Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bear-ing UGT1A1*28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of i...Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bear-ing UGT1A1*28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1*28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UG-T1A1*28 (TA 7/7), while UGT1A1*6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1*28 polymorphism (TA 6/7) as well as the UG-T1A1*6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinote-can dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1*28 and UGT1A1*6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinote-can. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1*28 and UGT1A1*6 polymorphisms.展开更多
Background: UGT1A1*28 polymorphism is associated with neutropenia and diarrhea in previous reports, while this study tried to investigate correlation with other toxicities like vomiting. Patients and Methods: This is ...Background: UGT1A1*28 polymorphism is associated with neutropenia and diarrhea in previous reports, while this study tried to investigate correlation with other toxicities like vomiting. Patients and Methods: This is a prospective case control study including all eligible cases of advanced colorectal cancer. The genotypes of UGT1A1*28 was assessed in the peripheral blood and/or in tissues by PCR. Patients were divided into two groups, Group 1: patients with no mutation, Group 2: patients with homo or hetero mutation. All patients received standard IFL regimen. Primary objectives were: 1) comparison between the 2 groups as regard vomiting, 2) assessment of the incidence of UGT1A1*28 polymorphism. Secondary objectives were: comparison between the 2 groups as regard: neutropenia, diarrhea, treatment delay, progressive diseases (PD), progression free survival (PFS) and overall survival (OS). Results: 46 cases of advanced colorectal cancer present to National Cancer Institute, Cairo University, aged between 19 and 71 years with a median age of 45 years were included and followed up during the period from September 2010 to January 2013 with a median follow-up of 9 months. UGT1A1*28 polymorphism was present in 20 patients (43%), of whom 15% are homozygous. Grade (II-IV) vomiting was found in 8.3% of Group 1 versus 52.5% of Group 2 (P = 0.01). Grade (II-IV) neutropenia was found in 20.8% of Group 1 versus 64.7% of Group 2 (P = 0.03). Grade (II-IV) diarrhea was found in 37.5% of patients of Group 1 and 27.5% of patients with Group 2. (P = 0.75). Treatment delay occurred in 29.16% of Group 1 versus 72.4% of Group 2 (P = 0.02). 25% of Group 1 showed PD versus 25% of Group 2 (P = 0.8). 1-year PFS was 19% in Group 1 versus 23% in Group 2 (P = 0.8) while there was a trend towards better OS in Group 1 (47% versus 35%) (P = 0.07). Conclusions: UGT1A1*28 polymorphism is present frequently (43%) in a Caucasian population and is associated with more vomiting, neutropenia and treatment delay.展开更多
This study attempts to discuss the correlation between UGT1A1＊28 as uridine diphosphate glucuronosyltransferase gene promoter and coding region Gly71 Arg gene polymorphism with neonatal hyperbilirubinemia of neonates...This study attempts to discuss the correlation between UGT1A1＊28 as uridine diphosphate glucuronosyltransferase gene promoter and coding region Gly71 Arg gene polymorphism with neonatal hyperbilirubinemia of neonates in Wuhan. A total of 168 neonates were divided into the hyperbilirubinemia group（case group, n=108） and healthy neonates group（control group, n=60）. Their DNA was obtained through blood extraction. The gene exon mutation of UGT1A1 was detected by Sanger sequencing, which revealed the relationship between UGT1A1＊28 and Gly71 Arg polymorphism with neonatal hyperbilirubinemia of neonates. The results showed that：（1） The frequency of UGT1A1＊28 allele mutation in the case group and the control group was 9.3% and 10% respectively, with the difference being not significant between the two groups（P〉0.05）.（2） The frequency of Gly71 Arg allele mutation in the case group and the control group was 35.1% and 21.7% respectively, with the difference being significant between the two groups（P〈0.01）.（3） The serum bilirubin level of Gly71 Arg mutant homozygous and heterozygous subgroups（n=66） in the case group was 302.7±31.4 μmol/L, which was significantly higher than 267.3±28.5 μmol/L of the wild subgroup（n=42）（P〈0.01）. It was suggested that the occurrence of neonatal hyperbilirubinemia of neonates in Wuhan was not associated with UGT1A1＊28 gene polymorphism, but closely with the Gly71 Arg gene polymorphism. Meanwhile, the Arg allele mutation was related to the degree of jaundice.展开更多
