Santos Lucas Vieira dos, Cruz Marcelo Rocha, Lopes Gilberto de Lima, Lima Joao Paulo da Silveira Nogueira
Departamento de Oncologia Clinica, Hemomed Instituto de Oncologia e Hematologia, São Paulo, Brazil.
Breast Cancer Res Treat. 2015 Jun;151(3):481-9. doi: 10.1007/s10549-015-3410-7. Epub 2015 May 7.
Bevacizumab may improve outcomes of patients with breast cancer, but the absence of an established biomarker hampers patient selection and researchers´ ability to demonstrate a clear survival benefit. Its putative target, circulating VEGF-A, emerged as the main candidate and we sought to identify the relationship between VEGF-A levels and outcomes through systematic review. We searched electronic databases and meeting proceedings for randomized controlled trials (RCTs) comparing the addition of bevacizumab to standard chemotherapy for breast cancer. RCTs were included if outcomes were presented separately according to VEGF-A plasma levels. Random-effects model were applied to calculate the pooled hazard ratios for progression-free survival, event-free survival (EFS), comprising disease recurrence, progression or any-cause death, and overall survival (OS), with respective confidence intervals (95 % CI). High and low VEGF-A levels subgroups followed each trial definition, and results were compared using the interaction test. Heterogeneity was calculated using χ (2) test (I (2)). Three trials enrolled a total of 3748 patients. 1713 patients had baseline VEGF-A levels in plasma available for assessment and were included. One trial added bevacizumab in the adjuvant setting (N = 2591) and two on first-line metastatic disease with taxane-based therapy (N = 1160) There was no interaction between VEGF-A levels and study setting (adjuvant vs. first line therapy). Bevacizumab improved PFS of patients with above median VEGF-A plasma levels (HR 0.56; 95 % CI 0.43-0.73; P < 0.001; I (2) = 0 %), but not of those with below median VEGF-A levels (HR 0.89; 95 % CI 0.68-1.15; P = 0.37; I (2) = 0 %), with relevant differences between these two groups, P-for interaction = 0.02. The same happened with EFS (VEGF-A above median HR 0.62; 95 % CI 0.39-0.79; P < 0.001; I (2) = 11 %; below median HR 0.89; 95 % CI 0.71-1.14; P = 0.98; I (2) = 17 %; P-for interaction = 0.03). OS data were not available. VEGF-A level is a reasonable candidate biomarker for bevacizumab in the treatment of breast cancer. Further studies have to confirm its surrogacy in overall survival and in other scenarios including other anti-angiogenic therapies.
贝伐单抗可能会改善乳腺癌患者的治疗结果，但由于缺乏成熟的生物标志物，阻碍了患者的选择以及研究人员证明其具有明确生存获益的能力。其假定靶点循环血管内皮生长因子A（VEGF-A）成为主要候选指标，我们试图通过系统评价来确定VEGF-A水平与治疗结果之间的关系。我们检索了电子数据库和会议论文集，以查找比较在乳腺癌标准化疗基础上加用贝伐单抗的随机对照试验（RCT）。如果根据VEGF-A血浆水平分别呈现治疗结果，则纳入该RCT。应用随机效应模型计算无进展生存期、无事件生存期（EFS，包括疾病复发、进展或任何原因导致的死亡）和总生存期（OS）的合并风险比及其各自的置信区间（95%CI）。高VEGF-A水平和低VEGF-A水平亚组遵循各试验的定义，并使用交互检验比较结果。使用χ²检验（I²）计算异质性。三项试验共纳入3748例患者。1713例患者有血浆中可用于评估的基线VEGF-A水平并被纳入分析。一项试验在辅助治疗中加用贝伐单抗（N = 2591），两项试验在一线转移性疾病中联合紫杉类药物治疗（N = 1160）。VEGF-A水平与研究治疗背景（辅助治疗与一线治疗）之间无交互作用。贝伐单抗改善了VEGF-A血浆水平高于中位数患者的无进展生存期（HR 0.56；95%CI 0.43 - 0.73；P < 0.001；I² = 0%），但未改善VEGF-A水平低于中位数患者的无进展生存期（HR 0.89；95%CI 0.68 - 1.15；P = 0.37；I² = 0%），两组间存在显著差异，交互作用P值 = 0.02。无事件生存期也出现同样情况（VEGF-A高于中位数HR 0.62；95%CI 0.39 - 0.79；P < 0.001；I² = 11%；低于中位数HR 0.89；95%CI 0.71 - 1.14；P = 0.98；I² = 17%；交互作用P值 = 0.03）。总生存期数据不可用。VEGF-A水平是贝伐单抗治疗乳腺癌的一个合理候选生物标志物。进一步研究需证实其在总生存期以及包括其他抗血管生成治疗在内的其他情况下的替代作用。
