UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil

AIM：To evaluate effects of UDP-glucuronosyltransferase1A1（UGT1A1） and thymidylate synthetase（TS） gene polymorphisms on irinotecan in metastatic colorectal cancer（mCRC）.METHODS：Two irinotecan-and fluorouracil-based regimens,FOLFIRI and IFL,were selected as second-line therapy for 138 Chinese mCRC pat...

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Published in:World journal of gastroenterology : WJG 2012-12, Vol.18 (45), p.6635-6644
Main Authors: Wang, Yan, Shen, Lin, Xu, Nong, Wang, Jin-Wan, Jiao, Shun-Chang, Liu, Ze-Yuan, Xu, Jian-Ming
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Antimetabolites, Antineoplastic - pharmacology
Antineoplastic Agents, Phytogenic - pharmacology
Brief
Camptothecin - analogs & derivatives
Camptothecin - pharmacokinetics
China
Colorectal Neoplasms - genetics
Female
Fluorouracil - pharmacokinetics
Genotype
Glucuronosyltransferase - genetics
Humans
Logistic回归分析
Male
Middle Aged
Neoplasm Metastasis
Polymorphism, Genetic
S基因型
Thymidylate Synthase - genetics
Treatment Outcome
基因多态性
大肠癌
氟尿嘧啶
治疗时间
限制性片段长度多态性
高效液相色谱法
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Summary:AIM：To evaluate effects of UDP-glucuronosyltransferase1A1（UGT1A1） and thymidylate synthetase（TS） gene polymorphisms on irinotecan in metastatic colorectal cancer（mCRC）.METHODS：Two irinotecan-and fluorouracil-based regimens,FOLFIRI and IFL,were selected as second-line therapy for 138 Chinese mCRC patients.Genomic DNA was extracted from peripheral blood samples before treatment.UGT1A1 and TS gene polymorphisms were determined by direct sequencing and restriction fragment length polymorphism,respectively.Gene polymorphisms of UGT1A1＊28,UGT1A1＊6 and promoter enhancer region of TS were analyzed.The relationship between genetic polymorphisms and clinical outcome,that is,response,toxicity and survival were assessed.Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes.Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography.Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared.RESULTS：One hundred and eight patients received the FOLFIRI regimen,29 the IFL regimen,and one irinotecan monotherapy.One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation.One hundred and thirty-six patients were tested for UGT1A1＊28 and ＊6 genotypes and 125 for promoter enhancer region of TS.Patients showed a higher frequency of wild-type UGT1A1＊28（TA6/6） compared with a Caucasian population（69.9% vs 45.2%）.No significant difference was found between response rates and UGT1A1 genotype,although wild-type showed lower response rates compared with other variants（17.9% vs 24.2% for UGT1A1＊28,15.7% vs 26.8% for UGT1A1＊6）.When TS was considered,the subgroup with homozygous UGT1A1＊28（TA7/7） and non-3RG genotypes showed the highest response rate（33.3%）,while wild-type UGT1A1＊28（TA6/6） with non-3RG only had a 13.6% response rate,but no significant difference was found.Logistic regression showed treatment duration was closely linked to clinical response.In toxicity comparison,UGT1A1＊28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea（27.8% vs 100%）,and significantly reduced the risk of grade 4 neutropenia compared with TA7/7（7.8% vs 37.5%）.Wild-type UGT1A1＊6（G/G） tended to have a lower incidence of grade 3/4 diarrhea vs homozygous mutant（A/A） genotype（13.0% vs 40.0%）.Taking UGT1A1 and TS genotypes together,lower incidence of grade 2-4 diarrhea was found in patients with no
ISSN:1007-9327
2219-2840
DOI:10.3748/wjg.v18.i45.6635