Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece.
Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
Pharmacogenomics J. 2014 Jun;14(3):248-55. doi: 10.1038/tpj.2013.36. Epub 2013 Sep 24.
The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a phase II trial. This study evaluated weekly docetaxel, as first-line treatment for metastatic breast cancer. Existing data from in vitro and animal model experiments suggest that docetaxel at low doses has anti-angiogenic activity. DNA was extracted from blood samples of 86 patients participating in the trial. Genotyping was performed for selected single-nucleotide polymorphisms (SNPs; VEGF-2578, -1498, -1154, and +936). Moreover, due to the highly polymorphic nature of the studied areas, we were able to analyze additional registered SNPs. All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (42.9% vs 0.0%, P=0.048). Moreover, the VEGF-2578 AA genotype was associated with longer PFS compared with CC (hazard ratio (HR)=0.40; 95% confidence interval (CI) 0.17-0.98; pairwise P=0.0457). Patients with the VEGF-1190 GG genotype demonstrated shorter PFS compared with those with the alternative genotypes (GA and AA) combined (HR=3.85; 95% CI: 1.20-12.50; P=0.0224). In addition, the VEGF-2551/-2534 homozygous del18bp and VEGF-2430/-2425 homozygous ins1bp genotypes were associated with worse PFS compared with no deletion and no insertion, respectively (HR=2.49; 95% CI: 1.02-6.07; pairwise P=0.0442 and HR=2.57; 95% CI: 1.05-6.27; pairwise P=0.0385, respectively). Furthermore, patients with the VEGF-1498 CC genotype exhibited longer median OS compared with those with the alternatives genotypes (CT and TT) combined (HR=0.27; 95% CI: 0.08-0.89; P=0.0311). In multivariate analysis, the VEGF-2578 AA genotype retained its significance (P=0.0220) for PFS. Our results support the association of specific VEGF genotypes with clinical outcome in patients with metastatic breast cancer treated with a potentially anti-angiogenic regimen, such as weekly docetaxel. However, current results should be validated prospectively in larger cohorts.
本研究旨在评估血管内皮生长因子（VEGF）基因型与 II 期试验中转移性乳腺癌患者接受治疗的疗效之间的相关性。本研究评估了每周使用多西紫杉醇作为转移性乳腺癌的一线治疗药物。现有的体外和动物模型实验数据表明，低剂量的多西紫杉醇具有抗血管生成活性。从参加试验的 86 名患者的血样中提取 DNA。对选定的单核苷酸多态性（VEGF-2578、-1498、-1154 和+936）进行基因分型。此外，由于研究区域的高度多态性，我们能够分析额外的已注册的 SNP。评估了所有候选基因型与总生存期（OS）、无进展生存期（PFS）和反应率的相关性。与有反应者相比，无反应者的 VEGF-1154 GG 基因型更为常见（42.9%vs0.0%，P=0.048）。此外，与 CC 相比，VEGF-2578 AA 基因型与更长的 PFS 相关（危险比（HR）=0.40；95%置信区间（CI）0.17-0.98；配对 P=0.0457）。与其他基因型（GA 和 AA）组合相比，VEGF-1190 GG 基因型的患者 PFS 更短（HR=3.85；95%CI：1.20-12.50；P=0.0224）。此外，与没有缺失和插入的情况相比，VEGF-2551/-2534 纯合缺失 18bp 和 VEGF-2430/-2425 纯合插入 1bp 基因型与更差的 PFS 相关（HR=2.49；95%CI：1.02-6.07；配对 P=0.0442 和 HR=2.57；95%CI：1.05-6.27；配对 P=0.0385）。此外，与其他基因型（CT 和 TT）组合相比，VEGF-1498 CC 基因型的患者中位 OS 更长（HR=0.27；95%CI：0.08-0.89；P=0.0311）。在多变量分析中，VEGF-2578 AA 基因型保留了其在 PFS 方面的意义（P=0.0220）。我们的结果支持在接受潜在抗血管生成方案（如每周多西紫杉醇）治疗的转移性乳腺癌患者中，特定 VEGF 基因型与临床结局之间的相关性。然而，目前的结果应该在更大的队列中前瞻性地验证。
