Originally published as JCO Early Release 10.1200/JCO.2004.07.173 on March 8 2004

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Genetic Variants in the UDP-glucuronosyltransferase 1A1 Gene Predict the Risk of Severe Neutropenia of Irinotecan

From the Departments of Medicine, Human Genetics, and Health Studies, University of Chicago, Chicago, IL

Address reprint requests to Mark J. Ratain, MD, 5841 S Maryland Ave, MC2115, Chicago, IL 60637; e-mail: mratain{at}medicine.bsd.uchicago.edu

	ABSTRACT

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PURPOSE: Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation.

PATIENTS AND METHODS: Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m² every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (–3279G>T, –3156G>A, promoter TA indel, 211G>A, 686C>A) were genotyped.

RESULTS: The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P = .001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P = .02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean ± standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 ± 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 ± 0.03 mg/dL; P < .001). The –3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The –3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r² = 0.51).

CONCLUSION: UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the –3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.

	INTRODUCTION

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Irinotecan is approved worldwide for the treatment of metastatic colorectal cancer. Although it prolongs survival, it causes severe diarrhea and neutropenia in 20% to 35% of patients treated.^1-8 Fatal events (up to 5.3% prevalence) during single-agent irinotecan treatment have been reported,⁷ and concerns have been expressed regarding an excessive rate of early deaths in colorectal cancer patients receiving irinotecan + fluorouracil regimens.⁹ How one predicts the patients who will eventually suffer intolerable and potentially fatal toxicities is currently unknown.¹⁰ Although this scenario seems discouraging, the risk of severe toxicity might be predicted by investigating the genetic variation of irinotecan disposition. Irinotecan is activated by hydrolysis to SN-38, a potent topoisomerase I inhibitor¹¹ that is primarily inactivated through biotransformation into SN-38 glucuronide (SN-38G) by UGT1A1.¹² Interpatient differences in SN-38G formation have been correlated with the occurrence of severe diarrhea.^13,14

UGT1A1 genetic variation has been extensively investigated in relation to hyperbilirubinemic syndromes, as the UGT1A1 enzyme catalyzes bilirubin glucuronidation.¹⁵ Gene transcriptional efficiency has been inversely correlated to the number of TA repeats in the TATA box (5 to 8 repeats).¹⁶ Homozygosity for the TA₇ allele has been associated with the classical picture of Gilbert’s syndrome, a common mild hyperbilirubinemia.^17,18 Because of the clinical importance of the glucuronidation pathway in irinotecan treatment, UGT1A1 was chosen as the candidate gene to be investigated as a predictor of severe toxicity.

Here we present the results of a prospective trial of irinotecan pharmacogenetics in patients with advanced disease refractory to other treatments. The primary objective was to study the association between UGT1A1 genetic variants and the prevalence of severe toxicity. In addition, this study aimed to identify other factors contributing to increased toxicity risk using multivariable analyses, with particular reference to irinotecan pharmacokinetics and baseline clinical characteristics.

	PATIENTS AND METHODS

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Study Design and Treatments
Patients with histologically confirmed solid tumors or lymphoma of a type known to respond to irinotecan or for which no therapy of proven benefit exists received irinotecan 350 mg/m² (90-minute infusion) once every 3 weeks (Table 1). Other eligibility criteria have been published previously.¹⁹ Irinotecan was supplied by the National Cancer Institute. CBC and serum chemistry profiles were conducted before first treatment, and every week. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria Version 2.0 (http://ctep.cancer.gov). Venous blood (7 mL) for pharmacokinetic analysis was collected on day 1 of cycle 1 into sodium heparinized evacuated tubes before irinotecan infusion, and at 0.5, 1.0, 1.5, 1.67, 1.83, 2.0, 2.25, 2.5, 3.0, 3.5, 5.5, 7.5, 13.5, and 25.5 hours after the start of the infusion. Chromatography and pharmacokinetic analyses were performed as previously described.¹⁹ In the present article, toxicity of diarrhea and neutropenia refer to events observed during cycle 1 of treatment.

UGT1A1 Genotyping Assays
Three promoter variants (–3156G>A, –3279G>T, and TA indel) and two exon 1 variants (211G>A [G71R], 686C>A [P229Q]) were typed. The TA indel was genotyped as previously described.²⁰ Alleles with 5, 6, 7, and 8 TA repeats are reported as TA_n, and genotypes are assigned based on the number of TA repeats in each allele (ie, 6/6, 6/7, 7/7, 6/8, etc).

