Association between the low-dose irinotecan regimen-induced occurrence of grade 4 neutropenia and genetic variants of UGT1A1 in patients with gynecological cancers

Abstract

The occurrence of severe neutropenia during treatment with irinotecan (CPT-11) is associated with the *6 and *28 alleles of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). However, the correlation between these variants and the occurrence of severe neutropenia in a low-dose CPT-11 regimen for the treatment of gynecological cancers has not been extensively studied. There are also no studies regarding the association between the 421C>A mutation in ATP-binding cassette sub-family G member 2 (ABCG2) and the occurrence of severe neutropenia in CPT-11-treated patients with gynecological cancers. The present study was designed to determine the factors associated with the occurrence of grade 4 neutropenia during chemotherapy for gynecological cancers with combinations of CPT-11 and cisplatin or mitomycin C. In total, 44 patients with gynecological cancer were enrolled in the study. The association between the absolute neutrophil count (ANC) nadir values, the total dose of CPT-11 and the genotypes of UGT1A1 or ABCG2 was studied. No correlation was observed between the ANC nadir values and the total dose of CPT-11. The ANC nadir values in the UGT1A1*6/*28 and *6/*6 groups were significantly lower compared with those in the *1/*1 group (P<0.01). Univariate analysis showed no association between the occurrence of grade 4 neutropenia and the ABCG2 421C>A mutation. Subsequent to narrowing the factors by univariate analysis, multivariate logistic regression analysis only detected significant correlations between the occurrence of grade 4 neutropenia and the UGT1A1*6/*6 and *6/*28 groups (P=0.029; odds ratio, 6.90; 95% confidence interval, 1.22–38.99). No associations were detected between the occurrence of grade 4 neutropenia and the heterozygous variant (*1/*6 or *1/*28) genotype, type of regimen or age. In conclusion, the UGT1A1*6/*28 and *6/*6 genotypes were found to be associated with the occurrence of severe neutropenia in the low-dose CPT-11 regimen for gynecological cancers. This finding indicates that the determination of UGT1A1 variants may be as useful in CPT-11 chemotherapy for gynecological conditions as it is in colorectal and lung cancer patients treated with this drug.

Correlation between UGT1A1 gene polymorphism and irinotecan chemotherapy in metastatic colorectal cancer：a study from Guangxi Zhuang

“…Nakaura et al (18) showed that the wildtype UGT1A1*28 accounted for 46% and 76% in the Caucasian and Asian populations, respectively, indicating significant inter-ethnic differences. Etienne-Grimald et al (19) (27). In this study, the homozygous and heterozygous mutations of UGT1A1 showed a predictive effect when the dose of irinotecan was reduced.…”

Correlation between UGT1A1 gene polymorphism and irinotecan chemotherapy in metastatic colorectal cancer: a study from Guangxi Zhuang

“…In many studies, Caucasians were enrolled and a larger initial dose of irinotecan may have been selected, but the dose of irinotecan was not investigated. Previous studies revealed that UGT1A1*28 and UGT1A1*6 have a predictive effect on the adverse reactions of intermediate or high dose of irinotecan, but not on a low dose of irinotecan [27]. In this study, the homozygous and heterozygous mutations of UGT1A1 showed a predictive effect when the dose of irinotecan was reduced.…”

Effect of drug metabolizing enzymes and transporters in Thai colorectal cancer patients treated with irinotecan-based chemotherapy

“…Moriya et al . 31 reported that ANC nadir in patients carrying UGT1A1*6/*28 , *6/*6 were significantly lower compared with those with *1/*1 .…”

“…This revealed that patients carrying variant of UGT1A1 genotype had a significantly lower ANC nadir in the first and second cycle. Moriya et al 31 reported that ANC nadir in patients carrying UGT1A1*6/*28, *6/*6 were significantly lower compared with those with *1/*1. ABCC2 protein is expressed in liver, kidney, and small intestine, and also plays a primary role in biliary excretion of irinotecan and its metabolites 32,33 .…”