UGT1A1*28基因多态性联合SN-38药代动力学检测在进展期结直肠癌以伊立替康为基础的二线治疗中的应用

The application of UGT1A1*28 genotype combined with pharmacokinetics of SN-38 in the detection of irinotecan-based second-line chemotherapy in patients with advanced colorectal cancer

目的:回顾性分析2010年6月-2012年1月来自于多家医疗中心的69例进展期结直肠癌接受以伊立替康(irinotecan,CPT-11)为基础的二线联合化疗患者的尿苷二磷酸葡醛酰转移酶1A1(uridine diphosphate glucuronosyl transferase1A1,UGT1A1)*28基因多态性的表达情况,探讨UGT1A1*28(TA)6/(TA)6和(TA)6/(TA)7型患者接受CPT-11治疗后的葡萄糖醛酸化SN-38(SN-38 glucuronide,SN-38G)峰浓度和谷浓度与不良反应和疗效之间的关系。方法:这是一项多中心的回顾性研究。研究对象为2010年6月—2012年1月接受以CPT-11为基础的二线联合化疗的69例进展期结直肠癌患者。化疗之前,检测UGT1A1基因多态性;在CPT-11化疗1.5和49.0h时,应用高效液相色谱法检测SN-38血药浓度。观察近期疗效和不良反应,采用逐步回归分析法分析不同的UGT1A1*28基因型患者SN-38血药浓度与近期疗效和不良反应的关系。结果:69例患者中,(TA)6/(TA)6型45例(65.22%),(TA)6/(TA)7型24例(34.78%),未发现(TA)7/(TA)7型。CPT-11治疗后,(TA)6/(TA)7型患者的SN-38平均峰浓度和谷浓度均高于(TA)6/(TA)6型患者(P=0.001,P=0.000)。逐步回归分析结果显示,(TA)6/(TA)6型患者的SN-38峰浓度与无病生存期相关,SN-38谷浓度与近期疗效相关;而(TA)6/(TA)7型患者的SN-38峰浓度与骨髓抑制相关,SN-38谷浓度与治疗后血浆总胆红素水平和迟发性腹泻相关。(TA)6/(TA)6型患者SN-38峰浓度>43.20ng/mL和谷浓度>9.41ng/mL的中位无进展生存期优于SN-38峰浓度≤43.20ng/mL(6.0和4.6个月,χ2=25.57,P=0.00)和谷浓度≤9.41ng/mL的患者(6.0和5.2个月,χ2=6.81,P=0.01)。(TA)6/(TA)7型患者SN-38峰浓度>50.60ng/mL和谷浓度>16.29ng/mL的中位无进展生存期并不明显优于SN-38峰浓度≤50.60ng/mL(7.0和6.0个月,χ2=0.18,P=0.67)和谷浓度≤16.29ng/mL的患者(6.0和7.3个月,χ2=0.56,P=0.46),而骨髓抑制发生率(P=0.02,P=0.02)和迟发性腹泻发生率(P=0.04,P=0.03)较高。结论:进展期结直肠癌患者以UGT1A1*28(TA)6/(TA)6型和(TA)6/(TA)7型占绝大多数。对于(TA)6/(TA)6型患者,如果CPT-11化疗后SN-38峰浓度≤43.20ng/mL或谷浓度≤9.41ng/mL,可逐步增加CPT-11剂量以提高治疗效果;对于(TA)6/(TA)7型患者,如果CPT-11化疗后SN-38峰浓度>50.60ng/mL或谷浓度>16.29ng/mL者,可适当减少CPT-11剂量以减轻不良反应,而不影响化疗效果。

