UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer

SN-38 is the active metabolite of irinotecan and it is metabolised through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). The major toxicity of irinotecan therapy is diarrhoea, which has been related to the enzymatic activity of UGT1A1. We examined the influence of the UGT1A1 gene promoter polymorphism in the toxicity profile, in the response rate and in the overall survival (OS) in 95 patients with metastatic colorectal cancer treated with an irinotecan-containing chemotherapy. Genotypes were determined by analysing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Clinical parameters and genotypes were compared by univariate and multivariate statistical methods. The more frequent adverse effects were asthenia (34 patients), diarrhoea (29 patients) and neutropenia (20 patients). Severe diarrhoea was observed in 7/10 homozygous (70%) and 15/45 heterozygous (33%) in comparison to 7/40 (17%) wild-type patients (P=0.005). These results maintained the statistical significance in logistic regression analysis (P=0.01) after adjustment for other clinical relevant variables. The presence of severe haematological toxicity increased from wild-type patients to UGT1A1(*)28 homozygotes, but without achieving statistical significance. No relationship was found between the UGT1A1(*)28 genotypes and infection, nausea or mucositis. In univariate studies, patients with the UGT1A1(*)28 polymorphism showed a trend to a poorer OS (P=0.09). In the multivariate analysis, the genotype was not related to clinical response or to OS. The role of the UGT1A1 genotype as a predictor of toxicity in cancer patients receiving irinotecan demands the performance of a randomized trial to ascertain whether genotype-adjusted dosages of the drug can help to establish safe and effective doses not only for patients with the UGT1A1(*)28 homozygous genotype but also for those with the most common UGT1A1 6/6 or 6/7 genotype.     

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.     

Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.

PURPOSE: Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation. PATIENTS AND METHODS: Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m(2) every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (-3279G>T, -3156G>A, promoter TA indel, 211G>A, 686C>A) were genotyped. RESULTS: The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P =.001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P =.02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean +/- standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 +/- 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 +/- 0.03 mg/dL; P <.001). The -3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The -3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r(2) = 0.51). CONCLUSION: UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the -3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.     

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。     

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。     

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。     

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。     

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。     

Clinical Observations on Associations Between the UGT1A1 Genotype and Severe Toxicity of Irinotecan

Background: Severe toxicity is commonly observed in cancer patients receiving irinotecan (CPT-11)UDPglucuronosyltransferase1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38 but therelationship between UGT1A1 and severe toxicity remains unclear. Our study aimed to assess this point to guideclinical use of CPT-11. Materials and Methods: 89 cancer patients with advanced disease received CPT-11-basedchemotherapy for at least two cycles. Toxicity, including GI and hematologic toxicity was recorded in detail andUGT1A1 variants were genotyped. Regression analysis was used to analyse relationships between these variablesand tumor response. Results: The prevalence of grade III-IV diarrhea was 10.1%, this being more common inpatients with the TA 6/7 genotype (5 of 22 patients, 22.7%) (p<0.05). The prevalence of grade III-IV neutropeniawas 13.4%and also highest in patients with the TA 6/7 genotype (4 of 22 patients; 18.2%) but without significance(p>0.05). The retreatment total bilirubin levels were significantly higher in TA6/7 patients (mean, 12.75μmol/L)with compared to TA6/6 (mean, 9.92 μmol/L) with p<0.05. Conclusions: Our study support the conclusion thatpatients with a UGT1A1*28 allele (s) will suffer an increased risk of severe irinotecan-induced diarrhea, whetherwith mid-or low-dosage. However, the UGT1A1*28 allele (s) did not increase severe neutropenia. Higher serumtotal bilirubin is an indication that patients UGT1A1 genotype is not wild-type, with significance for clinic usageof CPT-11.     

尿苷二磷酸葡萄糖醛酸转移酶1A1*28基因多态性和伊立替康毒副反应相关性研究

目的初步了解肿瘤患者血中尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)启动子的多态性分布,并研究其多态性和伊立替康化疗的毒副反应之间的关系。方法收集拟采用伊立替康为基础化疗方案的患者全血标本,直接测序分析UGT1A1~*28 TATA盒基因序列;并与化疗毒副反应进行相关性分析。结果 203例患者进行UGT1A1~*28 TATA基因启动子检测,UGT1A1~*28野生纯合型(TA6/6)最常见,共156例,占76.8%;其次为突变杂合型(TA6/7),共43例,占21.2%;突变纯合型(TA7/7)仅3例,占1.5%;TA5/6有1例,占0.5%。共有183例患者使用含伊立体康方案治疗。突变纯合型(TA7/7)与3度及以上迟发型腹泻和中性粒细胞减少明确相关(P=0.001、P=0.048),与化疗前总胆红素水平升高相关(P0.001);突变杂合型(TA6/7)和野生纯合型(TA6/6)在3度及以上迟发型腹泻和中性粒细胞减少方面的相关性类似(P=0.561、P=0.915),化疗前总胆红素水平类似(P=0.229)。结论 UGT1A1~*28突变纯合型(TA7/7)明显增加伊立替康所致3度及以上延迟性腹泻和中性粒细胞减少,增加化疗前胆红素水平;而UGT1A1~*28突变杂合型(TA6/7)并不增加3、4度迟发型腹泻和粒细胞减少的发生及化疗前总胆红素水平。     

