KDR基因遗传变异对贝伐珠单抗一线治疗晚期非小细胞肺癌患者临床疗效的影响

doi:10.12092/j.issn.1009-2501.2018.07.013

摘要/Abstract

摘要：

目的: 本研究旨在探讨激酶插入区受体（KDR）基因遗传变异对贝伐珠单抗联合化疗治疗晚期非小细胞肺癌（NSCLC）患者疗效的影响。方法:本研究纳入135例一线接受贝伐珠单抗治疗的NSCLC患者，收集外周血及活检癌组织标本分别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:在KDR的标记多态性位点中，只发现了V297I位点的临床意义。V297I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99例（73.33%），CT型33例（24.44%），TT型3例（2.23%），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=0.898）。后期比较将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（ORR）分别为41.67%和47.47%（P=0.549）。CT/TT和CC基因型患者的中位无进展生存期（mPFS）分别为6.2和8.6个月，差异具有统计学意义（P=0.003）。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18.9和21.5个月，差异具有统计学意义（P=0.017）。对无进展生存期（PFS）构建多变量的Cox模型校正之后发现CT/TT基因型对PFS的影响仍然具有统计学意义（OR=1.95，P=0.019）。另外，进一步在68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，且差异具有统计学意义（P<0.01）。结论:在接受贝伐珠单抗治疗的非小细胞肺癌患者中，KDR基因V297I位点可能通过影响KDR基因的表达从而影响贝伐珠单抗一线治疗非小细胞肺癌患者的疗效。

关键词: 非小细胞肺癌, 贝伐珠单抗, 激酶插入区受体, 多态性, 疗效

Abstract:

AIM: To investigate the association between KDR gene polymorphism and the efficacy of bevacizumab in patients with advanced non-small cell lung cancer. METHODS: A total of 135 patients with advanced non-small cell lung cancer who were treated by bevacizumab based first line regimens 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 KDR gene expression, respectively. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, and multivariate analysis was adjusted by Cox regression analysis. RESULTS: Among the polymorphisms analyzed, only V297I was of clinical significance. Located in the coding region, the prevalence rates of V297I in KDR among the study population were as follows: CC genotype 99 cases (73.33%), CT genotype 33 cases (24.44%), TT genotype 3 cases (2.23%), and minor allele frequency of V297I was 0.14. The distribution of three genotypes was in accordance with Hardy-Weinberg Equilibrium (P=0.898). TT and CT genotype patients were merged in the comparison of clinical outcomes. The analysis of patients with different genotypes found that the overall response rate (ORR) of CT/TT genotypes were 41.67% and 47.67% (P=0.549), respectively. And the median progression free survival (mPFS) of patients with CT/TT genotype and CC genotype were 6.2 and 8.6 months, respectively, which was statistically significant (P=0.003). In terms of overall survival (OS), the median overall survival (mOS) of the two genotypes were 18.9 and 21.5 (P=0.017), respectively. Adjusted in multivariate Cox regression analysis of PFS, CT/TT genotypes were an independent factor for PFS (HR=1.95,P=0.019). Additionally, among the 68 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<0.01). CONCLUSION: Among non-small cell lung cancer patients treated by bevacizumab, the polymorphism V297I of KDR may impact the clinical outcomes of first line bevacizumab treatment by influencing the mRNA expression of KDR.

Key words: non-small cell lung cancer, bevacizumab, kinase insertion region receptor, polymorphism, clinical outcomes

中图分类号:

R734.2

王海霞，刘兴安，侯继院，龚哲，单国用. KDR基因遗传变异对贝伐珠单抗一线治疗晚期非小细胞肺癌患者临床疗效的影响[J]. 中国临床药理学与治疗学, 2018, 23(7): 802-808.

WANG Haixia, LIU Xingan, HOU Jiyuan, GONG Zhe, SHAN Guoyong. Influence of genetic variation of KDR on clinical outcomes of advanced NSCLC treated by first line bevacizumab regimens[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(7): 802-808.

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