Comprehensive Analysis ofUGT1APolymorphisms Predictive for Pharmacokinetics and Treatment Outcome in Patients With Non–Small-Cell Lung Cancer Treated With Irinotecan and Cisplatin

Abstract

These findings suggest that UGT1A1*6 and UGT1A9*22 genotypes may be important for SN-38 glucuronidation and associate with irinotecan-related severe toxicity. Specifically, UGT1A1*6 might be useful for predicting tumor response and survival outcome of Korean patients with NSCLC treated with irinotecan-based chemotherapy.

UGT1A1*6, UGT1A7*3 and UGT1A9*1b polymorphisms are predictive markers for severe toxicity in patients with metastatic gastrointestinal cancer treated with irinotecan-based regimens

“…UGT1A1 * 6, which is found only in Asian populations, had the highest frequency [minor allele frequency (MAF), 22.5%] of the SNPs in UGT1A1 in the present study. The frequency of the UGT1A1 * 28 SNP (MAF, 9.3%) was comparable to the frequency previously found in the Asian population (MAF, 7.0%), and was much lower compared with the frequency in Caucasian patients (MAF, 31.6%), as previously reported (11,20). Other known UGT1A alleles, UGT1A1 * 80, UGT1A1 * 81, UGT1A7 * 2, UGT1A7 * 3 and UGT1A9 * 1b (UGT1A9 * 22), were found concurrently.…”

“…shown to affect the variability of irinotecan toxicity during clinical application (11,12). Considering the complex mechanism involved in the association between the UGT1A family and toxicity of irinotecan, the FDA has instructed the manufacturer of irinotecan to revise the label and add the caution of relative toxicity and dose titration in patients with the UGT1A1 * 28 polymorphism, as well as the advice for patients to undergo allelic detection (13).…”

“…Considering the complex mechanism involved in the association between the UGT1A family and toxicity of irinotecan, the FDA has instructed the manufacturer of irinotecan to revise the label and add the caution of relative toxicity and dose titration in patients with the UGT1A1 * 28 polymorphism, as well as the advice for patients to undergo allelic detection (13). For patients from the Asian population, UGT1A1 * 6 is considered to be another potential risk factor that is responsible for the toxicity among the Asian population in addition to the UGT1A1 * 28 allele (11,12,14). The Japanese Pharmaceuticals and Medical Devices Agency package insert for irinotecan states that individuals who are homozygous for the UGT1A1 * 6 or UCT1A1 * 28 alleles, or heterozygous with the UGT1A1 * 6/ * 28 genotype, are at an increased risk of severe adverse events, particularly neutropenia (15).…”

Three-week schedule of irinotecan plus cisplatin in patients with previously untreated extensive-stage small-cell lung cancer

“…Another phenotype associated with low tumour responses and high irinotecan-related toxicity is UGT1A1*28, and it is highly prevalent in Caucasian individuals with reported frequencies of 0.29 -0.47 (Bosma et al, 1995;Premawardhena et al, 2003), whereas it has much lower frequency in Asians (0.08 -0.19) . In Korean report, the frequency of UGT1A1*28 was 0.07 (Han et al, 2006). Therefore, it could be explained that ethnic differences might be involved in discrepant results in terms of efficacy and toxicity of irinotecan.…”

“…This glucuronidatioin is the major route of detoxification of irinotecan, thus inherited differences in irinotecan metabolism may have an important influence on the pharmacokinetics and toxicity of this drug. Han et al (2006) reported the UGT1A polymorphisms could predict treatment outcomes and toxicities of irinotecan in Korean patients. In this report, patients with homozygote of UGT1A1*6 allele had shorter PFS and more irinotecan-related toxicities.…”