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Originally published as JCO Early Release 10.1200/JCO.2005.03.0239 on April 24 2006 © 2006 American Society of Clinical Oncology. Comprehensive Analysis of UGT1A Polymorphisms Predictive for Pharmacokinetics and Treatment Outcome in Patients With Non–Small-Cell Lung Cancer Treated With Irinotecan and Cisplatin
From the Research Institute and Hospital, National Cancer Center, Goyang; Research Institute of Aging Science, Yonsei University; Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea Address reprint requests to Jin Soo Lee, MD, Lung Cancer Branch, National Cancer Center, 809 Madu-dong, Ilsan-gu, Goyang, Gyeonggi 411-769, Korea; e-mail:jslee{at}ncc.re.kr
Purpose To determine whether uridine diphosphate-glucuronosyltransferase 1A1, UGT1A7, and UGT1A9 polymorphisms affect the pharmacokinetics (PK) of irinotecan and treatment outcome of Korean patients with advanced non–small-cell lung cancer (NSCLC). Methods Eighty-one patients with advanced NSCLC were treated with irinotecan (80 mg/m2) on day 1 and 8 and cisplatin (60 mg/m2) on day 1 intravenously of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using direct sequencing. We analyzed the association of UGT1A genotypes with irinotecan PK and clinical outcomes. All statistical tests were two-sided. Results In genotype-PK association analysis, UGT1A1*6/*6 (n = 6), UGT1A7*3/*3 (n = 6), and UGT1A9-118(dT)9/9 (n = 11) were associated with significantly lower area under the time-concentration curve (AUC) SN-38G to SN-38 (AUCSN-38G/AUCSN-38) ratio (P = .002, P = .009, and P = .001, respectively). In linkage disequilibrium analysis, the UGT1A7 variants were highly linked with the UGT1A1*6 (D' = 0.85, r2 = 0.63) and UGT1A9*22 (D' = 0.95, r2 = 0.88), which was substantiated in haplotype analysis. Patients with UGT1A1*6/*6 had lower tumor response and higher incidence of severe neutropenia. UGT1A9-118(dT)9/9 also showed a trend for high incidence of severe diarrhea, but not tumor response. In survival analysis, patients with UGT1A1*6/*6 had significantly shorter progression-free survival (P = .001) and overall survival (P = .017). Conclusion 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.
Inherited genetic polymorphisms of the genes involved in the activation and metabolism of certain chemotherapeutic agents can affect the outcome of patients after treatment with such agents. Irinotecan, a semisynthetic camptothecin analog with topoisomerase I–inhibiting activity,1-3 shows excellent clinical efficacy in such hard-to-treat solid tumors as lung and colorectal cancers.4-6 It is an excellent candidate for the pharmacogenetic studies because of a well-characterized metabolic pathway and significant, sometimes unpredictable and life-threatening, adverse effects.7,8 Irinotecan is a prodrug that is converted by carboxylesterase to an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), which has a 100- to 1,000-fold higher cytotoxicity than irinotecan. SN-38 is then further metabolized in the liver by uridine diphosphate-glucuronosyltransferases (UGTs) to an inactive metabolite, SN-38 glucuronide (SN-38G).1-3 Because glucuronidation is the major route of detoxification and elimination of active metabolite SN-38, inherited differences in irinotecan glucuronidating capacity may have an important influence on the pharmacokinetics and toxicity of this drug.9,10 To date, 17 human UGTs have been characterized.11-13 Most of the UGTs are expressed in the liver as well as other extrahepatic tissues; however, some are exclusively extrahepatic.14 UGT1A1, which is highly expressed in the liver, is the main isoform involved in the formation of SN-38G.14-17 The clinical significance of the –53(TA)6>7 (UGT1A1*28) for SN-38 glucuronidation and irinotecan-related toxicity is well established.14-17 Other UGT1A1 variants such as –3279T>G (UGT1A1*60) and 211G>A (UGT1A1*6) have also been suggested to contribute the UGT1A1 enzyme function.18 In addition to UGT1A1, the hepatic UGT1A9 has been suggested to contribute to the hepatic metabolism of SN-38.14,19,20 Recently, Yamanaka et al21 found that one base insertion of thymidine in a promoter region of the UGT1A9 gene (–118(T)9>10, UGT1A9*22) has been associated with variable UGT1A9 enzyme expression. UGT1A7, which