EGFR-TKI代谢酶CYP3A4基因多态性与初治晚期NSCLC患者疗效及不良反应的关系

发布时间：2018-03-05 04:04

本文选题：晚期非小细胞肺癌　切入点：酪氨酸激酶抑制剂　出处：《石河子大学》2017年硕士论文　论文类型：学位论文

【摘要】：目的:探讨EGFR-TKI主要代谢酶CYP3A4基因多态性与初治晚期NSCLC患者TKI疗效及不良反应的关系。方法:收集初治晚期NSCLC患者清晨空腹外周静脉血液标本,按照血液基因组DNA提取试剂盒的步骤提取外周血DNA后,采用直接测序法对外周血DNA中CYP3A4 Exon2、CYP3A4 Exon 10(CYP3A4*18)的基因多态性进行检测,收集入组患者临床资料,并分析其与患者TKI疗效及不良反应的关系。结果:1.46例初治晚期NSCLC患者中,未发现CYP3A4 Exon 2基因突变位点;CYP3A4*18基因突变率为63.0%(29/46)。2.CYP3A4*18基因多态性与初治晚期NSCLC患者性别、发病年龄、吸烟史、EGOG评分、TKI药物种类、EGFR突变类型均无相关性,差异均无统计学意义(P0.05)。3.CYP3A4*18基因多态性与EGFR-TKI疗效的相关性分析:对于客观缓解率,CYP3A4*18基因突变型较野生型患者有较好趋势(ORR:27.6%vs 23.5%),但无统计学差异(P=1.000);对于疾病控制率,CYP3A4*18基因突变型对比野生型患者(DCR:69.0%vs 70.6%),差异无统计学意义(P=0.908)。4.CYP3A4*18基因型与EGFR-TKI不良反应的相关性分析:主要的不良反应为皮疹和腹泻。CYP3A4*18基因突变型对比野生型患者I~IV度皮疹(89.7%vs 35.3%)、腹泻(51.7%vs 17.6%)发生率高,差异均有统计学意义(P0.001,P=0.049)。5.单因素分析PFS:入组患者平均PFS为6.5±3.3个月;女性PFS长于男性(7.3±3.4个月vs 6.0±3.1个月,χ2=8.138,P=0.004),无吸烟史患者长于有吸烟史的患者(8.0±2.3个月vs 3.4±2.9个月,χ2=6.000,P=0.014),差异均有统计学意义。6.Cox多因素分析结果示:性别(P=0.007)、吸烟史(P0.001)是影响PFS的独立预后因素,而药物、年龄、ECOG评分、EGFR突变类型和CYP3A4*18基因型等其他临床特征均不是PFS的独立预后因素。结论:CYP3A4*18基因多态性与初治晚期NSCLC患者TKI疗效无相关性,但与其不良反应相关,检测患者CYP3A4*18基因型对不良反应的评估有意义。
[Abstract]:Objective: to investigate the relationship between the polymorphisms of CYP3A4 gene of major metabolic enzymes of EGFR-TKI and the efficacy and adverse reactions of TKI in patients with advanced NSCLC. Methods: the fasting peripheral venous blood samples were collected from the patients with NSCLC in the early morning. The peripheral blood DNA was extracted according to the steps of the blood genomic DNA extraction kit. The gene polymorphism of CYP3A4 Exon2CYP CYP3A4 Exon 10 (CYP3A4) in peripheral blood DNA was detected by direct sequencing method, and the clinical data of the patients were collected. Results the mutation rate of CYP3A4P18 gene in 1.46 patients with advanced NSCLC was not found. The mutation rate of CYP3A4P18 gene was 63.0%. 2. The polymorphism of CYP3A4P18 gene was associated with the sex and age of late NSCLC patients. There was no correlation between EGFR mutation type and TKI drug type in smoking history and EGOG score. There was no statistical significance between the polymorphism of CYP3A4P18 gene and the curative effect of EGFR-TKI: there was a better trend for objective remission rate of CYP3A4P18 mutation type than in wild type patients, but there was no statistical difference between ORR: 27.6 vs 23.5T, but there was no statistical difference between P1.000 and CYP3A4P18 gene for disease control rate. There was no significant difference in the correlation between the genotype of CYP3A4O18 and the adverse effects of EGFR-TKI: the main adverse reactions were rash and diarrhea. CYP3A4A4F18 gene mutation type compared with wild type patients with IIV degree rash 89.7 vs 35.33M, abdominal side effects were lower than those of wild type patients with DCR: 69.0% vs 70.6%, no significant difference was found between the genotypes of CYP3A4M18 and the adverse effects of EGFR-TKI: the main adverse reactions were skin rash and diarrhea .CYP3A4H4 gene mutation type compared with wild type patients. The incidence of diarrhea is high, 51.7% vs 17.6%. The differences were statistically significant (P 0.001, P 0.049). 5. Univariate analysis showed that the average PFS was 6.5 卤3.3 months. The PFS of women was longer than that of men (7.3 卤3.4 months vs 6.0 卤3.1 months, 蠂 2 + 8.138%, P < 0.004), and that of patients with no smoking history was 8.0 卤2.3 months vs 3.4 卤2.9 months, 蠂 ~ 2 + 6.000 P < 0.014 4, the difference was statistically significant. 6. Cox multivariate analysis showed that sex P 0.007, smoking history P 0.001) were independent prognostic factors of PFS. Other clinical features, such as drug, age score, EGFR mutation type and CYP3A4*18 genotype, were not independent prognostic factors of PFS. Conclusion there is no correlation between the polymorphism of the 1 / CYP3A4P18 gene and the efficacy of TKI in patients with NSCLC at the early stage of treatment, but it is associated with adverse reactions. Detection of CYP3A4*18 genotypes in patients is significant in the assessment of adverse reactions.
【学位授予单位】：石河子大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R734.2

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