本文選題：晚期非小細(xì)胞肺癌　切入點(diǎn)：酪氨酸激酶抑制劑　出處：《石河子大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：目的:探討EGFR-TKI主要代謝酶CYP3A4基因多態(tài)性與初治晚期NSCLC患者TKI療效及不良反應(yīng)的關(guān)系。方法:收集初治晚期NSCLC患者清晨空腹外周靜脈血液標(biāo)本,按照血液基因組DNA提取試劑盒的步驟提取外周血DNA后,采用直接測序法對外周血DNA中CYP3A4 Exon2、CYP3A4 Exon 10(CYP3A4*18)的基因多態(tài)性進(jìn)行檢測,收集入組患者臨床資料,并分析其與患者TKI療效及不良反應(yīng)的關(guān)系。結(jié)果:1.46例初治晚期NSCLC患者中,未發(fā)現(xiàn)CYP3A4 Exon 2基因突變位點(diǎn);CYP3A4*18基因突變率為63.0%(29/46)。2.CYP3A4*18基因多態(tài)性與初治晚期NSCLC患者性別、發(fā)病年齡、吸煙史、EGOG評分、TKI藥物種類、EGFR突變類型均無相關(guān)性,差異均無統(tǒng)計(jì)學(xué)意義(P0.05)。3.CYP3A4*18基因多態(tài)性與EGFR-TKI療效的相關(guān)性分析:對于客觀緩解率,CYP3A4*18基因突變型較野生型患者有較好趨勢(ORR:27.6%vs 23.5%),但無統(tǒng)計(jì)學(xué)差異(P=1.000);對于疾病控制率,CYP3A4*18基因突變型對比野生型患者(DCR:69.0%vs 70.6%),差異無統(tǒng)計(jì)學(xué)意義(P=0.908)。4.CYP3A4*18基因型與EGFR-TKI不良反應(yīng)的相關(guān)性分析:主要的不良反應(yīng)為皮疹和腹瀉。CYP3A4*18基因突變型對比野生型患者I~IV度皮疹(89.7%vs 35.3%)、腹瀉(51.7%vs 17.6%)發(fā)生率高,差異均有統(tǒng)計(jì)學(xué)意義(P0.001,P=0.049)。5.單因素分析PFS:入組患者平均PFS為6.5±3.3個月;女性PFS長于男性(7.3±3.4個月vs 6.0±3.1個月,χ2=8.138,P=0.004),無吸煙史患者長于有吸煙史的患者(8.0±2.3個月vs 3.4±2.9個月,χ2=6.000,P=0.014),差異均有統(tǒng)計(jì)學(xué)意義。6.Cox多因素分析結(jié)果示:性別(P=0.007)、吸煙史(P0.001)是影響PFS的獨(dú)立預(yù)后因素,而藥物、年齡、ECOG評分、EGFR突變類型和CYP3A4*18基因型等其他臨床特征均不是PFS的獨(dú)立預(yù)后因素。結(jié)論:CYP3A4*18基因多態(tài)性與初治晚期NSCLC患者TKI療效無相關(guān)性,但與其不良反應(yīng)相關(guān),檢測患者CYP3A4*18基因型對不良反應(yīng)的評估有意義。
[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 鹵3.3 months. The PFS of women was longer than that of men (7.3 鹵3.4 months vs 6.0 鹵3.1 months, 蠂 2 + 8.138%, P < 0.004), and that of patients with no smoking history was 8.0 鹵2.3 months vs 3.4 鹵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.
【學(xué)位授予單位】：石河子大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R734.2

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本文編號：1568641