is exclusively expressed in extrahepatic sites such as esophagus, gastrointestinal, and orolaryngeal tissues, has been demonstrated to glucuronidate several carcinogens.22,23 UGT1A7*3, a low-activity genotype, was found to be related to the increased risk of oropharyngeal, colorectal, and hepatocellular carcinomas in individuals with the polymorphism.24-26 Although it is an extrahepatic enzyme, recent in vitro study has demonstrated the effects of UGT1A7 on the glucuronidation of SN-38.18-20 Since those functionally important candidate UGT1A polymorphisms, including UGT1A1*6, UGT1A1*28, UGT1A1*60, UGT1A7*3, and UGT1A9*22, may affect the key enzyme activities of irinotecan metabolism, we postulated that those polymorphisms would eventually result in a difference in irinotecan-related toxicity and possibly the tumor response rates. Using DNA samples obtained from a predefined group of Korean patients with advanced non–small-cell lung cancers (NSCLC), who were enrolled in a prospective phase II study of irinotecan plus cisplatin chemotherapy,27 we examined the association of the genetic polymorphisms of UGT1A1 (*6, *28, and 60), UGT1A7 (1, *2, *3, *4), and UGT1A9 (*22) genes with the pharmacokinetic parameters of irinotecan metabolism and the clinical outcome.
Patients and Control Subjects A total of 81 patients with advanced NSCLC were enrolled onto a phase II study of irinotecan and cisplatin chemotherapy. The study subjects were described in detail elsewhere.27 Treatment consisted of irinotecan 80 mg/m2 intravenously on days 1 and 8 and cisplatin 60 mg/m2 intravenously on day 1 of a 21-day cycle. All patients gave written informed consent approved by the institutional review board of the National Cancer Center Hospital. The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Pharmacokinetic Study
UGT1A1, UGT1A7, and UGT1A9 Genotyping Assay
PCR products were purified using the Montage PCR96 Cleanup Kit (Millipore, Billerica, MA) and eluted in 20 µL nuclease-free water. DNA sequencing was carried out with BigDye Terminator V 3.1 Cycle Sequencing Kit (PerkinElmer, Fremont, CA). For dye terminator removal, Multiscreen SEQ 384 well filter plates were used, and sequences were analyzed using an Applied Biosystems (Foster City, CA) 3700 DNA Analyzer. All SNPs and sequence alignments were analyzed by the Polyphred 5.04 (University of Washington, Seattle, WA; http://droog.mbt.washington.edu/PolyPhred.html).
Statistical Analysis The genotype frequencies for each SNP were checked for consistency between the observed values and those expected from Hardy–Weinberg equilibrium using Haploview version 3.2 (Massachusetts Institute of Technology, Cambridge, MA; http://www.broad.mit.edu/mpg/haploview/index.php). Haploview based on the expectation-maximization method,29 were used to estimate the haplotype frequencies, the Lewontin's coefficients D',30 and correlation coefficient r2.31 The block structures and their haplotype frequencies were estimated using Haploview version 2.05.
UGT1A Genotypes and Allele Frequencies The UGT1A1, UGT1A7, and UGT1A9 variants typed in this study and their allele frequencies are listed in Table 1. The fine-scale map of those polymorphisms is shown in Figure 1. Concerning the allele frequencies, the frequencies of UGT1A9 –118 (*22), UGT1A1-3279T>G (*60), and 211G>A (*6, G71R) were comparable to the data previously reported in Asian patients.14,18 As expected, the frequency of the –53(TA)7 (*28) allele was very low compared with the data in white patients.14 Interestingly, there was no homozygous UGT1A1*28 in this study. All those variants were in Hardy-Weinberg equilibrium (P > .05).
UGT1A Genotype-Dependent Glucuronidation of SN-38 We examined the association of each UGT1A genotype with irinotecan-PK in 81 patients with NSCLC (Table 2). Patients with homozygous UGT1A1*6 (n = 6), UGT1A9-1189/9 (n = 11), and UGT1A7*3/*3 (n = 6) had significantly higher AUCSN-38 values than the others (P = .002, P = .046, and P = .006, respectively). Those patients also showed a significantly lower AUCSN-38G/AUCSN-38 ratio than others (P = .002, P = .001, and P = .009, respectively). However, there was no significant difference in pharmacokinetic characteristics including AUCSN-38G/AUCSN-38 ratio in patients with UGT1A1*28 or UGT1A1*60.
