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Originally published as JCO Early Release 10.1200/JCO.2005.05.2464 on April 24 2006 © 2006 American Society of Clinical Oncology.
Irinogenetics: What Is the Right Star?University of Chicago, Section of Hematology/Oncology, Cancer Research Center, Chicago, IL The response of patients to drug therapy is variable and unpredictable. The current focus of pharmacogenetics is to find common genetic variants that are predictors of clinical phenotypes associated with drug therapy. This goal is usually pursued by genotyping patients for a particular polymorphism (a genetic variant occurring in > 1% of the population), a set of polymorphisms in the same gene, or different polymorphisms in different genes. The genes of interest in pharmacogenetics are those involved in the mechanism of action and/or disposition of a certain drug. For the classic cytotoxic agents commonly used in oncology, the elucidation of potential genetic predispositions of patients to severe toxicity has been of interest with a goal of improving their therapeutic index. The pharmacogenetics of irinotecan (irinogenetics)1 indicate that a common polymorphism in the uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) gene predisposes patients to severe toxicity. This variant is a TA repeat promoter polymorphism reducing the expression of the UGT1A1 gene. In this issue, Han et al2 analyzed the association between common variants in several UGT1A genes, including UGT1A1, and evaluated the impact of these variants on toxicity and efficacy of irinotecan administered with cisplatin in a population of Korean non–small-cell lung cancer (NSCLC) patients. This article indicates that, in addition to the TA repeat polymorphism, another common variant found only in individuals of East Asian descent might have a predictive role. Moreover, this article suggests that these polymorphisms might have an impact on the antitumor efficacy of irinotecan. To have a better understanding of the findings of Han et al,2 we need to clarify the structure of the UGT1A gene. In humans, there are nine functional UGT1A enzymes with different patterns of tissue distribution. As partly shown in Figure 1 of the article by Han et al,2 UGT1A isoforms are generated from a single UGT1A gene by splicing of individual exons 1 with common exons 2 to 5, spanning more than 200 Kb of genomic sequence on chromosome 2. Polymorphisms in the common exons are relatively uncommon but would potentially affect the expression or function of all UGT1A isoforms. However, there are many common polymorphisms that affect the expression or function of single isoforms, either in their exon 1 or in the upstream promoter area. Irinotecan is mainly used in metastatic colorectal cancer patients. Regimens containing irinotecan are often relegated to second-line therapy because of unpredictable toxicity and the availability of equally effective agents (eg, oxaliplatin). Irinotecan causes severe diarrhea and neutropenia in 20% to 35% of patients.3-7 The late-onset grade 3 or 4 diarrhea often does not respond to the recommended loperamide therapy and can require hospitalization, irinotecan dose modifications, and/or dose interruptions, potentially compromising efficacy. Fatal events (up to 5.3% prevalence) during single-agent irinotecan treatment have been reported,6 and concerns have been expressed regarding an excessive rate of early deaths in colorectal cancer patients receiving irinotecan/fluorouracil regimens.8 Despite this discouraging scenario, recent studies9,10 have shown that irinotecan is an active drug with an important role in standard-of-care treatment regimens for colorectal cancer.11 Overall survival of metastatic colorectal cancer patients can be excellent if patients receive all active drugs, including irinotecan, during their course of treatment.12 The understanding of irinotecan pharmacology and genetic variability of key genes has made possible the identification of a subset of patients who are genetically predisposed to severe toxicity. In normal and tumor tissues, the hydrolysis of irinotecan leads to the formation of SN-38, a potent topoisomerase inhibitor. SN-38 formation within the tumor may be an important determinant of antitumor activity. The inactivation of SN-38 occurs by glucuronidation to SN-38 glucuronide (SN-38G), mainly through UGT1A1, an isoform expressed in the liver and also in extrahepatic tissues. In addition to UGT1A1, other UGT1A isoforms (including UGT1A6, UGT1A7, UGT1A9, and UGT1A10) are capable of metabolizing SN-38. It is likely that the exposure of patients to SN-38 is the ultimate result of the contribution of several UGT1As, in particular those that are highly expressed in the liver. High interpatient variability in irinotecan clearance and SN-38 area under the curve (AUC) has been observed,13-15 but there is no consistency across different studies on whether the AUC of irinotecan, SN-38, SN-38G, or a combination of these three parameters (the biliary index) is the strongest predictor of either severe neutropenia or diarrhea.16,17 However, it is certainly clear that changes in function of the UGT1A1 gene in patients will affect the exposure to SN-38, resulting in different susceptibility to toxicity among patients. The most studied polymorphism in irinogenetics is