Objective： This multicenter study was conducted to retrospectively investigate the gene polymorphism of UGT1A1＊28 （uridine diphosphate glucuronosyl transferase 1A1＊28） in patients with advanced colorectal cancer receiving CPT-11 （irinotecan）-based second-line chemotherapy between June 2010 and January 2012. The associations between peak and valley concentrations of SN-38 with the efficacy and adverse effects of these patients carrying genotype （TA）6/（TA）6 or （TA）6/（TA）7 after chemotherapy with CPT-11. Methods： This was a retrospective multicenter study. Sixty-nine patients with advanced colorectal cancer receiving CPT-11 （irinotecan）-based second-line chemotherapy between June 2010 and January 2012 were collected. The frequency of TA repeats in the TATA box region of the UGT1A1 gene was detected before chemotherapy and the plasma concentration of SN-38 was detected by HPLC （high-performance liquid chromatography） at 1.5 h and 49.0 h after CPT-11 infusion. The short- term response and adverse effects were observed. The relationships of the concentration of plasma SN-38 with the short-term response and adverse effects of patients carrying genotype （TA）6/（TA）6 or （TA）6/（TA）7 were analyzed by stepwise regression analysis. Results： Of sixty-nine patients, （TA）6/（TA）6 genotype was identified in forty-five patients （65.22%）, （TA）6/（TA）7 genotype was identified in twenty-four patients （34.78%）, and （TA）7/（TA）7 genotype was identified in none patients. The average plasma peak and valley concentrations of SN-38 after CPT-11 infusion in patients carrying （TA）6/（TA）7 genotype were both significantly higher than those in patients carrying （TA）6/（TA）6genotype （P = 0.001, P = 0.000）. Stepwise regression analysis showed that for patients carrying （TA）6/（TA）6genotype, the peak plasma concentration of SN-38 was related with progression-free survival, and the valley plasma concentration of SN-38 was related with short-term response; for patients carrying （TA）6/（TA）7 genotype, the peak plasma concentration of SN-38 was related with bone marrow suppression, and the valley plasma concentration of SN-38 was related with plasma total bilirubin level and delayed diarrhea after CPT-11 infusion. For patients carrying （TA）6/（TA）6 genotype, the median progression-free survival of patients whose peak plasma concentration of SN-38 was above 43.20 ng/mL and the valley plasma concentration of SN-38 was above 9.41 ng/mLwas significantly prolonged as compared with that of the patients whose peak plasma concentration of SN-38 was less than or equal to 43.20 ng/mL （6.0 vs 4.6 months, χ2 = 25.57, P = 0.00） and the valley plasma concentration of SN-38 was less than or equal to 9.41 ng/mL （6.0 vs 5.2 months, χ2 = 6.81, P = 0.01）. For patients carrying （TA）6/（TA）7 genotype, the median progression-free survival of patients whose peak plasma concentration of SN-38 was above 50.60 ng/mL and the valley plasma concentration of SN-38 was above 16.29 ng/mL was not significantly prolonged as compared with that of the patients whose peak plasma concentration of SN-38 was less than or equal to 50.60 ng/ mL （7.0 vs 6.0 months,χ2 = 0.18, P = 0.67） and the valley plasma concentration of SN-38 was less than or equal to 16.29 ng/mL （6.0 vs 7.3 months, χ2 = 0.56, P = 0.46）; the rates of bone marrow suppression （P = 0.02, P = 0.02） and delayed diarrhea were higher （P = 0.04, P = 0.03）. Conclusion： The genotypes of （TA）6/（TA）6 and （TA）6/（TA）7 account for the majority of advanced colorectal cancer. For patients carrying （TA）6/（TA）6 genotype, CPT-11 dosage can be increased gradually to improve the response of patients with peak plasma concentration ofSN-38 ≤ 43.20 ng/mLor peak valley concentration ofSN-38 ≤ 9.41 ng/mL after CPT-11 infusion; for patients carrying （TA）6/（TA）7 genotype, CPT-11 dosage can be reduced appropriately to reduce serious adverse effects without affecting the response of patients with peak plasma concentration ofSN-38 〉 50.60 ng/mL or peak valley concentration ofSN-38 〉 16.29 ng/mL after CPT-11 infusion.