VEGFR2多态性对贝伐珠单抗联合化疗一线治疗晚期非小细胞肺癌患者效果及安全性的影响

摘要

目的 探讨血管内皮生长因子受体2基因(VEGFR2)多态性对贝伐珠单抗联合化疗一线治疗晚期非小细胞肺癌(NSCLC)患者效果及安全性的影响.方法 纳入2013年1月至2017年1月郑州大学第一附属医院肿瘤科148例接受贝伐珠单抗联合化疗的晚期NSCLC患者,收集患者外周血标本用来进行VEGFR2多态性位点的基因分型,另外收集部分患者的活检癌组织标本用来进行VEGFR2mRNA表达测定.对基因型和其他变量以及VEGFR2 mRNA表达进行相关性分析.基因型和预后的单变量分析用Kaplan-Meier生存分析方法,并通过Cox风险比例模型对其他变量进行校正.结果 在VEGFR2的标记多态性位点中,只发现了889C＞T位点的临床意义.889C＞T位点位于该基因的编码区,在研究人群的基因分布频率为:CC型108例(72.97％),CT型36例(24.32％),TT型4例(2.71％),最小等位基因频率为0.15,三种基因型分布频率符合哈迪温伯格平衡(P=0.636).预后比较将TT型和CT型患者合并,对不同基因型患者进行疗效分析发现:CT/TT基因型患者和野生型CC型患者的客观缓解率分别为40.00％和48.15％(P=0.377).CT/TT和CC基因型患者的中位无进展生存期分别为6.1和8.7个月(P=0.002);两种基因型患者的中位总生存期分别为18.7和21.4个月(P=0.012).经过多变量校正889C＞T位点仍对无进展生存期有独立的影响意义(OR=1.96,P=0.014).安全性分析中未发现889C＞T位点和不良反应的相关性.在69例癌组织标本中,CT/TT基因型患者癌组织中VEGFR2mRNA的表达显著高于野生型CC型患者(P＜0.001).结论 VEGFR2 889C＞T位点可降低贝伐珠单抗联合化疗一线治疗晚期NSCLC患者的效果,对安全性无显著影响.%Objective To investigate the influence of polymorphisms of vascular endothelial growth factor receptor-2(VEGFR2) on clinical outcomes and safety of advanced non-small-cell lung cancer (NSCLC) treated by first line Bevacizumab plus chemotherapy regimens.Methods A total of 148 patients with advanced NSCLC who were treated by bevacizumab based first line regimens from January 2013 to January 2017 in the Department of Oncology of the First Affiliated Hospital of Zhengzhou University were included in this study.Peripheral blood and the biopsy tissue specimens of the NSCLC patients were collected for the genotyping of genetic variation and VEGFR2 mRNA expression,respectively.The association between genotype and other characteristics and VEGFR2 mRNA expression were analyzed.The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis,and multivariate analysis were adjusted by Cox regression analysis.Results Of the polymorphisms analyzed,only 889C＞T was of clinical significance.Located in the coding region,the prevalence of 889C＞T in VEGFR2 among the study population were as follows:CC genotype 108 cases (72.97％),CT genotype 36 cases (24.32％),TT genotype 4 cases (2.71％),minor allele frequency of 889C＞T was 0.15.The distribution of three genotypes was in accordance with Hardy-Weinberg Equilibrium (P=0.636).TT and CT genotype patients were merged in the comparison of clinical outcomes.The analysis of patients with different genotypes found that the objective response rates (ORR) of CT/TT genotypes and CC genotypes were 40.00％ and 48.15％ (P=0.377),respectively.And the median progression free survival (mPFS) of patients with CT/ TT genotype and CC genotype were 6.1 and 8.7 months,respectively,which was statistically significant (P=0.002).In terms of overall survival (OS),the median overall survival (mOS) of the two genotypes were 18.7 and 21.4 months (P=0.012),respectively.Adjusted in multivariate analysis,889C＞T were an independent factor for progression free survival (OR=1.96,P=0.014).No association between the 889C＞T and adverse reactions was found in the safety analysis.Of the 69 biopsy tissue specimens,gene expression analysis showed that the mRNA expression of VEGFR2 in cancer tissues of the patients with CT/TT genotypes were significantly higher than those of the CC genotype patients (P＜0.001).Conclusion The polymorphism 889C＞T of VEGFR2 may have worse influence on clinical outcomes of advanced NSCLC treated by first line bevacizumab plus chemotherapy regimens,while no significant impact on safety.