AIM: To examine the predictive effects of baseline serum bilirubin levels and UDP-glucuronosyltransferase(UGT) 1A1*28 polymorphism on response of colorectal cancer to irinotecan-based chemotherapy.METHODS: The present...AIM: To examine the predictive effects of baseline serum bilirubin levels and UDP-glucuronosyltransferase(UGT) 1A1*28 polymorphism on response of colorectal cancer to irinotecan-based chemotherapy.METHODS: The present study was based on a prospective multicenter longitudinal trial of Chinese metastatic colorectal cancer(m CRC) patients treated with irinotecan-based chemotherapy(NCT01282658). Baseline serum bilirubin levels, including total bilirubin(TBil) and unconjugated bilirubin(UBil), were measured,and genotyping of UGT1A1*28 polymorphism was performed. Receiver operating characteristic curve(ROC) analysis was used to determine cutoff values of TBil and UBil. The TBil values were categorized into > 13.0 or ≤ 13.0 groups; the UBil values were categorized into > 4.1 or ≤ 4.1 groups. Combining the cutoff values of TBil and UBil, which was recorded as Co Bil, patients were classified into three groups. The classifier's performance of UGT1A1*28 and Co Bil for predicting treatment response was evaluated by ROC analysis. Associations between response and Co Bil or UGT1A1*28 polymorphism were estimated using simple and multiple logistic regression models. RESULTS: Among the 120 m CRC patients, the serum bilirubin level was significantly different between the UGT1A1*28 wild-type and mutant genotypes. Patients with the mutant genotype had an increased likelihood of a higher TBil(P = 0.018) and a higher UBil(P = 0.014) level compared with the wild-type genotype. Patients were stratified into three groups based on Co Bil. Group 1 was patients with TBil > 13.0 and UBil > 4.1; Group 2 was patients with TBil ≤ 13.0 and UBil > 4.1; and Group 3 was patients with TBil ≤ 13.0 and UBil ≤ 4.1. Patients in Group 3 had more than a 10-fold higher likelihood of having a response in the simple(OR = 11.250; 95%CI: 2.286-55.367; P = 0.003) and multiple(OR = 16.001; 95%CI: 2.802-91.371; P = 0.002) analyses compared with the Group 1 individuals. Patients carrying the UGT1A1*28(TA)7 allele were 4-fold less likely to present with a response compared with the individuals harboring a homozygous(TA)6 genotype in the simple(OR = 0.267; 95%CI: 0.100-0.709; P = 0.008) and multiple(OR = 0.244; 95%CI: 0.088-0.678; P = 0.007) analyses. Classifier's performance of Co Bil and UGT1A1*28 were comparable.CONCLUSION: Co Bil and UGT1A1*28 are both independent biomarkers for predicting the treatment response of m CRC patients to irinotecan-based chemotherapy. After validation, Co Bil, an easily determinable index in the clinic, might be helpful in facilitating stratification of m CRC patients for individualized treatment options.展开更多
基金Supported by National Natural Science Foundation Project,Grants No.30971579Capital Development Foundation,No.2007-2029
文摘Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bear-ing UGT1A1*28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1*28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UG-T1A1*28 (TA 7/7), while UGT1A1*6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1*28 polymorphism (TA 6/7) as well as the UG-T1A1*6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinote-can dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1*28 and UGT1A1*6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinote-can. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1*28 and UGT1A1*6 polymorphisms.
文摘Background: UGT1A1*28 polymorphism is associated with neutropenia and diarrhea in previous reports, while this study tried to investigate correlation with other toxicities like vomiting. Patients and Methods: This is a prospective case control study including all eligible cases of advanced colorectal cancer. The genotypes of UGT1A1*28 was assessed in the peripheral blood and/or in tissues by PCR. Patients were divided into two groups, Group 1: patients with no mutation, Group 2: patients with homo or hetero mutation. All patients received standard IFL regimen. Primary objectives were: 1) comparison between the 2 groups as regard vomiting, 2) assessment of the incidence of UGT1A1*28 polymorphism. Secondary objectives were: comparison between the 2 groups as regard: neutropenia, diarrhea, treatment delay, progressive diseases (PD), progression free survival (PFS) and overall survival (OS). Results: 46 cases of advanced colorectal cancer present to National Cancer Institute, Cairo University, aged between 19 and 71 years with a median age of 45 years were included and followed up during the period from September 2010 to January 2013 with a median follow-up of 9 months. UGT1A1*28 polymorphism was present in 20 patients (43%), of whom 15% are homozygous. Grade (II-IV) vomiting was found in 8.3% of Group 1 versus 52.5% of Group 2 (P = 0.01). Grade (II-IV) neutropenia was found in 20.8% of Group 1 versus 64.7% of Group 2 (P = 0.03). Grade (II-IV) diarrhea was found in 37.5% of patients of Group 1 and 27.5% of patients with Group 2. (P = 0.75). Treatment delay occurred in 29.16% of Group 1 versus 72.4% of Group 2 (P = 0.02). 25% of Group 1 showed PD versus 25% of Group 2 (P = 0.8). 1-year PFS was 19% in Group 1 versus 23% in Group 2 (P = 0.8) while there was a trend towards better OS in Group 1 (47% versus 35%) (P = 0.07). Conclusions: UGT1A1*28 polymorphism is present frequently (43%) in a Caucasian population and is associated with more vomiting, neutropenia and treatment delay.
