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 / 肿瘤

ABSTRACT

Objective: This multicenter study was conducted to retrospectively investigate the gene polymorphism of UGT 1A 1 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 UGT 1A 1 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 shortterm 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)6 genotype (P = 0.001, P = 0.000). Stepwise regression analysis showed that for patients carrying (TA)6/(TA)6 genotype, 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/mL was 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 of SN-38 ≤ 43.20 ng/mL or peak valley concentration of SN-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 of SN-38 > 50.60 ng/mL or peak valley concentration of SN-38 > 16.29 ng/mL after CPT-11 infusion. Copyright © 2013 by TUMOR.