UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study

The aim of the study was to investigate the associations between UGT1A1(*)28 genotype and (1) response rates, (2) febrile neutropenia and (3) dose intensity in patients with metastatic colorectal cancer treated with irinotecan. UGT1A1(*)28 genotype was determined in 218 patients receiving irinotecan (either first-line therapy with capecitabine or second-line as monotherapy) for metastatic colorectal cancer. TA(7) homozygotes receiving irinotecan combination therapy had a higher incidence of febrile neutropenia (18.2%) compared to the other genotypes (TA(6)/TA(6) : 1.5%; TA(6)/TA(7) : 6.5%, P=0.031). TA(7) heterozygotes receiving irinotecan monotherapy also suffered more febrile neutropenia (19.4%) compared to TA(6)/TA(6) genotype (2.2%; P=0.015). Response rates among genotypes were not different for both regimens: combination regimen, P=0.537; single-agent, P=0.595. TA(7) homozygotes did not receive a lower median irinotecan dose, number of cycles (P-values >or=0.25) or more frequent dose reductions compared to the other genotypes (P-values for trend; combination therapy: 0.62 and single-agent: 0.45). Reductions were mainly (>80%) owing to grade >or=3 diarrhoea, not (febrile) neutropenia. TA(7)/TA(7) patients have a higher incidence of febrile neutropenia upon irinotecan treatment, but were able to receive similar dose and number of cycles compared to other genotypes. Response rates were not significantly different.     

UGT1A1基因多态性与伊立替康临床用药安全性及疗效的关系

目的：研究 UGT1A1基因多态性与伊立替康治疗结直肠癌患者的不良反应及疗效之间的关系。方法：自外周血中抽提基因组 DNA,进行 PCR 扩增,应用直接测序法分析2012年3月至2013年3月,于我院行基因检测的65例结直肠癌患者 UGT1A1*28和 UGT1A1*6基因多态性的分布情况。并对这65例应用含伊立替康方案化疗的患者出现的不良反应及化疗疗效,进行观察记录,比较不同基因型间的差异。结果：65例患者中,UGT1A1*28野生型 TA6／6有49例（75．4％）,杂合突变型 TA6／7有14例（21．5％）,纯合突变型TA7／7有2例（3．1％）。UGT1A1*6野生型 G／G 有47例（72．3％）,杂合突变型 G／A 有15例（23．1％）,纯合突变型 A ／A 有3例（4．6％）。在以上65例结直肠癌患者中,UGT1A1基因启动子区28位点,TA6／6、TA6／7和TA7／7型,发生3级以上腹泻者分别为8．2％、37．5％;发生3级以上中性粒细胞减少者分别为28．6％、62．5％。UGT1A1基因启动子区6位点,G／G、G／A 和 A ／A 型,发生3级以上腹泻者分别为12．8％、44．4％;发生3级以上中性粒细胞减少者分别为14．9％、22．2％。各组之间疗效无统计学差异。结论：患者 UGT1A1*28和UGT1A1*6多态性分布基本一致,UGT1A1*28突变型可以使应用含伊立替康化疗患者发生3级以上腹泻和中性粒细胞减少的风险增加。UGT1A1*6突变型可增加3级以上腹泻的发生风险。因此,UGT1A1基因型的检测对伊立替康相关的不良反应有一定的预测作用,可提高用药安全性,在临床用药中起到了指导作用。     

Genetic polymorphisms of the UDP-glucuronosyltransferase 1A7 gene and irinotecan toxicity in Japanese cancer patients.