Association of UGT1A Genotypes With Tumor Response, Toxicity, and Delivered Dose of Irinotecan Of the 81 patients enrolled, 77 were assessable for response, and 36 (47%) of 77 assessable patients achieved partial responses.27 By genotype, patients with homozygous UGT1A1*6 showed a significantly lower response rate (0% v 50%, P = .038; Table 3). Patients with UGT1A7*3/*3 also showed a trend for lower response rate (P = .034).
We also examined the association of UGT1A genotypes with the toxicity profile for all 81 patients enrolled. The most common severe toxicity was National Cancer Institute Common Toxicity Criteria grade 4 neutropenia, which occurred in 22 (27%) patients, whereas grade 3 diarrhea developed in only eight patients (10%). Patients with homozygous UGT1A1*6 were only associated with higher incidence of grade 4 neutropenia (P = .044, Table 3). Patients with UGT1A9-118(T)9/9 or UGT1A7*3/*3 showed a trend for high incidence of grade 3 diarrhea (P = .037 and P = .028, respectively). However, UGT1A1*28 and UGT1A1*60 did not show any significant association with either objective tumor response or toxicity. Because UGT1A variants with lower enzyme activity were associated with higher incidence of severe toxicity and lower tumor responses, we analyzed the association of each UGT1A genotype with the actually delivered dose of irinotecan (mg/m2/wk). However, there was no significance (Table 3).
Linkage Disequilibrium Analysis
Association of UGT1A Genotypes and Survival We analyzed the survival outcome according to functionally important UGT1A1 and UGT1A9 genotypes. Patients with UGT1A1*6/*6 showed significantly shorter progression-free survival (P = .001; Fig 3A) and overall survival (P = .017; Fig 3B) when compared with patients with other genotypes. Meanwhile, no significant difference in survival outcome was observed according to UGT1A1*28, UGT1A1*60, and UGT1A9*22 genotypes.
Haplotype Analysis We constructed haplotypes using those five polymorphisms including UGT1A9*22, UGT1A7*, UGT1A1*60, UGT1A1*28, and UGT1A1*6 to clearly show the effect of those key SNPs, and found 16 haplotypes. The three most common haplotypes were 1, 2, and 3, which account for 82.7% of all haplotypes (Table 4). A total of 23 diplotypes were found, and the commonly observed diplotypes were 1,3 (n = 16); 1,2 (n = 16); 1,1 (n = 16); 2,2 (n = 5); and 2,3 (n = 4; Table 5).
We analyzed the effects of the most commonly observed haplotypes, 1, 2, 3, and 4, on the AUCSN-38G-AUCSN-38 ratio. The Kruskal-Wallis test showed that only haplotypes 1 (P = .008, Fig 4A) and 2 (P = .01, Fig 4B) were significantly associated with the AUCSN-38G/AUCSN-38 ratio. The presence of haplotype 1 (+/– or +/+) showed significantly higher AUCSN-38G-AUCSN-38 ratios than the absence of haplotype 1 (–/–; P = .016 and 0.003, post hoc analysis by the Mann-Whitney test, Fig 4A), whereas the homozygous haplotype 2 (+/+) showed a significantly lower AUCSN-38G/AUCSN-38 ratio than the absence of haplotype 2 (–/–; P = .001, post hoc analysis by the Mann-Whitney test, Fig 4B). Haplotypes 1 and 2 differ by the presence of UGT1A1*6, UGT1A7*3, and UGT1A9-118(T)9. Because UGT1A7 variants were highly linked with UGT1A1*6 or UGT1A9*22, these findings suggest that UGT1A1*6 and UGT1A9-118 may be functionally important for SN-38 glucuronidation.