a common TA repeat variant in the UGT1A1 promoter. In the population, five, six, seven, and eight TA repeats can be found. UGT1A1 expression in individuals is inversely correlated with the number of TA repeats. In pharmacogenetics, gene variants are numbered with a "*" (star) preceding a number. The *1 allele of a gene is the allele of the reference sequence (previously referred to as wild-type allele, a term that is becoming obsolete). Hence, the six TA repeat allele is the reference sequence, is classified as *1, and is the most common allele. The seven TA repeat allele is the second most common and is classified as *28. The five and eight TA repeat alleles are rarely found in whites and Asians and have a low frequency in individuals of African descent. In whites, homozygosity for UGT1A1*28 has been associated with the classical picture of Gilbert's syndrome, a common mild and generally medically inconsequential hyperbilirubinemia syndrome. The frequency of *1/*1, *1/*28, and *28/*28 genotypes varies depending on different ethnicities (24% to 77%, 13% to 39%, and 1% to 24%, respectively).18-20 The clinical importance of the *28 allele has been elucidated in several studies. The risk of severe toxicity of irinotecan (both hematologic and GI) is higher in *28/*28 patients compared to *1/*1 and *1/*28 patients, with an odds ratio ranging from 7.2 to 11 in different studies.13,21-23 In the study by Han et al,2 in addition to *28, several other variants in the UGT1A genes were investigated. Among them, the ones associated with phenotypic changes were UGT1A1*6, UGT1A7*3, and UGT1A9*22. UGT1A1*6 was associated with grade 4 neutropenia; UGT1A9*1 and UGT1A7*3 were associated with grade 3 diarrhea. UGT1A1*6, UGT1A7*3, and UGT1A9*1 were associated with lower SN-38G/SN-38 AUC ratios and a higher SN-38 AUC. These results suggest that the effects of these variants on toxicity are mediated through altered exposure of patients to SN-38, as previously reported.13 However, the quantitative contribution of each of these variants to the observed effects is difficult to establish because of the fact that, among these variants, there is a high degree of linkage disequilibrium (the nonrandom distribution of the alleles of genes that reside on the same chromosome). For example, in data of Han et al,2 UGT1A1*6 is highly linked with UGT1A7*3, and close linkage exists between UGT1A7*3 and UGT1A9*22. Hence, what is the right star (such as the main allele) responsible for the bulk of the phenotypic effects in the study by Han et al?2 We believe that the UGT1A1*6 allele is the main allele responsible for severe toxicity of irinotecan in Asians. Its defective glucuronidating function has been well established at a molecular level,24,25 and this variant has been associated with Gilbert's syndrome in Asians.25,26 The UGT1A1*6 allele is found almost exclusively in Asian individuals (frequency of approximately 20%) and is rare in other ethnic groups. Interestingly, the frequency of the *28 allele is much lower in Asians compared with other populations, and, during evolution, the UGT1A1*6 variant might have been positively selected in Asians to compensate for the reduced frequency of the UGT1A1*28 allele and maintain the homeostasis of bilirubin levels.27 Concerning UGT1A7*3, this variant leads to reduced enzyme activity, but this enzyme is not expressed in the liver, suggesting a minor role in systemic SN-38 glucuronidation. In the GI tract, UGT1A7 is primarily expressed in the upper digestive tract,28-31 ruling out a local protective effect of UGT1A7 at the level of the intestinal mucosa. On the contrary, UGT1A9 is highly expressed in the liver, but data are discordant regarding its catalytic efficiency for SN-38 glucuronidation relative to UGT1A1.32-34 In addition, there are conflicting results regarding the molecular function of the UGT1A9*22 allele.27,35,36 These results are also in conflict with a recent study that suggested that the UGT1A9*22 allele was associated with more severe toxicity of irinotecan.37 Although UGT1A9 variation might contribute to the UGT1A1-mediated effects, the role of UGT1A9 variants in irinotecan toxicity remains to be clearly established. In Asian patients receiving irinotecan, what would be the effect of the UGT1A1*6 variant when combined with the UGT1A1*28 allele? Would a synergistic or additive effect be expected? First of all, the UGT1A1*6 variant is infrequently found on the same haplotype containing the UGT1A1*28 allele.27,38,39 Haplotypes are the specific combinations of linked alleles in a gene or a cluster of genes. Patients who are homozygous for UGT1A1*6 are unlikely to be homozygous or heterozygous for the UGT1A1*28 allele. However, combined heterozygosity (such as patients heterozygous for both UGT1A1*28 and UGT1A1*6) might potentially lead to the phenotypic effects ascribed to the homozygous state for each variant (such as an additive effect). Although the UGT1A1*28 frequency is low in Asians, this allele might still have independent effects, in particular in UGT1A1*28 homozygotes. In the study by Han et al,2 because of the lack of UGT1A1*28 homozygotes, such an effect on toxicity could not be detected, which is contrary to the retrospective study of Ando et al21 in Japanese patients treated with irinotecan. The article by Han et al2 poses another