Irinotecan often causes unpredictably severe, occasionally fatal, toxicity involving leukopenia or diarrhea. It is converted by carboxyesterase to an active metabolite, SN-38, which is further conjugated and detoxified to SN-38-glucuronide by UDP-glucuronosyltransferase (UGT). We genotyped the UGT1A7 gene by direct sequencing analysis and polymerase chain reaction-restriction fragment length polymorphism in 118 cancer patients and 108 healthy subjects. All the patients had received irinotecan-containing chemotherapy and were evaluated to see whether the variant UGT1A7 genotype would increase the likelihood of severe toxicity of irinotecan consisting of grade 4 leukopenia and/or grade 3 or more diarrhea. Among the 26 patients with severe toxicity, the allele frequencies were 61.5% for UGT1A7 (*)1, 15.4% for UGT1A7 (*)2, and 23.1% for UGT1A7 (*)3. On the other hand, the frequencies were 63.6% for UGT1A7 (*)1, 15.8% for UGT1A7 (*)2, and 20.7% for UGT1A7 (*)3 among the 92 patients without severe toxicity. None of the 118 patients had UGT1A7 (*)4. Neither univariate analysis (odds ratio, 1.13; 95% confidential interval, 0.46 - 2.75) nor multivariate logistic regression analysis (odds ratio, 0.74; 95% confidential interval, 0.26 - 2.07) found any significant association between carrying at least one of the variant alleles and the occurrence of severe toxicity. The distribution of UGT1A7 genotypes in 108 healthy subjects was not significantly different from that in the patients (P = 0.99 and 0.86 for those with and without severe toxicity, respectively), but significantly less than that in Caucasians reported previously (P < 0.001). The results suggested that determination of UGT1A7 genotypes would not be useful for predicting severe toxicity of irinotecan.     

川东北地区人群结直肠癌患者UGT1A1*28基因多态性与伊立替康所致毒副反应的相关性

目的:观察结直肠癌患者UGT1A1*28基因多态性的分布频率,了解UGT1A1*28基因多态性与结直肠癌患者应用伊立替康联合5-氟尿嘧啶化疗毒副反应的相关性。方法:从384例接受伊立替康联合氟尿嘧啶一线化疗的晚期结直肠癌病例中采外周血提取DNA。采用PCR 法扩增目的基因片段,直接测序法分析UGT1A1*28基因多态性。临床观察并评价患者化疗毒副反应分级,统计分析UGT1A1*28基因表型与化疗毒副反应相关性。结果:全部 384例患者 UGT1A1*28基因多态性分布情况:TA6/6野生基因型287例(74.7％),TA6/7杂合基因型73例（19.0％）,TA7/7纯合基因型24例（6.3％）。化疗毒副反应和UGT1A1*28基因多态性进行临床单因素分析显示UGT1A1*28基因纯合型TA7/7、杂合型TA6/7与3-4度白细胞减少、中性粒细胞减少、腹泻、胆红素升高具有明显相关性（P<0.01）,UGT1A1*28基因纯合型TA7/7及杂合型TA6/7患者发生中性粒细胞减少的风险较UGT1A1*28基因野生型TA6/6患者高5.625倍（OR=5.625）。UGT1A1*28基因纯合型TA7/7和UGT1A1*28基因杂合型TA6/7患者发生腹泻的风险较UGT1A1*28基因野生型TA6/6患者高6.778倍（OR=6.778）。结论:UGT1A1*28基因纯合型TA7/7及杂合型TA6/7患者应用伊立替康化疗后发生重度中性粒细胞减少、重度腹泻的风险高于UGT1A1*28基因野生型TA6/6,为临床伊立替康用药选择、剂量调整、毒副反应的提前干预提供理论依据。     

Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis

Irinotecan unexpectedly causes severe toxicity of leukopenia or diarrhea. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Genetic polymorphisms of the UGT1A1 would affect an interindividual variation of the toxicity by irinotecan via the alternation of bioavailability of SN-38. In this case-control study, retrospective review of clinical records and determination of UGT1A1 polymorphisms were performed to investigate whether a patient with the variant UGT1A1 genotypes would be at higher risk for severe toxicity by irinotecan. All patients previously received irinotecan against cancer in university hospitals, cancer centers, or large urban hospitals in Japan. We identified 26 patients who experienced severe toxicity and 92 patients who did not. The relationship was studied between the multiple variant genotypes (UGT1A1*28 in the promoter and UGT1A1*6, UGT1A1*27, UGT1A1*29, and UGT1A1*7 in the coding region) and the severe toxicity of grade 4 leukopenia (< or =0.9 x 10(9)/liter) and/or grade 3 (watery for 5 days or more) or grade 4 (hemorrhagic or dehydration) diarrhea. Of the 26 patients with the severe toxicity, the genotypes of UGT1A1*28 were homozygous in 4 (15%) and heterozygous in 8 (31%), whereas 3 (3%) homozygous and 10 (11%) heterozygous were found among the 92 patients without the severe toxicity. Multivariate analysis suggested that the genotype either heterozygous or homozygous for UGT1A1*28 would be a significant risk factor for severe toxicity by irinotecan (P < 0.001; odds ratio, 7.23; 95% confidence interval, 2.52-22.3). All 3 patients heterozygous for UGT1A1*27 encountered severe toxicity. No statistical association of UGT1A1*6 with the occurrence of severe toxicity was observed. None had UGT1A1*29 or UGT1A1*7. We suggest that determination of the UGT1A1 genotypes might be clinically useful for predicting severe toxicity by irinotecan in cancer patients. This research warrants a prospective trial to corroborate the usefulness of gene diagnosis of UGT1A1 polymorphisms prior tb irinotecan chemotherapy.     

UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters

The Food and Drug Administration and Pfizer changed the package insert for irinotecan to include a patient's UGT1A1*28 genotype as a risk factor for severe neutropenia on the basis of the findings of four pharmacogenetic studies, which found that irinotecan-treated patients who were homozygous for the UGT1A1*28 allele had a greater risk of hematologic toxic effects than patients who had one or two copies of the wild-type allele (UGT1A1*1). Findings of subsequent irinotecan pharmacogenetic studies have been inconsistent. In a meta-analysis, we reviewed data presented in nine studies that included a total of 10 sets of patients (for a total of 821 patients) and assessed the association of irinotecan dose with the risk of irinotecan-related hematologic toxicities (grade III-IV) for patients with a UGT1A1*28/*28 genotype. The risk of toxicity was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 or UGT1A1*1/*28 genotype at both medium (odds ratio [OR] = 3.22, 95% confidence interval [CI] = 1.52 to 6.81; P = .008) and high (OR = 27.8, 95% CI = 4.0 to 195; P = .005) doses of irinotecan. However, risk was similar at lower doses (OR = 1.80, 95% CI = 0.37 to 8.84; P = .41). Low doses of irinotecan (100-125 mg/m2) are in the commonly used therapeutic range. The risk of experiencing irinotecan-induced hematologic toxicity for patients with a UGT1A1*28/*28 genotype thus appears to be a function of the dose of irinotecan administered.     

UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities without affecting treatment outcome and survival in patients with metastatic colorectal carcinoma

BACKGROUND: It is known that the uridine-diphosphoglucuronosyl transferase 1A1 (UGT1A1)*28 polymorphism reduces UGT1A1 enzyme activity, which may lead to severe toxicities in patients who receive irinotecan. This study was conducted to assess the influence of this polymorphism on the efficacy and toxicity of irinotecan treatment in Chinese patients with metastatic colorectal carcinoma (CRC). METHODS: In total, 128 patients with metastatic CRC who had received previous treatment with irinotecan plus 5-fluorouracil/leucovorin were analyzed retrospectively. Genomic DNA samples were obtained from patients' leukocytes, and genotypes were determined by analyzing the sequence of TATA boxes in the UGT1A1 gene. The influence of the UGT1A1*28 polymorphism on toxicity and treatment outcome was analyzed. RESULTS: Approximately 20% of patients were identified with the UGT1A1*28 polymorphism, including 15.6% (n = 20 patients) with the thymine-adenine (TA)6/TA7 genotype and 4.7% (n = 6 patients) with the TA7/TA7 genotype. The remaining 79.7% of patients (n = 102) had wild type TA6/TA6. Marked increases in grade 3 or 4 neutropenia (53.8% vs 4.9%; P < .01), neutropenic fever (38.5% vs 3.9%; P < .01), diarrhea (26.9% vs 5.9%; P < .01), and pretreatment bilirubin level (23.1% vs 8.8%; P = .04) were observed in patients who had the TA6/TA7 or TA7/TA7 genotypes. Patients' pretreatment bilirubin levels correlated well with irinotecan-induced neutropenia (P < .01). It was noted that, although the requirement for irinotecan dose reduction was significantly greater in patients who had this genetic variant (42.3% vs 12.7%; P < .01), it did not affect the response rate to irinotecan-based chemotherapy (42.3% vs 45.1%; P = .80), and it did not significantly affect progression-free survival (10 months vs 11 months; P = .94) or overall survival (19 months vs 18 months; P = .84). CONCLUSIONS: The current data suggested that the UGT1A1*28 polymorphism may be a key determinant for predicting irinotecan-induced severe toxicities without affecting treatment outcome for patients with metastatic CRC. Further prospective studies are warranted for using this polymorphism to optimize irinotecan-based chemotherapy.     