The –3279G>T, –3156G>A, 211G>A, and 686C>A variants were genotyped by single base extension (SBE) and separated on a denaturing high performance liquid chromatography (DHPLC) system.²¹ Genotyping of the –3279G>T and –3156G>A variants was performed simultaneously. The polymerase chain reaction (PCR) primers (5'-ACC TCT AGT TAC ATA ACC TGA A-3' [forward primer] and 5'-AAT AAA CCC GAC CTC ACC AC-3' [reverse primer]) amplified the region containing both single nucleotide polymorphisms. PCR-amplified products were purified before the SBE reaction. SBE reactions in 10 µL were performed in duplex for genotyping of both variants and contained 1 µmol/L extension primer (5'-GCC AAG GGT AGA GTT CAG T-3' for –3279G>T and 5'-GAC CCC AGC CCA CCT GTC-3' for –3156G>A), 250 µmol/L each ddNTP, and 1.25 U ThermoSequenase (Amersham Pharmacia Biotech, Buckinghamshire, United Kingdom). Reactions were denatured initially at 96°C for 2 minutes, then cycled at 96°C for 30 seconds, 55°C for 30 seconds, and 60°C for 30 seconds for 60 cycles. Separation of the SBE products was performed on a WAVE 3500HT DHPLC system (Transgenomic Inc, Omaha, NE) at 70°C after denaturation of the samples. The gradient was 24% to 34% B over 2 minutes. Extended products were eluted in the order of C<G<T<A, which is dependent on the hydrophobicity differences of the four bases.

Genotyping of the 211G>A and 686C>A variants was performed together. The PCR primers (5'-ATG CTG GGA AGA TAC TGT TG-3' [forward primer] and 5'-TTT GGT GAA GGC AGT TGA TT-3' [reverse primer]) amplified the region containing both single nucleotide polymorphisms. SBE reactions were performed using the following extension primers: 5'-GTC TTC AAG GTG TAA AAT GCT C-3' for 211G>A and 5'-GTG CGA CGT GGT TTA TTC CC-3' for 686C>A.

Statistical Analysis
The study was originally designed to prospectively investigate the relationship between genetic variation in the UGT1A1 promoter and grade 3 diarrhea. Based on a 20% to 35% prevalence of diarrhea with 350 mg/m² irinotecan given every 3 weeks,⁸ a sample size of 60 patients would have had power of 0.8 at = .05 to detect a linear trend in the proportion of patients within each genotype experiencing grade 3 diarrhea, defined by 60% of 7/7 patients, 30% of 6/7 patients, and 10% of 6/6 patients.

The low prevalence of grade 3 diarrhea in this trial did not allow any formal statistical analysis of this end point, and the analyses were focused instead on neutropenia. Using the observed genotype frequencies (see Results), the power to detect a similar gradient for grade 4 neutropenia is 80%.

Nonparametric trend tests were used to investigate how the genotype is related to pharmacokinetic parameters, pretreatment bilirubin, and absolute neutrophil count (ANC) nadir. The relationship between genotype, diplotypes, and grade 4 neutropenia was assessed by Fisher’s exact test and calculation of the relative risk. The pre- and posttreatment variables were considered jointly via analysis of covariance (ANCOVA) models to identify the variables predictive of ln(ANC nadir). ANC nadir was transformed to natural log scale to reduce skewness in the residuals. Final models were determined by backward elimination.

	RESULTS

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Among 65 patients, haplotypes were inferred based on previous knowledge of linkage disequilibrium in the UGT1A1 promoter region²² (Table 1). Diplotype and TA indel genotype frequencies are presented in Table 2. Allele frequencies of TA₅, TA₆, TA₇, and TA₈ were 0.01, 0.68, 0.29, and 0.02, respectively. Allele frequencies of –3279T and –3156A were 0.55 and 0.26, respectively. No exon 1 variants were detected.

View larger version (58K): [in this window] [in a new window]   Fig 1. Correlation between absolute neutrophil count (ANC) nadir (log scale) and TA indel genotype. Bars represent the means. The shaded area represents the ANC levels of grade 4 neutropenia. The 7/8 patient was not assessable for neutropenia.