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。     

UGT1A1基因多态性与伊立替康安全性和有效性的临床研究

  目的  观察57例应用伊立替康治疗进展期消化道肿瘤患者的安全性和有效性。  方法  采用全血基因组DNA提取、PCR法扩增目的基因片段, 直接测序法分析UGT1A1基因多态性, 检测2011年8月至2012年6月在河北医科大学第四医院肿瘤内科住院治疗的57例进展期消化道肿瘤患者应用伊立替康的情况, 观察并记录化疗中出现的不良反应以及疗效。  结果  57例进展期消化道肿瘤患者中, UGT1A1基因启动子区28位点, TA序列6次重复的纯合野生型TA6/6有43例（75.4%）; 基因型为TA序列6次和7次重复的杂合型TA6/7有13例（22.8%）; 基因型为TA序列7次重复的纯合突变型TA7/7有1例（1.8%）。UGT1A1基因启动子区6位点野生型G/G有48例（84.2%）, 杂合突变型G/A有7例（12.3%）, 纯合突变型A/A有2例（3.5%）。在57例采用含伊立替康方案化疗的进展期消化道肿瘤患者中, UGT1A1基因启动子区28位点, TA6/6、TA6/7和TA7/7野生型和突变型发生3级以上中性粒细胞减少者分别为7.0%、14.3%, 发生3级以上腹泻者分别为9.3%、14.3%, 其中纯合突变型仅1例患者, 100%的发生率。UGT1A1基因启动子区6位点, G/G、G/A和A/A野生型和突变型发生3级以上中性粒细胞减少者分别为4.2%、55.6%, 发生3级以上腹泻者分别为12.5%、44.4%, 具有统计学差异。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*6突变型患者应用伊立替康化疗发生3级以上中性粒细胞减少和腹泻的风险增加, 而UGT1A1*28突变型与以上不良反应并无绝对相关性, UGT1A1各基因型之间疗效无明显差异。能否通过对UGT1A1的筛查, 选择合适患者安全有效的应用伊立替康, 值得临床进一步扩大样本量深入研究。      

Importance of UDP-glucuronosyltransferase 1A1*6 for irinotecan toxicities in Japanese cancer patients

Recent pharmacogenetic studies on irinotecan have revealed the impact of UDP glucuronosyltransferase (UGT) 1A1*28 on severe irinotecan toxicities. Although the clinical role of UGT1A1*6, which is specifically detected in East Asian patients, in irinotecan toxicities is suggested, clear evidence remains limited. To examine the impact of *6, the association of UGT1A1 genotypes with severe irinotecan toxicities was retrospectively investigated in Japanese cancer patients. A significant *6-dependent increase in the incidence of grade 3 or 4 neutropenia was observed in 49 patients on irinotecan monotherapy (p=0.012). This study further clarifies the clinical importance of *6 in irinotecan therapy in East Asians.     

Associations between UGT1A1*6 or UGT1A1*6/*28 polymorphisms and irinotecan-induced neutropenia in Asian cancer patients

Purpose

Neutropenia is a life-threatening side effect of irinotecan, and uridine diphosphate glucuronosyltransferases (UGTs) gene polymorphisms are considered to be one of the predictive markers of irinotecan-related toxicities. Many studies have demonstrated that patients bearing UGT1A1*28 have a higher risk of severe neutropenia on toxicity of irinotecan. However, UGT1A1 (TA7/TA7) was very rare in Asian populations. Some researches reported that UGT1A1*28 and/or UGT1A1*6 could predict irinotecan-induced toxicities in Asian populations, but controversial conclusions still remained. This study aims to investigate the association between UGT1A1 gene polymorphisms *6, *6/*28 and irinotecan-related neutropenia in Asian cancer patients receiving irinotecan regimen chemotherapy.

Experimental design

Meta-analyses were done to assess the relationship between UGT1A1*6 or UGT1A1*6/*28 and irinotecan-induced neutropenia.