UGT1A1基因多态性与伊立替康治疗结直肠癌不良反应的关系

背景与目的：尿苷二磷酸葡萄糖醛酸转移酶1A1(uridine diphosphoglucu-ronosyltransferase 1A1,UGTlA1)是伊立替康代谢关键酶,其活性受基因多态性影响显著。本研究探讨结直肠癌患者中,UGT1A1*28和UGT1A1*6基因多态性与伊立替康治疗相关不良反应之间的关系。方法：入组2013年4月—2013年12月于复旦大学附属中山医院肿瘤内科接受治疗的消化道恶性肿瘤患者160例。抽提外周血中基因组DNA,分别采用STR方法和Sanger测序法,检测UGT1A1*28和UGT1A1*6基因型,分析UGT1A1基因多态性分布情况。对其中82例化疗方案中含伊立替康的结直肠癌患者进行随访,记录不良反应发生情况和严重程度,比较不同基因型患者之间的差异。结果：160例消化道肿瘤患者中,UTG1A1*28(启动子TATA盒区域TA重复次数)野生型TA6/6124例(77.5%);杂合子TA6/7 33例(20.5%);纯合子TA7/7 3例(2.0%)。UGT1A1*6位点(211G>A)野生型GG 105例(65.6%),杂合子GA 48例(30.0%);纯合子AA 7例(4.4%)。82例化疗方案中含伊立替康的结直肠癌患者中,*28基因型(TA6/7和TA7/7)显著增加发生3级以上中性粒细胞减少的风险(58.3% vs 0.0%,P<0.001),并增加整体不良反应发生率(76.0% vs 45.6%,P<0.001);*6基因型(GA和AA)、年龄、性别、化疗方案和伊立替康相关不良反应发生无显著相关性。结论：接受伊立替康化疗的结直肠癌患者,UGT1A1*28位点多态性显著增加中性粒细胞减少发生的风险,可预测伊立替康引起的骨髓抑制性不良反应,辅助临床选择合适的化疗方案。     

中国人尿苷二磷酸葡糖苷酸转移酶1A基因多态性与伊立替康毒性的相关性

目的评价伊立替康(CVT-11)联合5-氟尿嘧啶(5-Fu)和亚叶酸钙(LV)治疗晚期大肠癌的毒性与尿苷二磷酸葡糖苷酸转移酶1A(UGT1A)基因多态性的相关性。方法收集70例晚期大肠癌患者及健康志愿者的外周血,提取基因组DNA,PCR法扩增目的基因片段,直接测序法分析UGT1A基因多态性,并与毒性进行相关性分析。结果70例晚期大肠癌患者的3～4度中性粒细胞减少发生率为20.O%(14/70);2～4度迟发性腹泻发生率为22.9%(16/70),其中3-4度迟发性腹泻率仅为5.7%(4/70)。UGT1A1*28的野生基因型TA6/6患者的2-4度迟发性腹泻发生率为15.7%,低于TA6/7和TA7/7基因型的患者(P=0.027)。健康人群和大肠癌患者UGT1A基因家族中各个基因多态性的分布无差别。结论UGT1A1*28的野生基因型TA6/6在中国人中分布频率较高,这也是CPT-11为主方案治疗晚期大肠癌发生严重迟发性腹泻较少的原因。     

Genotype-directed, dose-finding study of irinotecan in cancer patients with UGT1A1*28 and/or UGT1A1*6 polymorphisms