Pretreatment total bilirubin levels were significantly correlated with the TA indel genotype (P < .01; Fig 2). Total bilirubin levels were significantly higher in 7/7 patients compared with 6/6 and 6/7 patients (mean ± SE, 0.80 ± 0.12 mg/dL and 0.48 ± 0.03 mg/dL, respectively; t₅₉ = –3.64, P = .0003). Concerning the distribution of the –3156 genotypes in each TA indel genotype group (Fig 2), the three 6/7 patients who were GG at –3156 had low bilirubin levels of 0.3 to 0.4 mg/dL. Similarly, the two 6/8 patients (GG at –3156) had low levels of bilirubin at 0.2 to 0.3 mg/dL. The one 7/7 patient who was GA at –3156 had a bilirubin level of 0.6 mg/dL, which is in the low range for this genotype group. The 7/8 patient (GA at –3156) did not have markedly elevated levels of bilirubin as would be expected if the TA₈ allele resulted in decreased glucuronidation. The –3279G>T variant was not associated with bilirubin when TG6/TG6 patients were compared with TG6/GG6 patients and when TG6/GA7 patients were compared with GG6/GA7 patients (P > .05). Higher bilirubin levels were observed in patients with grade 4 neutropenia (0.83 ± 0.08 mg/dL) compared with those without grade 4 neutropenia (0.47 ± 0.03 mg/dL; t₆₁ = 4.24; P = .001). Of the seven patients with total bilirubin higher than 0.7 mg/dL, four had grade 4 neutropenia. No grade 4 neutropenia was reported in patients with total bilirubin less than 0.6 mg/dL (Fig 3).

View larger version (16K): [in this window] [in a new window]   Fig 2. Pretreatment total bilirubin levels and distribution of the –3156 genotype (GG, AG, AA) in each TA indel genotype. Bars represent the mean values.

View larger version (40K): [in this window] [in a new window]   Fig 3. Correlation between absolute neutrophil count (ANC) nadir (log scale) and pretreatment total bilirubin levels. The shaded area represents the ANC levels of grade 4 neutropenia. (), less than 0.6 mg/dL; (•), 0.6 to 0.7 mg/dL; (), 0.8 mg/dL.

In order to understand the source of variability in neutropenia in multiple regression models, the –3156 variant was used instead of the TA indel genotype because it seemed to be a better predictor of the patient’s UGT1A1 functional status (Fig 2). Univariate regression of ln(ANC nadir) selected SN-38 AUC, total bilirubin, and the –3156 genotype as the three most highly correlated variables (r² of 0.35, 0.30, and 0.24, respectively; P < .001). Other significant (P < .01) variables were irinotecan AUC (r² = 0.13) and SN-38G/SN-38 AUC ratios (r² = 0.12). Sex showed a nonsignificant association (r² = 0.04; P = .1) with ANC nadir, but it was included in further models because of possible sex differences in glucuronidation. Other variables (SN-38 AUC, age 70 years, ethnicity, ln[pretreatment ANC], and performance status) were not significantly associated (P > .05).

Several multivariable predictive models were considered. The final model incorporating only pretreatment variables (r² = 0.40, intercept = 8.19 ± 0.28; P < .0001) included –3156 genotype (AA v GG + GA; coefficient = –0.94, SE = 0.40; P = .022), sex (males v females; coefficient = 0.43, SE = 0.20; P = .035), and total bilirubin (coefficient = –1.85, SE = 0.48; P < .001). After determining the predictive model using pretreatment variables, the pharmacokinetic parameters were added, and the final model (r² = 0.51; intercept = 8.31 ± 0.15; P < .0001) includes –3156 genotype (AA v GG + GA; coefficient = –1.38, SE = 0.32; P < .001), and SN-38 AUC (coefficient = –0.0019, SE = 0.0003; P < .001). The three AG patients with grade 4 neutropenia had very high levels of SN-38 AUC: two of them had the two highest values among all the patients (1,096 and 1,957 ng*h/mL), and the other had a value of 622 ng*h/mL—the sixth highest value.

One patient died of neutropenia-related sepsis. He had an AA genotype and the highest level of total bilirubin (1.2 mg/dL). Two partial tumor responses (colorectal and head and neck cancer patients, both AG genotype) and one complete response (colorectal cancer patient, GG genotype) were observed.

