University Hospital Gasthuisberg, Leuven, Belgium.
J Clin Oncol. 2012 Jun 10;30(17):2119-27. doi: 10.1200/JCO.2011.39.9824. Epub 2012 May 7.
The AVAGAST study showed that adding bevacizumab to chemotherapy in patients with advanced gastric cancer improves progression-free survival and tumor response rate but not overall survival. To examine the hypothesis that angiogenic markers may have predictive value for bevacizumab efficacy in gastric cancer, AVAGAST included a prospective, mandatory biomarker program.
Patients with previously untreated, locally advanced or metastatic gastric cancer were randomly assigned to bevacizumab (n = 387) or placebo (n = 387) in combination with chemotherapy. Blood and tumor tissue samples were collected at baseline. Prespecified biomarkers included plasma vascular endothelial growth factor-A (VEGF-A), protein expression of neuropilin-1, and VEGF receptors-1 and -2 (VEGFR-1 and VEGFR-2). Correlations between biomarkers and clinical outcomes were assessed by using a Cox proportional hazards model.
Plasma was available from 712 patients (92%), and tumor samples were available from 727 patients (94%). Baseline plasma VEGF-A levels and tumor neuropilin-1 expression were identified as potential predictors of bevacizumab efficacy. Patients with high baseline plasma VEGF-A levels showed a trend toward improved overall survival (hazard ratio [HR], 0.72; 95% CI, 0.57 to 0.93) versus patients with low VEGF-A levels (HR, 1.01; 95% CI, 0.77 to 1.31; interaction P = .07). Patients with low baseline expression of neuropilin-1 also showed a trend toward improved overall survival (HR, 0.75; 95% CI, 0.59 to 0.97) versus patients with high neuropilin-1 expression (HR, 1.07; 95% CI, 0.81 to 1.40; interaction P = .06). For both biomarkers, subgroup analyses demonstrated significance only in patients from non-Asian regions.
Plasma VEGF-A and tumor neuropilin-1 are strong biomarker candidates for predicting clinical outcome in patients with advanced gastric cancer treated with bevacizumab.
AVAGAST 研究表明，在晚期胃癌患者中，将贝伐珠单抗联合化疗可提高无进展生存期和肿瘤缓解率，但不能提高总生存期。为了检验血管生成标志物可能对胃癌贝伐珠单抗疗效具有预测价值的假说，AVAGAST 纳入了一项前瞻性、强制性的生物标志物研究计划。
这项研究共纳入了 727 例（94%）可评估基线时肿瘤组织标本的患者，其中 387 例患者接受贝伐珠单抗联合化疗，387 例患者接受安慰剂联合化疗。 患者为既往未经治疗的局部晚期或转移性胃癌。 预先设定的生物标志物包括血浆血管内皮生长因子 A（VEGF-A）、神经纤毛蛋白-1 蛋白表达和血管内皮生长因子受体-1 和 -2（VEGFR-1 和 VEGFR-2）。 采用 Cox 比例风险模型评估生物标志物与临床结局的相关性。
712 例患者（92%）提供了血浆标本，727 例患者（94%）提供了肿瘤组织标本。 基线时血浆 VEGF-A 水平和肿瘤神经纤毛蛋白-1 表达被确定为贝伐珠单抗疗效的潜在预测标志物。 基线时血浆 VEGF-A 水平较高的患者总生存期改善趋势优于 VEGF-A 水平较低的患者（风险比 [HR]，0.72；95%置信区间 [CI]，0.57 至 0.93）（交互 P =.07）。 基线时神经纤毛蛋白-1 表达水平较低的患者总生存期改善趋势也优于神经纤毛蛋白-1 表达水平较高的患者（HR，0.75；95% CI，0.59 至 0.97）（交互 P =.06）。 对于这两个标志物，亚组分析仅在非亚洲地区的患者中显示出显著意义。
血浆 VEGF-A 和肿瘤神经纤毛蛋白-1 是预测接受贝伐珠单抗治疗的晚期胃癌患者临床结局的有前途的生物标志物候选物。
