Objective: To investigate the clinical outcomes of advanced non-small cell lung cancer (NSCLC) treated by apatinib regimens and the influence of VEGFR2-906T>C polymorphism. Methods: A total of 109 patients with advanced NSCLC who were treated by apatinib after three and more lines from March 2015 to December 2017 in the Department of Oncology of the First Affiliated Hospital of Zhengzhou University were included in this study. Overall response rates were evaluated after 2 cycles, then progression free survival (PFS) and overall survival (OS) were investigated, and safety data were recorded. Additionally, peripheral blood and the biopsy tissue specimens of some NSCLC patients were collected for the genotyping of genetic variation and VEGFR2 gene mRNA expression, respectively. The association between genotype and other characteristics and VEGFR2 gene 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: The treatment effect could be evaluated in all the 109 patients, among them, complete remission (CR) 0 case, partial remission (PR) 19 case, stable disease (SD) 58 case, progression disease (PD) 32 case. Overall response rate (ORR) was 17.43%, disease control rate (DCR) was 70.64%, median PFS was 4.35 months, median OS was 8.35 months. Of the polymorphisms analyzed, only -906T>C was of clinical significance. The prevalence of -906T>C in VEGFR2 among the study population were as follows: TT genotype 64 cases (58.72%), TC genotype 37 cases (33.94%), CC genotype 8 cases (7.34%), minor allele frequency of -906T>C was 0.24. The distribution of three genotypes was in accordance with Hardy-Weinberg Equilibrium (P=0.418). CC and TC genotype patients were merged in the comparison of clinical outcomes. The analysis of patients with different genotypes found that the ORR of CC/TC genotypes and TT genotypes were 13.33% and 20.31% (P=0.377), respectively. And the median PFS of patients with CC/TC genotype and TT genotype were 3.25 and 5.35 months, respectively, which was statistically significant (P=0.007). In terms of OS, the median OS of the two genotypes were 7.35 and 9.15 (P=0.014), respectively. Adjusted in multivariate Cox regression analysis of PFS, TC/CC genotypes were an independent factor for PFS (OR=1.83, P=0.015). The correlation between -906T>C and adverse reactions was not found in the safety analysis. Additionally, of the 69 biopsy tissue specimens, gene expression analysis was conducted. And the results show that the mRNA expression of VEGFR2 in cancer tissues of the patients with CC/TC genotypes were significantly higher than those of the TT genotype patients (P<0.001). Conclusions: Apatinib is safe and effective for patients with advanced non-small cell in multiline therapy. VEGFR2 -906T>C CC/TC genotype has a worse effect on apatinib multiline treatment in patients with advanced NSCLC.
目的： 探讨阿帕替尼对晚期非小细胞肺癌（NSCLC）患者的疗效及血管内皮生长因子受体2基因（VEGFR2）-906T>C多态性位点的影响。 方法： 纳入2015年3月至2017年12月郑州大学第一附属医院肿瘤科接受阿帕替尼治疗的109例3线及以后的晚期NSCLC患者，治疗2个周期后评价有效率，随后评价无进展生存期（PFS）和总生存期（OS），并记录安全性数据。另外，收集患者外周血标本提取DNA，进行VEGFR2多态性位点的基因分型，收集部分患者的活检癌组织标本进行VEGFR2 mRNA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，通过Cox风险比例模型对其他变量进行校正。 结果： 109例患者均可评价疗效，其中完全缓解0例，部分缓解19例，疾病稳定58例，疾病进展32例。客观缓解率（ORR）为17.43%，疾病控制率为70.64%。中位PFS为4.35个月，中位OS为8.35个月。在VEGFR2多态性位点中，只发现-906T>C位点的临床意义，其基因型分布频率为：TT型64例（58.72%），TC型37例（33.94%），CC型8例（7.34%）；最小等位基因频率为0.24，三种基因型分布频率符合哈迪温伯格平衡（P=0.418）。CC/TC基因型患者和TT型患者ORR分别为13.33%和20.31%（P=0.377），中位PFS分别为3.25和5.35个月（P=0.007），中位OS分别为7.35和9.15个月（P=0.014）。CC/TC基因型对PFS有独立的影响意义（OR=1.83，P=0.015）。未发现-906T>C位点和不良反应的相关性。69例癌组织标本中，CC/TC基因型患者癌组织中VEGFR2 mRNA的表达显著高于TT型患者（P<0.001）。 结论： 阿帕替尼在晚期NSCLC患者后线治疗中安全有效，VEGFR2-906T>C位点CC/TC基因型的患者疗效较差。.
Keywords: Apatinib; Non-small cell lung cancer; Polymorphism, single nucleotide; Treatment outcome; Vascular endothelial growth factor receptor-2.