基金supported by the National Natural Science Foundation of China(No.81370099)
文摘This study attempts to discuss the correlation between UGT1A1＊28 as uridine diphosphate glucuronosyltransferase gene promoter and coding region Gly71 Arg gene polymorphism with neonatal hyperbilirubinemia of neonates in Wuhan. A total of 168 neonates were divided into the hyperbilirubinemia group（case group, n=108） and healthy neonates group（control group, n=60）. Their DNA was obtained through blood extraction. The gene exon mutation of UGT1A1 was detected by Sanger sequencing, which revealed the relationship between UGT1A1＊28 and Gly71 Arg polymorphism with neonatal hyperbilirubinemia of neonates. The results showed that：（1） The frequency of UGT1A1＊28 allele mutation in the case group and the control group was 9.3% and 10% respectively, with the difference being not significant between the two groups（P〉0.05）.（2） The frequency of Gly71 Arg allele mutation in the case group and the control group was 35.1% and 21.7% respectively, with the difference being significant between the two groups（P〈0.01）.（3） The serum bilirubin level of Gly71 Arg mutant homozygous and heterozygous subgroups（n=66） in the case group was 302.7±31.4 μmol/L, which was significantly higher than 267.3±28.5 μmol/L of the wild subgroup（n=42）（P〈0.01）. It was suggested that the occurrence of neonatal hyperbilirubinemia of neonates in Wuhan was not associated with UGT1A1＊28 gene polymorphism, but closely with the Gly71 Arg gene polymorphism. Meanwhile, the Arg allele mutation was related to the degree of jaundice.
基金Supported by the National Natural Science Foundation of China,No.81372664
文摘AIM: To examine the predictive effects of baseline serum bilirubin levels and UDP-glucuronosyltransferase(UGT) 1A1*28 polymorphism on response of colorectal cancer to irinotecan-based chemotherapy.METHODS: The present study was based on a prospective multicenter longitudinal trial of Chinese metastatic colorectal cancer(m CRC) patients treated with irinotecan-based chemotherapy(NCT01282658). Baseline serum bilirubin levels, including total bilirubin(TBil) and unconjugated bilirubin(UBil), were measured,and genotyping of UGT1A1*28 polymorphism was performed. Receiver operating characteristic curve(ROC) analysis was used to determine cutoff values of TBil and UBil. The TBil values were categorized into > 13.0 or ≤ 13.0 groups; the UBil values were categorized into > 4.1 or ≤ 4.1 groups. Combining the cutoff values of TBil and UBil, which was recorded as Co Bil, patients were classified into three groups. The classifier's performance of UGT1A1*28 and Co Bil for predicting treatment response was evaluated by ROC analysis. Associations between response and Co Bil or UGT1A1*28 polymorphism were estimated using simple and multiple logistic regression models. RESULTS: Among the 120 m CRC patients, the serum bilirubin level was significantly different between the UGT1A1*28 wild-type and mutant genotypes. Patients with the mutant genotype had an increased likelihood of a higher TBil(P = 0.018) and a higher UBil(P = 0.014) level compared with the wild-type genotype. Patients were stratified into three groups based on Co Bil. Group 1 was patients with TBil > 13.0 and UBil > 4.1; Group 2 was patients with TBil ≤ 13.0 and UBil > 4.1; and Group 3 was patients with TBil ≤ 13.0 and UBil ≤ 4.1. Patients in Group 3 had more than a 10-fold higher likelihood of having a response in the simple(OR = 11.250; 95%CI: 2.286-55.367; P = 0.003) and multiple(OR = 16.001; 95%CI: 2.802-91.371; P = 0.002) analyses compared with the Group 1 individuals. Patients carrying the UGT1A1*28(TA)7 allele were 4-fold less likely to present with a response compared with the individuals harboring a homozygous(TA)6 genotype in the simple(OR = 0.267; 95%CI: 0.100-0.709; P = 0.008) and multiple(OR = 0.244; 95%CI: 0.088-0.678; P = 0.007) analyses. Classifier's performance of Co Bil and UGT1A1*28 were comparable.CONCLUSION: Co Bil and UGT1A1*28 are both independent biomarkers for predicting the treatment response of m CRC patients to irinotecan-based chemotherapy. After validation, Co Bil, an easily determinable index in the clinic, might be helpful in facilitating stratification of m CRC patients for individualized treatment options.
