-CSF, the growth factor for neutrophils, correlated with VEGF-A-dependent angiogenesis. In another independent cohort (BELOB trial), which compared lomustine versus lomustine plus bevacizumab at recurrence, bevacizumab only benefited patients with high CSF3 expression in the tumor. These data suggest that only patients with a high peripheral neutrophil count before bevacizumab treatment benefited from this therapy.