Irinotecan-induced severe neutropenia is associated with homozygosity for the UGT1A1*28 or UGT1A1*6 alleles. In this study, we determined the maximum-tolerated dose (MTD) of irinotecan in patients with UGT1A1 polymorphisms. Patients who had received chemotherapy other than irinotecan for metastatic gastrointestinal cancer were enrolled. Patients were divided into three groups according to UGT1A1 genotypes: wild-type (*1/*1); heterozygous (*28/*1, *6/*1); or homozygous (*28/*28, *6/*6, *28/*6). Irinotecan was given every 2 weeks for two cycles. The wild-type group received a fixed dose of irinotecan (150 mg/m(2)) to serve as a reference. The MTD was guided from 75 to 150 mg/m(2) by the continual reassessment method in the heterozygous and homozygous groups. Dose-limiting toxicity (DLT) and pharmacokinetics were evaluated during cycle 1. Of 82 patients enrolled, DLT was assessable in 79 patients (wild-type, 40; heterozygous, 20; and homozygous, 19). Dose-limiting toxicity occurred in one patient in the wild-type group, none in the heterozygous group, and six patients (grade 4 neutropenia) in the homozygous group. In the homozygous group, the MTD was 150 mg/m(2) and the probability of DLT was 37.4%. The second cycle was delayed because of neutropenia in 56.3% of the patients given the MTD. The AUC(0-24 h) of SN-38 was significantly greater (P < 0.001) and more widely distributed in the homozygous group. Patients homozygous for the UGT1A1*28 or UGT1A1*6 allele can receive irinotecan in a starting dose of 150 mg/m(2), but many required dose reductions or delayed treatment in subsequent cycles. UMIN Clinical Trial Registration number: UMIN000000618.     

Genetic Polymorphisms of the UDP-Glucuronosyltransferase 1A7 Gene and Irinotecan Toxicity in Japanese Cancer Patients

Irinotecan often causes unpredictably severe, occasionally fatal, toxicity involving leukopenia or diarrhea. It is converted by carboxyesterase to an active metabolite, SN–38, which is further conjugated and detoxified to SN–38–glucuronide by UDP-glucuronosyltransferase (UGT). We genotyped the UGT1A7 gene by direct sequencing analysis and polymerase chain reaction-restriction fragment length polymorphism in 118 cancer patients and 108 healthy subjects. All the patients had received irinotecan-containing chemotherapy and were evaluated to see whether the variant UGT1A7 genotype would increase the likelihood of severe toxicity of irinotecan consisting of grade 4 leukopenia and/or grade 3 or more diarrhea. Among the 26 patients with severe toxicity, the allele frequencies were 61.5% for UGT1A7*1 , 15.4% for UGT1A7*2 , and 23.1% for UGT1A7*3. On the other hand, the frequencies were 63.6% for UGT1A7*1 , 15.8% for UGT1A7*2 , and 20.7% for UGT1A7*3 among the 92 patients without severe toxicity. None of the 118 patients had UGT1A7*4. Neither univariate analysis (odds ratio, 1.13; 95% confidential interval, 0.46–2.75) nor multivariate logistic regression analysis (odds ratio, 0.74; 95% confidential interval, 0.26–2.07) found any significant association between carrying at least one of the variant alleles and the occurrence of severe toxicity. The distribution of UGT1A7 genotypes in 108 healthy subjects was not significantly different from that in the patients ( P =0.99 and 0.86 for those with and without severe toxicity, respectively), but significantly less than that in Caucasians reported previously ( P <0.001). The results suggested that determination of UGT1A7 genotypes would not be useful for predicting severe toxicity of irinotecan.     

