KDR基因遗传变异对贝伐珠单抗1线治疗晚期结直肠癌患者临床疗效的影响

The impact of genetic variation of KDR on clinical outcomes of advanced colorectal cancer patients treated by first line bevacizumab based regimens

目的 探讨激酶插入区受体（KDR）基因遗传变异对贝伐珠单抗治疗晚期结直肠癌患者疗效的影响.方法 本研究纳入118例1线接受贝伐珠单抗联合化疗的晚期结直肠癌患者,收集患者外周血及活检癌组织标本用来进行基因分型及表达测定.多态性位点的基因型和其他变量的相关性通过logistic回归模型进行分析.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 KDR基因889 C〉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86例（72.88％）,CT型30例（25.42％）,TT型2例（1.70％）,最小等位基因频率为0.14,三种基因型分布频率符合哈迪温伯格平衡（P=0.737）.不同基因型患者基线临床资料分布均衡.在疗效比较上,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（ORR）分别为34.38％和43.02％（P=0.395）.CT/TT和CC基因型患者的中位无进展生存期（mPFS）分别为7.5和9.7个月,差异有统计学意义（P=0.009）.在总生存期（OS）方面两种基因型患者的中位总生存期（mOS）分别为19.2和20.1个月,差异有统计学意义（P=0.025）.对PFS构建多变量的Cox模型校正之后发现CT/TT基因型患者较差的PFS影响仍然存在,差异有统计学意义（OR=1.88,P=0.023）.进一步在57例癌组织标本的表达分析中发现,CT/TT基因型患者相对于野生型的CC型患者,癌组织中KDR的表达明显较高,差异有统计学意义（P〈0.001）.结论 在接受贝伐珠单抗治疗的晚期结直肠癌患者中,KDR基因889 C〉T位点可能通过影响了KDR的表达从而影响了贝伐珠单抗1线治疗结直肠癌患者的疗效.

Objective To investigate the association between kinase insertion region receptor （KDR） gene genetic variation and the efficacy of bevacizumab in patients with advanced colorectal cancer （CRC） were investigated in this study.Methods 118 patients with advanced colorectal cancer who were treated by bevacizumab based first line regimens were included in this study .Peripheral blood and the biopsy tissue specimens of the CRC patients were collected for the genotyping of genetic variation and KDR gene expression, respectively.The univariate analysis of genotypes and prognosis was carried out by Kaplan -Meier survival analysis, and multivariate were adjusted by Cox regression analysis .Results Located in the coding region, the prevalence of 889 C 〉T in KDR among the study population were as follows ： CC genotype 86 cases （72.88%）, CT genotype 30 cases （25.42%）, TT genotype 2 cases （1.70%）, minor allele frequency of 889 C 〉T is 0.14.The distribution of three genotypes in accordance with Hardy -Weinberg Equilibrium （P =0.737） .There were no statistical differences in the distribution of the genotypes in baseline clinical data.TT and CT genotype patients were merged in the comparison of clinical outcomes .The clinical outcomes analysis of patients with different genotypes found that the objective response rates （ORR） of CT/TT genotypes were 34.38% and 43.02% （P =0.395）, respectively.And the median progression free survival （ PFS） of patients with CT /TT genotype and CC genotype were 7.5 and 9.7 months respectively, which was statistically significant （P =0.009）.In terms of overall survival （OS）, the median OS of the two genotypes were 19.3 and 20.1 （ P =0.025）, respectively.Adjusted in multivariate Cox regression analysis of PFS, CT/TT genotypes were an independent factor for PFS （OR =1.88, P =0.023）. Additionally, of the 57 biopsy tissue specimens, gene expression analysis was conducted.And the results showed that the expression of KDR in cancer tissues of the patients with CT /TT genotypes were significantly higher than those of the CC genotype patients （P 〈0.001）.Conclusion Among advanced colorectal cancer patients treated by bevacizumab , the polymorphism 889 C 〉T of KDR may impact the clinical outcomes of bevacizumab first line treatment by influencing the mRNA expression of KDR .