	DISCUSSION

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Identifying the patients genetically predisposed to severe toxicity of classical cytotoxic agents is a critical issue. In this study, grade 4 neutropenia was found to be highly correlated with the TA indel genotype. It is striking that none of the 29 patients with the 6/6 genotype experienced such severe toxicity. The effect of the TA indel genotype on neutropenia was already noted, but the correlation with the prevalence of severe neutropenia could not be established.¹⁹ Our study is in agreement with a retrospective analysis by Ando et al,²³ in which the TA₇ allele was a significant predictor of severe toxicity in patients receiving irinotecan-containing regimens. Due to its prospective nature, this study provides additional evidence of the role of the TA indel in the risk of severe neutropenia. A precise assessment of the sensitivity of the TA indel diagnostic test would require a larger number of patients, as also indicated by the quite wide 95% CIs of the test parameters. However, low sensitivity should not limit the utility of diagnostic tests aiming to predict toxicity outcomes.

The analysis of the role of other UGT1A1 promoter variants may shed light on the source of UGT1A1 phenotypic variability. The distribution of –3156 genotypes across each TA indel genotype shows that, regardless of the TA indel genotype, patients with the –3156G allele tend to have lower levels of total bilirubin, an established marker of the UGT1A1 status.^24-26 Our data suggest that the –3156G>A variant might be a better predictor of the UGT1A1 status than the TA indel. The functional significance of the –3156G>A variant is still unknown, and our analysis is limited by the small number of TA₇/-3156G haplotypes. If our hypothesis is confirmed in larger studies, the clinical implications of these findings would be major, as the –3156 variant might discriminate the individuals who are UGT1A1-deficient from those who are not. Based on the TA indel information, the risk of severe toxicity of irinotecan may be overestimated in a subset of 7/7 patients and in TA₈ patients. Moreover, although there is a significant association between diplotypes and occurrence of grade 4 neutropenia (table 3a), it is not possible to ascribe this effect to a particular UGT1A1 variant. As a matter of fact, it is possible that the association is mainly driven by the different distribution of the GA7 haplotype between the two patient groups (Table 3). The role of the most common UGT1A1 haplotypes will be investigated in a larger study (N = 500) in relation to total bilirubin levels in normal volunteers.

Another important conclusion of this article is that pretreatment total bilirubin is a useful predictor of severe neutropenia. The current data cannot establish whether total bilirubin is a better predictor than genotype in identifying the patients at risk of severe toxicity. It is of interest that in the model including only pretreatment data, both bilirubin and genotype were statistically significant, suggesting that each added predictive value. Nonetheless, total bilirubin might replace genotyping information when the latter is not available, as the two parameters seem to have comparable predictive power in univariate analyses.

This article highlights the importance of SN-38 exposure relative to the UGT1A1 status, as higher SN-38 levels are systemically available when UGT1A1 is deficient. This suggests that interplay between UGT1A1 function and genetic variability in SN-38 disposition pathways may have a major impact on irinotecan pharmacodynamics.

Understanding the genetic predisposition of cancer patients for developing severe toxicity has major clinical consequences. Our data indicate that irinotecan 350 mg/m² is relatively safe in cancer patients with either –3156 GG genotype or low bilirubin levels. On the contrary, severe and potentially life-threatening toxicity may occur and should be avoided in patients with AA or 7/7 genotype or with total bilirubin in the upper normal limit. This patient subset should probably receive a reduced irinotecan dose or, alternatively, an oxaliplatin-fluoropyrimidine regimen.^27,28

	Authors’ Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Mark J. Ratain, Variagenics. Acted as a consultant within the last 2 years: Mark J. Ratain, Variagenics.

	Acknowledgment

 
We thank Carla Buterman, Larry House, Suzanne Powaga, and Andrea Yoder Graber for the analysis of plasma samples.

	NOTES

 
Supported by the Pharmacogenetics of Anticancer Agents Research (PAAR) Group (http://pharmacogenetics.org; NIH/NIGMS grant U01 GM61393), the Phase I Clinical Trials of Anticancer Agents Grant (NIH/NCI U01 CA69852), the UCCRC Cancer Center Support Grant (P30 CA14599), and the University of Chicago General Clinical Research Center Grant (M01 RR00055). Data will be deposited into PharmGKB (supported by NIH/NIGMS U01 GM61374, http://pharmgkb.org/).

Preliminary data were presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted July 24, 2003; accepted December 9, 2003.

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