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

Abstract

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 ¼ 0.005). These results maintained the statistical significance in logistic regression analysis (P ¼ 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 ¼ 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.

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

“…Interestingly, diarrhea did not correlate with UGT1A1 genotype in this study population, perhaps owing to reduced enterohepatic recycling of SN-38G and a lower intestinal exposure to SN-38. However, Marcuello et al (2004) contradicted these findings in that the UGT1A1*28 genotype associated with diarrhea but not neutropenia in 95 patients with metastatic CRC. Additionally, as with irinotecan pharmacokinetics, UGT1A7 and 1A9 have been reported to predict irinotecan toxicity (Carlini et al, 2005).…”

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy

“…Carriers of the UGT1A1*28 7/7 homozygous genotype showed higher risk for suffering Grade III/IV neutropenia than UGT1A1*28 6/6 carriers. The association the UGT1A1*28 variant and side-effects from irinotecan-based chemotherapy has been described in previous studies [20][21][22][23] and according to present and recently reported data, it seems that the side-effect that is more frequently associated with UGT1A1*28 status is myelotoxicity. 23,[40][41][42][43] Toffoli et al 23 also found a favorable association between UGT1A1*28 7/7 better response rate and survival.…”

“…4 UGT1A1*28 has been correlated with increased risk of severe toxicity after irinotecan chemotherapy, [20][21][22][23] and it is unclear whether this variant may also influence treatment outcomes. 23 In experimental models, SN-38 showed induction of DNA damages, which require the activation of the nucleotideexcision repair (NER), the base-excision repair (BER) and the homologous recombination repair (HR) pathways.…”

Association study between single-nucleotide polymorphisms in 199 drug-related genes and commonly measured quantitative traits of 752 healthy Japanese subjects

“…20,21 The clinical application of the genetic test for the UGT1A1*28 allele before irinotecan therapy has been in practice in the United States since 2005, based on a cumulative evidence supporting the significant association of this variant with severe irinotecan toxicity. 20,[22][23][24][25] The five most associated SNPs included rs4148323 (G4A, UGT1A1*6). Homozygotes of the UGT1A1*6 allele showed significantly high values in serum total bilirubin levels, supporting the evidence from earlier studies.…”