To elucidate the most important functional polymorphism that determine the clinical outcome of NSCLC patients treated with irinotecan-based chemotherapy, we examined the interaction of various candidate polymorphisms of the UGT1A1, UGT1A7, and UGT1A9 genes. In our study, UGT1A1*6/*6 and UGT1A9-118(dT)9/9 were associated with significantly lower AUCSN-38G/AUCSN-38 ratios (P = .002 and P = .001, respectively). This was also substantiated in haplotype analysis. Although the UGT1A7*3 allele was related to lower SN-38 glucuronidation activity, high LD was observed across UGT1A7*3, UGT1A1*6, and UGT1A9*22, which attributed to the specific phenotype of UGT1A7*3 in this study. Furthermore, those patients with homozygous UGT1A1*6 or UGT1A9-118(T)9/9 had higher incidences of irinotecan-related severe toxicities. Specifically, patients with homozygous UGT1A1*6 had lower tumor response rates and shorter progression-free and overall survival than the patients with other genotypes. These findings suggest that UGT1A1*6 and UGT1A9*22 genotypes might be important for SN-38 glucuronidation and also could predict the clinical outcome of Korean patients treated with irinotecan-based chemotherapy. Regarding the effects of UGT1A genotypes on clinical outcome, Carlini et al32 reported that UGT1A9-118(dT)9/9 and UGT1A7*2/*2 and *3/*3 were significantly associated with better response and less severe toxicity in patients with colorectal cancer. In this study, we found that patients with UGT1A9-118(dT)9/9 or UGT1A7*3/*3 were significantly associated with a decreased AUCSN-38G/AUCSN-38 ratio and had a trend for higher incidence of severe toxicities. Because glucuronidation is the major route of detoxification and elimination of active metabolite SN-38, inherited differences in irinotecan glucuronidating capacity is known to have an important influence on the pharmacokinetics and toxicity of irinotecan.3,9,33 Furthermore we found that UGT1A9-118(dT)9>10 is highly linked with UGT1A7 variants. These findings with the well-balanced association of a decreased AUCSN-38G/AUCSN-38 ratio and higher incidence of severe toxicity in our study support the adverse pharmacogenetic effects of UGT1A9-118(dT)9/9 in irinotecan-based chemotherapy. Several studies have demonstrated an association between UGT1A1*28, a low-activity phenotype, and the increased incidence of irinotecan-related severe toxicity.15-17,33 Indeed, we observed a decreased AUCSN-38G/AUCSN-38 ratio in patients with the UGT1A*28 allele; however, it was not statistically significant when compared with the wild type in this study. In fact, UGT1A1*28 is highly prevalent in white individuals, with reported frequencies of 0.29 to 0.47,34,35 while it has much lower frequency (0.08 to 0.19) in Asians.36 In this study, the allele frequency of UGT1A1*28 was 0.07. Furthermore, there was no homozygous UGT1A1*28. Therefore, we could not completely rule out the functional importance of UGT1A1*28 in this study. Meanwhile, UGT1A1*6 is more prevalent (0.11 to 0.13) than UGT1A1*28 among the Asian population. It is also most commonly associated with Gilbert's syndrome among Asians.37 In our study, the allele frequency of UGT1A1*28 was lower than that of UGT1A1*6 (0.148 v 0.395, P = .001). This finding suggests that UGT1A1*6 may be more important than UGT1A1*28 in predicting the outcome of irinotecan-containing treatment among Korean patients. In summary, comprehensive analysis of UGT1A1, UGT1A7, and UGT1A9 genotypes showed that theses genes are strongly linked to each other and the interaction among functional polymorphisms are related to the alteration in the activity of these enzymes. Although it is still hypothetical, we suggest that UGT1A1*6 and/or UGT1A9*22 genotypes might be important for predicting severe toxicity and treatment outcome after irinotecan-based chemotherapy. To confirm the data observed in this study, further larger studies are needed in an independent data set, preferably in a group of patients of similar ethnicity.
The authors indicated no potential conflicts of interest.
This study was supported by Grants No. 0210130, 0210140, 0510140, and 0510080 from the National Cancer Center, Goyang, Korea. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or Fisher's exact test for categoric variables, or Mann-Whitney U test for continuous ones. The analysis of a trend of phenotype across the genotype was performed with the Armitage trend test in the SAS system, version 8 (SAS Institute Inc, Cary, NC). Kaplan-Meier estimates and the log-rank test were used in univariate analyses of overall survival. 
–42(TA)6>7 (*28), and 211G>A (*6) (