伊立替康联合顺铂或5-FU治疗UGT1A1*28野生型TA6/6患者不良反应的比较

目的：比较尿苷二磷酸葡萄糖醛酸转移酶1A1（UGT1A1）*28启动子为野生型的TA6/6患者在使用伊立替康（irinotecan,CPT-11）联合顺铂与CPT-11联合5-FU/亚叶酸钙治疗时不良反应方面的差异。方法根据采取的治疗方案将98例UGT1A1*28野生型TA6/6患者分为CPT-11联合顺铂组（IP组,n＝47）和CPT-11联合5-FU/亚叶酸钙组（FOLFIRI组,n＝51）,对患者进行UGT1A1*28启动子多态性检测,比较不良反应差异。结果在总体3～4级不良反应方面,IP组的发生率（61.7%）明显高于FOLFIRI组（39.2%）,且组间差异具有统计学意义（P=0.026）。在血液学不良反应方面,IP组3～4级白细胞减少、中性粒细胞减少、血小板减少和血红蛋白减少发生率分别为34.0%、51.1%、14.9%和8.5%,FOLFIRI组的发生率分别为11.8%、29.4%、2.0%、0,组间差异均有统计学意义（均P＜0.05）;在非血液学方面,FOLFIRI组3～4级迟发性腹泻发生率为9.8%,IP组未发生3～4级腹泻,两组间发生率的差异有统计学意义（P=0.028）。结论 UGT1A1*28野生型TA6/6患者在接受CPT-11联合顺铂和CPT-11联合5-FU/亚叶酸钙两种化疗方案治疗的不良反应谱存在差异;应用CPT-11时,不但要考虑到UGT1A1*28启动子多态性对不良反应的影响,而且还要考虑CPT-11联合不同药物出现不良反应情况。     

UGT1A1基因多态性在FOLFIRI方案二线治疗转移性结直肠癌中的临床意义

目的 探讨尿苷二磷酸葡萄糖醛酸转移酶（UGT）1A1基因多态性在FOLFIRI方案二线治疗转移性结直肠癌（mCRC）中的安全性和作为疗效预测指标的价值。方法在FOLFIRI方案化疗前分离mCRC患者外周血中单核细胞,采用荧光定量PCR-HRM法测定UGT1A1基因型。根据NCI CTC 3.0和RECIST 10标准分别评价化疗的不良反应和疗效,并分析UGT1A1基因多态性与不良反应和近期有效率（RR）的关系。用Kaplan-Meier法进行生存分析,Log-rank 检验分析UGT1A1基因型对无进展生存期（PFS）的影响。结果38例患者中,UGT1A1*28位点的野生型（TA6／6）有31例（81.6％）,杂合突变型（TA6／7）2例（5.3％）,纯合突变型（TA7／7）5例（13.2％）;UGT1A1*6位点的野生型（G／G）有28例（73.7％）,杂合突变型（G／A）8例（21.1％）,纯合突变型（A／A）2例（5.3％）。在3～4级延迟性腹泻和中性粒细胞减少的发生率方面,UGT1A1*28的野生型（TA6／6）显著低于TA6／7和TA7／7基因型（P＜0.05）,UGT1A1*6的野生型（G／G）也显著低于G／A和A／A基因型（P＜0.05）。RR和PFS在UGT1A1各种基因型之间差异无统计学意义（P＞0.05）。结论 在FOLFIRI方案二线治疗mCRC中,UGT1A1*28位点和UGT1A1*6位点突变可以作为严重的延迟性腹泻和中性粒细胞减少的预测指标,但UGT1A1基因多态性与疗效无关。     

Pharmacogenetic impact of polymorphisms in the coding region of the UGT1A1 gene on SN-38 glucuronidation in Japanese patients with cancer

Pharmacogenetic testing for UDP-glucuronosyltransferase (UGT) 1A1*28, a promoter variant of the UGT1A1 gene, is now carried out clinically to estimate the risk of irinotecan-associated toxicity. We studied the clinical significance of UGT1A1*6 and UGT1A1*27, two variants in exon 1 of the UGT1A1 gene that are found mainly in Asians. The study group comprised 46 Japanese patients who received various regimens of chemotherapy including irinotecan at doses from 50 to 180 mg/m(2). Pharmacogenetic relationships were explored between the UGT1A1 genotype and the ratio of the area under the plasma concentration-time curve (AUC) of the active metabolite of irinotecan (SN-38) to that of SN-38 glucuronide (SN-38G), used as a surrogate for UGT1A1 activity (AUC(SN-38)/AUC(SN-38G)). No patient was homozygous for UGT1A1*28, and none had UGT1A1*27. Two were heterozygous for UGT1A1*28. Two were homozygous and 15 heterozygous for UGT1A1*6, all of whom were wild type with respect to UGT1A1*28. Two patients were simultaneously heterozygous for UGT1A1*28 and UGT1A1*6, present on different chromosomes. The other 25 patients had none of the variants studied. The two patients simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 and the two patients homozygous for UGT1A1*6 had significantly higher AUC(SN-38)/AUC(SN-38G) ratios than the others (P = 0.0039). Concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, altered the disposition of irinotecan remarkably, potentially increasing susceptibility to toxicity. Patients homozygous for UGT1A1*6 should also be carefully monitored. UGT1A1 polymorphisms in the coding region of the UGT1A1 gene should be genotyped in addition to testing for UGT1A1*28 to more accurately predict irinotecan-related toxicity, at least in Asian patients.     

