Genetic testing for UGT1A1*28 and *6 in Japanese patients who receive irinotecan chemotherapy

Abstract

Polymorphisms of the UDP-glucuronosyltransferase (UGT) 1A1 gene, such as UGT1A1*28 and UGT1A1*6, can cause severe neutropenia and diarrhea in patients who receive irinotecan [1, 2]. Homozygosity for UGT1A1*28 is associated with less efficient glucuronidation of SN-38, the active metabolite of irinotecan, resulting in increased plasma SN-38 concentrations. Four pharmacogenetic trials have demonstrated an association between UGT1A1*28 genotype and irinotecan-induced hematologic toxicity, diarrhea, or both [3]. In response to these findings, the United States Food and Drug Administration has approved genetic testing for UGT1A1*28 and recommends that the initial dose of irinotecan is reduced by at least one level in patients who are homozygous for UGT1A1*28, albeit the effectiveness of such testing remains to be confirmed prospectively. UGT1A1*6 is also associated with severe irinotecan-related toxicity [4]. Given that the area under the time versus concentration curve ratio (SN-38 glucuronide/SN-38) seen in patients homozygous for UGT1A1*28 and *6 are almost equal [4], the impact of these variants on glucuronidation capacity of UGT1A1 for SN-38 is almost the same. The distribution of genotypes associated with these polymorphisms varies considerably among ethnic groups. UGT1A1*28 is found in Japanese and whites, but the allele frequency in Japanese is lower than that in whites [2, 4]. UGT1A1*6 is found in Japanese, but not in whites [4]. Homozygosity for UGT1A1*28 or UGT1A1*6 and heterozygosity for both UGT1A1*6 and UGT1A1*28 are associated with severe irinotecan-related neutropenia in Japanese patients [1, 4]. The Ministry of Health, Labour and Welfare in Japan has therefore recently approved genetic testing for UGT1A1*28 and *6. The value of genetic testing for UGT1A1 depends on genotype frequency and the association of genetic variants with irinotecan-induced toxicity. The higher the frequency of toxicity-related polymorphisms, the greater is the number of patients who would benefit from genetic testing. Large prospective studies are needed to accurately estimate the distribution of UGT1A1 polymorphisms in a given population. We have carried out the largest prospective study to date, examining the distributions of UGT1A1*28 and UGT1A1*6 genotypes in 300 Japanese patients (male/female, 172 of 128) with various solid tumors (200 colorectal, 43 gastric, 15 ovarian, 14 breast, 10 lung, and 18 others). All patients gave written informed consent, and the study protocol was approved by the Institutional Review Board of Saitama Medical University. Genotyping was carried out as described elsewhere [5]. UGT1A1*28 and UGT1A1*6 were in Hardy–Weinberg equilibrium (P > 0.05). Only 2 of 300 patients were UGT1A1*28 homozygotes (0.7%) (Table 1). The frequency of homozygosity for UGT1A1*28 was much lower than that in other prospective studies in Japan (2.3%, 4 of 176) [4]. The frequency of UGT1A1*6 homozygosity was 5.7% (Table 1), higher than that reported previously (2.8%) [4]. Eleven patients were both heterozygous for UGT1A1*6 and UGT1A1*28 (3.7%). The combined frequency of patients with two ‘risk alleles’ (i.e. *28/*28, *6/*6, and *6/*28) was 10.1% (95% confidence interval, 6.8% to 14.0%). Such patients might be at increased risk for irinotecan-related neutropenia. Given the genotype frequencies of UGT1A1*28 and UGT1A1*6, genetic testing for UGT1A1 might not be essential for identifying homozygotes for UGT1A1*28, but useful for identifying homozygotes for UGT1A1*6 as well as heterozygotes for UGT1A1*6 and UGT1A1*28, thereby avoiding severe irinotecan-induced toxicity in Japanese patients. The present results and considerations are likely to have application across East Asia. Prospective evaluations of genetic testing for UGT1A1 polymorphisms, encompassing both medical aspects and cost effectiveness, appear to be warranted, especially in East Asian countries including Japan. Table 1. Genotype frequencies of UGT1A1*28 and UGT1A1*6 in Japanese