UGT1A1*28genotype predicts gastrointestinal toxicity in patients treated with intermediate-dose irinotecan (original) (raw)
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Journal of Pharmacology and Experimental Therapeutics, 2013
Background: Despite the importance of UGT1A1*28 in irinotecan pharmacogenetics, our capability to predict drug-induced severe toxicity remains limited. Objective: We aimed at identifying novel genetic markers that would improve prediction of irinotecan toxicity and response in advanced colorectal cancer patients treated with FOLFIRI-based regimens. Approach: The relationships between UGT1A candidate markers across the gene (n=21) and toxicity were prospectively evaluated in 167 patients. We included variants in the 3'UTR region of UGT1A locus, not studied in this context yet. These genetic markers were further investigated in 250 Italian FOLFIRI-treated patients. Results: Several functional UGT1A variants including UGT1A1*28 significantly influenced risk of severe hematological toxicity. As previously reported in the Italian cohort, a 5-markers risk haplotype (HII; UGTs 1A9/1A7/1A1) was associated with severe neutropenia in our cohort (OR=2.43; p=0.004). The inclusion of a 3'UTR SNP permitted refinement of the previously defined HI, in which HIa was associated with the absence of severe neutropenia in combined cohorts (OR=0.55; p=0.038). Among all tested UGT1A variations and upon multivariate analyses, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to neutropenia grade 3-4. Haplotype analyses of these markers with the 3'UTR SNP allowed the identification of a protective HI (OR=0.50; p=0.048) and two risk haplotypes HII and HIII, characterized by 2 and 3 unfavorable alleles respectively, revealing a dosage effect (ORs of 2.15 and 5.28; p≤0.030). Conclusions: Our results suggest that specific SNPs in UGT1A, other than UGT1A1*28, may influence irinotecan toxicity and should be considered to refine pharmacogenetic testing.
Oncology letters, 2016
Irinotecan-induced severe neutropenia and diarrhea, which remain unpredictable, has restrained the dose and clinical efficiency of irinotecan administration. In the present study, a total of 70 irinotecan-treated patients with histologically confirmed metastatic gastrointestinal cancer were enrolled. Despite genotyping well-reported alleles, direct sequencing was specifically adopted to avoid ethnic heterogeneity and to identify novel variations. The promoter (-1000 bp) and exon 1 regions of UDP glucuronosyltransferase family 1 member A complex locus (UGT1A1) gene family members UGT1A1, UGT1A7 and UGT1A9 were sequenced, and comprehensive analysis of their genetic polymorphisms was performed to determine the association between inherited genetic variations and irinotecan-induced toxicity. A total of 23 different genetic variants were detected in the present study, including 2 novel polymorphisms. The results of the present study revealed that UGT1A1*6 and UGT1A7*3 are risk factors fo...
Genetics in Medicine, 2009
Disclaimer: This recommendation statement is a product of the independent EGAPP Working Group. Although the Centers for Disease Control and Prevention (CDC) provides support to the EGAPP Working Group, including staff support in the preparation of this document, recommendations made by the EGAPP Working Group should not be construed as official positions of the CDC or the US Department of Health and Human Services. Summary of Recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found that the evidence is currently insufficient to recommend for or against the routine use of UGT1A1 genotyping in patients with metastatic colorectal cancer who are to be treated with irinotecan, with the intent of modifying the dose as a way to avoid adverse drug reactions (severe neutropenia). Rationale: The EGAPP Working Group (EWG) found no intervention trials showing that targeted dosing of irinotecan based on UGT1A1 genotyping could reduce the rates of two specific adverse drug events, severe (Grade 3-4) neutropenia or diarrhea. Observational studies indicate a significant association between UGT1A1 genotypes, particularly *28/*28 and *1/*28, and the occurrence of severe neutropenia. Observational studies also indicate a possible association between severe diarrhea and these UGT1A1 genotypes, but the association is not statistically significant. An additional finding was the suggestion that reducing irinotecan dose may result in patient harms due to diminished effectiveness of treatment in highest risk individuals (*28/*28 homozygotes), and that a higher dose might be warranted among individuals at lower risk of adverse drug events (*1/*1 and *1/*28 genotypes). This review did not consider higher risk patients (e.g., having previous adverse reactions to irinotecan or additional risk factors for neutropenia). Analytic Validity: The EWG found adequate evidence to conclude that analytic sensitivity and specificity were high for the commonly tested alleles, but evidence was inadequate for rarer alleles. Clinical Validity: The EWG found adequate evidence of a significant association between UGT1A1 genotype and the incidence of severe neutropenia at standard doses of irinotecan. The EWG found adequate evidence of a possible association between genotype and severe diarrhea, but the effect was smaller and not statistically significant. The EWG found adequate evidence of a significantly higher rate of tumor response to standard irinotecan dosing among individuals with the genotype at highest risk of adverse drug events (*28/*28). Clinical Utility: The EWG found no evidence to support clinical utility in the proposed clinical scenario. Preliminary modeling suggests that, even if targeted dosing were to be highly effective, it is not clear that benefits (reduced adverse drug events) outweigh harms (unresponsive tumors). Contextual Issues: Addressing patient preferences regarding risk of side effects and quality of life, versus aggressive treatment to potentially improve effectiveness, is expected practice. In addition, a recent study reported that risk for neutropenia was lower at lower irinotecan doses. For treatment regimens utilizing lower irinotecan doses, UGT1A1 genotype may not be a useful indicator of risk for adverse drug events. Further rigorous evaluation of UGT1A1 genotyping using current and promising irinotecan treatment protocols is warranted.
UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan
2007
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-11adjuvant 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. Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin) (CPT-11) is a water-soluble analogue of 20(S)-camptothecin (CPT) and is an inactive prodrug. Its major metabolite, SN-38, is a potent active topoisomerase I inhibitor and is known to be toxic (1). Due to its efficacy, CPT-11 is currently approved worldwide for use as first-line therapy in metastatic colorectal cancer, in combination with 5-fluorouracil (5FU) and leucovorin (LV; ref. 2). Adjuvant CPT-11 in combination with 5FU has recently been investigated in colorectal cancer. One limitation of CPT-11 is the unpredictable and occasionally fatal gastrointestinal and hematologic toxicity, which varies greatly between individuals. Predictive markers of CPT-11 toxicity may thus be deduced from the CPT-11 metabolic pathway. CPT-11 is metabolized by carboxylesterase (CES), essentially the isoenzyme CES2, to active SN-38, then is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme to yield its h-glucuronide, SN-38 G (3, 4). SN-38 G is excreted in the small intestine via the bile, where bacterial glucuronidase breaks down the glucuronide into SN-38 and glucuronic acid (5). Bilurubin undergoes the same glucuronidation by
British journal of cancer, 2008
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 freq...
The Open Colorectal Cancer Journal, 2009
Aim: To investigate the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity in Taiwanese patients with metastatic colorectal cancer (mCRC) receiving irinotecan chemotherapy. Methods: We genotyped the UGT1A1 gene by direct sequencing. All the patients were evaluated to see whether the variant UGT1A1 genotype would correlate to severe toxicity of irinotecan consisting of grade III-IV neutropenia, diarrhea and nausea/vomiting. Genomic DNA was genotyped for UGT1A1, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the promoter region. Results: The results showed that the genotype distribution of UGT1A1 in Taiwanese subjects differed significantly from that in Caucasians. Furthermore, patients with 6/7 or 7/7 genotype were associated with a higher incidence of grade III-IV neutropenia or diarrhea or nausea/vomiting (all p < 0.0001). The less frequencies of 6/7 and 7/7 genotypes may be responsible for the considerably lower occurrence of grade III-IV neutropenia and diarrhea in Taiwanese patients. Indeed, the UGT1A1 genotype was closely related to clinical response (p = 0.018). Conclusion: UGT1A1 genotyping is a potential predictor of severe toxicity for Taiwanese mCRC patients treated with irinotecan chemotherapy, and may be useful to identify patients at-risk of toxicity, and thus could be used as a screening tool prior to therapy.
British journal of cancer, 2010
The impact of thymidylate synthase (TYMS) and UDP-glucoronosyltransferase 1A (UGT1A) germline polymorphisms on the outcome of colorectal cancer (CRC) patients treated with irinotecan plus 5-fluorouracil (irinotecan/5FU) is still controversial. Our objective was to define a genetic-based algorithm to select patients to be treated with irinotecan/5FU. Genotyping of TYMS (5'TRP and 3'UTR), UGT1A1(*)28, UGT1A9(*)22 and UGT1A7(*)3 was performed in 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy enrolled in a randomised phase 3 study. Their association with response, toxicity and survival was investigated by univariate and multivariate statistical analysis. TYMS 3TRP/3TRP genotype was the only independent predictor of tumour response (OR=5.87, 95% confidence interval (CI)=1.68-20.45; P=0.005). UGT1A1(*)28/(*)28 was predictive for haematologic toxicity (OR=6.27, 95% CI=1.09-36.12; P=0.04), specifically for neutropenia alone (OR=6.40, 95% CI=1.11-3...