The value of genetic polymorphisms to predict toxicity in metastatic colorectal patients with irinotecan-based regimens

Lamas, María Jesús; Duran, Goretti; Balboa, Emilia; Bernárdez, Beatriz; Candamio, Sonia; Vidal, Yolanda López; Mosquera, Alicia; Giráldez, José María; López, Rafael; Carracedo, Ángel; Barros, Francisco

doi:10.1007/s00280-012-1866-2

Cited by 19 publications

(14 citation statements)

References 30 publications

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“…Inconsistent patient responses to irinotecan imply that factors such as age, organ function, concomitant therapy [3, 4], and dose of irinotecan [7] might modulate the therapeutic and adverse effects of this drug. However, the variable responses might also be explained by the synergic effect of UGT1A1*28 and other UGT1A polymorphisms, such as UGT1A1*6 and UGT1A7*3 [12, 13, 20, 28]. Our finding that there is a significantly different distribution of UGT1A polymorphisms in Uzbekistan and Japan strengthens this hypothesis, and provides further evidence that extensive studies of the relationships between UGT1A haplotypes and the risk of irinotecan toxicity would be worthwhile.…”

Section: Discussionsupporting

confidence: 75%

Differences in UGT1A1, UGT1A7, and UGT1A9 Polymorphisms between Uzbek and Japanese Populations

et al. 2014

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Background and ObjectivesUridine-diphosphate glucuronosyltransferase 1A (UGT1A) is a key enzyme involved in irinotecan metabolism, and polymorphisms in the UGT1A gene are associated with irinotecan-induced toxicity. The aim of this study was to elucidate the allele frequencies of UGT1A polymorphisms in healthy Uzbek volunteers, and to compare them with those of the Japanese population.MethodA total of 97 healthy volunteers from Uzbekistan were enrolled and blood samples were collected from each participant. Genotyping analysis was performed by fragment size analysis for UGT1A1*28, direct sequencing for UGT1A7*3 and UGT1A9*22, and TaqMan assays for UGT1A1*93, UGT1A1*6, UGT1A1*27, UGT1A1*60, and UGT1A7*12. The frequencies of polymorphisms were compared with the Japanese population by using the data previously reported from our study group.ResultsWhen the Uzbek and Japanese populations were compared, heterozygotes or homozygotes for UGT1A1*28, UGT1A1*60, and UGT1A1*93 were significantly more frequent in the Uzbek population (P < 0.01). The rate of UGT1A7*12 was not significantly different between the two populations, whereas UGT1A1*6 and UGT1A9*22 were significantly less frequent in the Uzbek population (P < 0.05). UGT1A7*1 were less prevalent in the Uzbek population than in the Japanese population (P < 0.01).ConclusionThe Uzbek population has different frequencies of polymorphisms in UGT1A genes compared with the Japanese population. A comprehensive study of the influence of UGT1A1 polymorphisms on the risk of irinotecan-induced toxicity is necessary for optimal use of irinotecan treatment.

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Section: Discussionsupporting

confidence: 75%

Differences in UGT1A1, UGT1A7, and UGT1A9 Polymorphisms between Uzbek and Japanese Populations

et al. 2014

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“…Many published studies have focused on associations between irinotecan toxicity, irinotecan efficacy, or both and any one or more of each UGT1A variants examined here (10–19,31,32). Patients, especially Asian patients, homozygous for UGT1A1*6 or *28 or compound heterozygous for these variants are at high risk for hematologic toxicity (13,33,34).…”

Section: Discussionmentioning

confidence: 99%

A novel system for predicting the toxicity of irinotecan based on statistical pattern recognition with UGT1A genotypes