Impact of UGT1A1 genotype on the efficacy and safety of irinotecan-based chemotherapy in metastatic colorectal cancer

The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second-line treatment for metastatic colorectal cancer. We evaluated the associations between the UGT1A1 genotype linked to adverse events—caused by irinotecan—and the efficacy and safety of mXELIRI and FOLFIRI. The UGT1A1 genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression-free survival, response rate, and safety were assessed. The UGT1A1 genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12-2.09; P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62-1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79-1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39-1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second-line chemotherapy in terms of efficacy and safety regardless of the UGT1A1 genotype.     

Clinical and pharmacogenetic factors associated with irinotecan toxicity

Irinotecan is a topo-isomerase-I inhibitor with broad antitumor activity in solid tumors. Its use may lead to severe toxicities, predominantly neutropenia and diarrhea which can be life-threatening. This review discusses clinical determinants and pharmacogenetic factors associated with irinotecan toxicity. Age, performance status, co-medication and elevated transaminases have been associated with increased risk of diarrhea or neutropenia. Also, elevated bilirubin levels, due to liver impairment, conjugation disorders or UGT1A1 *28 genotype, have been associated with increased incidence of grades 3 intestinal toxicity and neutropenia. UGT1A1 *28 homozygosity is strongly associated with irinotecan-induced neutropenia and polymorphisms in the transporting peptides ABCB1 and OATP1B1 have also been associated with gastrointestinal toxicity and irinotecan pharmacokinetics, respectively. In the irinotecan product label, it is advised to reduce the irinotecan starting dose for UGT1A1 *28 homozygotes. However, due to the lack of prospective data, it is yet unknown whether dose reduction leads to reduced toxicity or altered antitumor effect. Combined toxicity analysis reveals that most patients experiencing grade 3-4 diarrhea and/or neutropenia are not homozygous for UGT1A1 *28. Future studies should combine pharmacogenetics with clinical determinants such as performance status and co-medication as to predict irinotecan toxicity and to develop predefined dosing algorithms.     

UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan.

PURPOSE: Irinotecan (CPT-11) is approved in metastatic colorectal cancer treatment and can cause severe toxicity. The main purpose of our study was to assess the role of different polymorphisms on the occurrence of hematologic toxicities and disease-free survival in high-risk stage III colon cancer patients receiving 5-fluorouracil (5FU) and CPT-11 adjuvant chemotherapy regimen in a prospective randomized trial. EXPERIMENTAL DESIGN: Four hundred patients were randomized in a phase III trial comparing LV5FU2 to LV5FU2 + CPT-11. DNA from 184 patients was extracted and genotyped to detect nucleotide polymorphism: 3435C>T for ABCB1, 6986A>G for CYP3A5, UGT1A1*28 and -3156G>A for UGT1A1. RESULTS: Genotype frequencies were similar in both treatment arms. In the test arm, no significant difference was observed in toxicity or disease-free survival for ABCB1 and CYP3A5 polymorphisms. UGT1A1*28 homozygous patients showed more frequent severe hematologic toxicity (50%) than UGT1A1*1 homozygous patients (16.2%), P = 0.06. Moreover, patients homozygous for the mutant allele of -3156G>A UGT1A1 polymorphism showed more frequent severe hematologic toxicity (50%) than patients homozygous for wild-type allele (12.5%), P = 0.01. This toxicity occurred significantly earlier in homozygous mutant than wild-type homozygous patients (P = 0.043). In a Cox model, the hazard ratio for severe hematologic toxicity is significantly higher for patients with the A/A compared with the G/G genotype [hazard ratio, 8.4; 95% confidence interval, 1.9-37.2; P = 0.005]. CONCLUSIONS: This study supports the clinical utility of identification of UGT1A1 promoter polymorphisms before LV5FU2 + CPT-11 treatment to predict early hematologic toxicity. The -3156G>A polymorphism seems to be a better predictor than the UGT1A1 (TA)(6)TAA>(TA)(7)TAA polymorphism.     

UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan.

PURPOSE: Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11). EXPERIMENTAL DESIGN: Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m(2)) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m(2), twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies. RESULTS: The overall objective response rate was 45% with 21 patients (31%) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5%) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response (p = 0.013) and lack of severe gastrointestinal toxicity (p = 0.003). In addition, the UGT1A9 -118 (dT)(9/9) genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response. CONCLUSIONS: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT)(9/9) genotype may be particularly likely to exhibit greater antitumor response with little toxicity.     

Dose-dependent association between UGT1A1128 polymorphism and irinotecan-induced diarrhoea: A meta-analysis

Life-threatening diarrhoea is observed in up to 25% of cancer patients receiving irinotecan. The associations between the UGT1A1128 polymorphism and irinotecan-induced diarrhoea remains controversial because of conflicting data in the literature. Meta-analyses were performed on published data in terms of relationships between UGT1A1128 and severe diarrhoea. We searched databases for relevant studies that were published in English or Chinese. Two reviewers extracted data and assessed methodological quality. UGT1A1128 related odds ratios (ORs) were pooled by use of a fixed-effects model. The studies included were stratified into subgroups representing different races and irinotecan doses, and meta-regression analyses were performed to investigate the effect of study characteristics on the association between UGT1A1128 and diarrhoea. Twenty trials including a total of 1760 cancer patients were included. The risk of severe diarrhoea at medium and high irinotecan doses was higher among patients with a UGT1A1128/128 genotype than among those with a UGT1A111/11 genotype (OR = 3.69, 95% confidence interval [CI] = 2.00–6.83; P < 0.001). Considering the patients with a UGT1A111/128 genotype, the risk of toxicity was also higher than among those with a wild-type genotype at medium and high doses (OR = 1.92, 95% CI = 1.31–2.82; P = 0.001). No association was observed between UGT1A1128 and severe diarrhoea at low doses (<125 mg/m²). In conclusion, patients carrying UGT1A1128 allele(s) are at an increased risk of irinotecan-induced severe diarrhoea. This increased risk is only apparent in those who are administrated with medium or high irinotecan doses.     

Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism

(Cancer Sci 2010; 101: 722–727) Although individuals carrying the UGT1A1 allele *28 have an increased risk of severe toxicities associated with irinotecan, no phase I study has been conducted based on the polymorphism. This report presents the recommended doses of irinotecan for patients with the respective genotypes. Twenty‐seven patients with advanced colorectal cancer were enrolled in this study, and the UGT1A1*28 polymorphism was genotyped before chemotherapy. One course of chemotherapy consisted of irinotecan infused once every 2 weeks at 70, 100, 120, and 150 mg/m² at dose levels 1, 2, 3, and 4, respectively, and doxifluridine was administered orally. This treatment continued for at least 12 weeks. The dose‐limiting toxicity was determined as grade 3 hematological and non‐hematological toxicities for the TA₆/TA₆ (6/6) and TA₆/TA₇ (6/7) genotypes. The pharmacokinetics of irinotecan, SN‐38, and SN‐38 glucuronide, was assessed at dose level 2. Eighteen and nine patients had the 6/6 and 6/7 genotypes, respectively. The maximum tolerated dose (MTD) was not observed up to dose level 4 in patients with the 6/6 genotype. In contrast, MTD was observed at dose level 2 (100 mg/m²) in patients with the 6/7 genotype. Patients with the 6/7 genotype had a significantly higher area under the plasma time–concentration curve _0‐∞ SN‐38 (P = 0.022) and biliary index (P = 0.030) than those with 6/6. The recommended starting doses of biweekly irinotecan for phase II/III were 150 mg/m² for patients with the UGT1A1 6/6 genotype and 70 mg/m² for those with the 6/7 genotype, respectively. The gene polymorphism should be considered when determining the precise recommended doses to be administered in phase I studies.