Results

The risk of neutropenia was significantly higher among patients with a UGT1A1*6 genotype than among those carrying the UGT1A1*1 allele(s) [odds ratio (OR) 3.276; 95 % confidence interval (CI) 1.887–5.688; P = 0.000 (*6/*6 vs. *1/*6 or *1/*1)], [OR 1.542; 95 % CI 1.180–2.041; P = 0.001 (*6/*6 or *1/*6 vs. *1/*1)]. Also, the risk was significantly higher among patients with a UGT1A1*6/*28 than among those carrying the UGT1A1*1 allele(s) [OR 3.275; 95 % CI 2.152–4.983; P = 0.000 (*6/*6 or *28/*28 or *6/*28 vs. *1/*6 or *1/*28 or *1/*1)].

Conclusions

In conclusion, the UGT1A1*6 and UGT1A1*6/*28 genotypes were associated with an increased risk of irinotecan-induced neutropenia in Asian cancer patients.     

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.     

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.     

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.     

UGT1A1*28基因多态性与中药预防伊立替康腹泻效果的关系

  目的  探讨中药对伊立替康化疗后腹泻的预防作用,同时结合尿苷二磷酸葡萄糖醛酸转移酶1A1*28（UGT1A1*28）基因多态性进行中药疗效分析。  方法  自2011年10月至2013年5月共200例患者被随机分为对照组（单纯化疗）和中药组（化疗联合中药）。全部患者在化疗开始前均接受UGT1A1*28基因多态性的检测。化疗采用标准FOLFIRI方案,中药于化疗前2 d开始服用,至伊立替康化疗后第5天结束。期间记录患者不良反应,并进行疗效评价。  结果  200例患者中TA6/6野生基因型144例,非野生基因型56例（TA7/7纯合型12例和TA6/7杂合型44例）。2级以上腹泻者共58例,中药组腹泻发生率较对照组下降14%（22% vs. 36%,P=0.029）。除腹泻以外,2级以上呕吐发生率中药组也明显低于对照组（15% vs. 27%,P=0.037）。患者总体有效率为37.5%,中药组和对照组相比差异无统计学意义（40% vs. 35%,P=0.465）。UGT1A1*28野生基因型患者2级以上腹泻发生率（22.9% vs. 44.6%,P=0.002）和呕吐发生率（16.7% vs. 23.2%,P=0.016）均低于与非野生基因型患者。在中药治疗组中,非野生基因型与野生型相比,2级以上腹泻发生率（22.2% vs. 21.9%,P=0.974）和呕吐发生率（18.5% vs. 13.7%,P=0.777）差异无统计学意义。  结论  中药可有效预防伊立替康引起的迟发性腹泻,对于UGT1A1*28非野生基因型患者的迟发性腹泻同样具有预防作用。UGT1A1*28基因非野生基因型腹泻发生率明显高于野生基因型,在使用伊立替康治疗前应检测患者的该基因状态。      

Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients

BACKGROUND:

Metastatic colorectal cancer is frequently treated with irinotecan, a topoisomerase‐I inhibitor. The UGT1A1 gene encodes for an enzyme that metabolizes irinotecan, and its genetic variants were shown to be associated with increased drug toxicity. We evaluated clinical outcomes associated with the UGT1A1*28 variant.

METHODS:

The study included 329 colorectal cancer patients from the Israeli population‐based Molecular Epidemiology of Colorectal Cancer study who were treated with a chemotherapy regimen that included irinotecan. Patients with metastases or disease recurrence were followed up for a median period of 2 years after occurrence of the event. Study end points were appearance of grade 3‐4 hematological and gastroenterological toxicity, hospitalization due to toxic events (mostly neutropenia, fever, diarrhea, or vomiting), length of hospitalization, and overall survival. UGT1A1*28 was genotyped from peripheral blood DNA by fragment analysis and reported as number of TATA sequence repeats in the promoter of the gene.

RESULTS:

The 7/7 variant of UGT1A1*28 was detected in 11.9% of the 329 participants. Grade 3‐4 hematological toxicity was significantly higher in 7/7 carriers compared with 6/7 and 6/6 carriers (48.0%,10.2%, and 7.7% respectively; P < .001), as was the risk of toxicity‐related hospitalization (45.8%, 25.3%, and 14.4% respectively; P = .001). Both short‐term death within 2 months of treatment start (12.8%, 5.2%, and 2.9%, respectively) and median overall survival (1.6, 2.0, and 2.4 years, respectively; P = .01) were significantly worse in the 7/7 carriers. The age/stage‐adjusted hazard ratio for patients with the 7/7 genotype compared with 6/6 was 1.7 (95% confidence interval, 1.1‐2.3).

CONCLUSIONS:

The UGT1A1*28 7/7 genotype is strongly associated with severe hematological toxicity and higher hospitalization rate and predicts lower survival of colorectal cancer in users of irinotecan. Cancer 2011. © 2011 American Cancer Society.     

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.