Tsunedomi¹,

Hazama²,

Fujita³

et al. 2014

International Journal of Oncology

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To predict precisely severe toxicity of irinotecan, we evaluated the association of UGT1A variants, haplotypes and the combination of UGT1A genotypes to severe toxicity of irinotecan. UGT1A1*6 (211G>A), UGT1A1*28 (TA6>TA7), UGT1A1*60 (−3279T>G), UGT1A7 (387T>G), UGT1A7 (622T>C), and UGT1A9*1b (−118T9>T10, also named *22) were genotyped in 123 patients with metastatic colorectal cancer who had received irinotecan-based chemotherapy. Among the 123 patients, 73 were enrolled in either of two phase II studies of the FOLFIRI (leucovorin, 5-fluorouracil and irinotecan) regimen; these patients constituted the training population, which was used to construct the predicting system. The other 50 patients constituted the validation population; these 50 patients either had participated in a phase II study of irinotecan/5′-deoxy-5-fluorouridine or were among consecutive patients who received FOLFIRI therapy. This prediction system used sequential forward floating selection based on statistical pattern recognition using UGT1A genotypes, gender and age. Several UGT1A genotypes [UGT1A1*6, UGT1A7 (387T>G), UGT1A7 (622T>C) and UGT1A9*1b] were associated with the irinotecan toxicity. Among the haplotypes, haplotype-I (UGT1A1: −3279T, TA6, 211G; UGT1A7: 387T, 622T; UGT1A9: T10) and haplotype-II (UGT1A1: −3279T, TA6, 211A; UGT1A7: 387G, 622C; UGT1A9: T9) were also associated with irinotecan toxicity. Furthermore, our new system for predicting the risk of irinotecan toxicity was 83.9% accurate with the training population and 72.1% accurate with the validation population. Our novel prediction system using statistical pattern recognition depend on genotypes in UGT1A, age and gender; moreover, it showed high predictive performance even though the treatment regimens differed among the training and validation patients.

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“…These results might reflect a lower dose intensity of irinotecan in patients with *28/*28 or *1/*28 alleles, due to severe toxicities. Representative studies evaluated in these meta-analyses are listed in Table 2 22,26–36…”

Section: Ugt1a1*28 Allele and Efficacy Of Irinotecan-based Therapymentioning

confidence: 99%

“…Many studies have evaluated toxicities in patients treated with irinotecan-based therapy according to UGT1A1*28 genotypes 22,26–36Table 2 summarizes representative studies evaluating the incidence of neutropenia and diarrhea.…”

Section: Ugt1a1*28 Allele and The Toxicities Of Irinotecan-based Therapymentioning

confidence: 99%

UGT1A1 polymorphisms in cancer: impact on irinotecan treatment

Takano¹,

Sugiyama²

2017

PGPM

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Mutations in the UGT1A1 gene have been implicated in Gilbert syndrome, which shows mild hyperbilirubinemia, and a more aggressive childhood subtype, Crigler–Najjar syndrome. To date, more than 100 variants have been found in the UGT1A1 gene. Among them, UGT1A1*28 and UGT1A1*6 have been reported to be associated with severe toxicities in patients treated with irinotecan-based chemotherapy by increasing the dose of SN-38 (7-ethyl-10-hydroxycamptothecin), an active form of irinotecan. Many association studies and meta-analyses have demonstrated the contribution of UGT1A1*28 and UGT1A1*6 polymorphisms to the toxicities caused by irinotecan-based therapy. The aim of this review was to evaluate the impact of these variants upon the toxicities and the efficacy of irinotecan-based chemotherapy.

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The value of genetic polymorphisms to predict toxicity in metastatic colorectal patients with irinotecan-based regimens

Abstract: The impact of increased risk of toxicity attributed to the UGT1A variants may be offset by irinotecan in clinical practice by dose reduction or the use of colony-stimulating factor.

Cited by 19 publications

References 30 publications

Differences in UGT1A1, UGT1A7, and UGT1A9 Polymorphisms between Uzbek and Japanese Populations

Differences in UGT1A1, UGT1A7, and UGT1A9 Polymorphisms between Uzbek and Japanese Populations

A novel system for predicting the toxicity of irinotecan based on statistical pattern recognition with UGT1A genotypes

UGT1A1 polymorphisms in cancer: impact on irinotecan treatment

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