important question. Are the UGT1A polymorphisms markers of irinotecan efficacy? In advanced NSCLC patients, the irinotecan/cisplatin doublet has shown response rates of 29% to 52% and a median survival time of 43 to 52 weeks.40-42 Similar to other more commonly used doublet regimens, markers predictive of survival after irinotecan therapy remain to be found. In the study by Han et al,2 UGT1A1*6 homozygous patients had more toxicity but also lower response rates and less survival time than the rest of the patients. These findings are difficult to explain, and there may be several reasons. Predictors of efficacy can result in false positives if the efficacy data are not controlled for other genetic and environmental factors, patient demographics, and tumor histology; no such factors were taken into account by Han et al2 in their survival analysis. For example, it is well known that sex is a prognostic factor in NSCLC,43-45 but the distribution of UGT1A1*6 by sex is not reported. Among the different mechanisms of resistance to chemotherapy, chromosomal and genetic instability of tumors, gene amplification, and somatic mutations in oncogenes and target proteins play a critical role. Increased SN-38 glucuronidation has been regarded as one of the mechanisms of irinotecan resistance.46,47 However, lower intratumoral inactivation of SN-38 in tumor cells (as a result of the presence of the defective glucuronidation) should be associated with higher cytotoxicity and better survival (not worse survival). The most plausible explanation of the negative effect of UGT1A1*6 on efficacy is that irinotecan dose-intensity/density or cycle number might have been lower in *6 carriers because of toxicity observed during the first cycle of chemotherapy. Although the mean delivered dose of irinotecan seems to be lower in *6/*6 patients (40.8 mg/m2/wk) compared with the rest of the patients (44.1 mg/m2/wk), this difference is not statistically significant (see Table 3 in Han et al2). However, dose delays and the number of cycles of treatment delivered per patient are not reported. So far, the efficacy data in UGT1A1*28-genotyped patients have been discordant. In NSCLC patients treated with irinotecan and docetaxel, a nonsignificant trend toward better time to progression and survival was observed in UGT1A1*28 carriers, but differences in severe toxicity were not observed.48 In metastatic colorectal cancer patients, a nonsignificant trend toward better survival in noncarriers of UGT1A1*28 was observed, possibly because of reduced irinotecan dose-intensity in patients who experienced severe toxicity.23 The role of UGT1A variants on irinotecan dose-intensity and its consequences on efficacy require further investigation because the results to date are inconclusive. Until recently, irinotecan dose has been calculated solely based on body-surface area. However, the irinotecan label has recently been revised based on the results of a prospective study conducted in primarily white patients13 (http://www.pfizeroncology.com/hcp/camptosar.aspx). The label now warns that homozygosity for UGT1A1*28 is a risk factor for severe neutropenia and recommends that patients with this genotype should be treated with a reduced starting dose of irinotecan. The data of Han et al2 indicate that UGT1A1*28 testing alone may be insufficient to predict the risk of severe toxicity in patients of Asian origin. Instead, these patients may need to be tested for both UGT1A1*28 and UGT1A1*6. Full individualization of irinotecan dosing has not yet been accomplished. The UGT1A1 genetic test can be used to avoid severe toxicity in predisposed patients who might benefit from either a reduced irinotecan dose or other alternative regimens for colorectal cancer. Patients without the UGT1A1*28 or UGT1A1*6 alleles can probably tolerate a higher dose of irinotecan, possibly resulting in improved efficacy compared with the standard dose. Moreover, the safe dose of irinotecan in UGT1A1*28 homozygous patients has not been definitively identified yet, although it is likely to be approximately a 20% dose reduction given the relationship of genotype to SN-38 exposure.13 Hence, future applications of the UGT1A1 genetic test could lead to the individualization of irinotecan dose by genotype, and genotype-directed trials have been planned at the University of Chicago and by the Cancer and Leukemia Group B. The genetic makeup of patients might differ not only because of the presence or absence of a risk allele, but also because of the presence of other alleles in the same gene changing such risk, depending on the ethnic background of patients. The field of pharmacogenetics is moving from genotype-based to haplotype-based investigations.1 Genetic tests of prediction of toxicity and efficacy will become more and more common practice in oncology. Few oncologists are familiar with the complexity of the structure of the UGT1A gene, the impact of ethnic differences in the genetic makeups of patients, the linkage disequilibrium among alleles, the haplotypic structure of genes, and the nomenclature of gene alleles. We believe that the elucidation of these concepts has become timely as a result of the recent introduction of the information related to the UGT1A1*28 variant in the irinotecan label, as well as the commercialization of diagnostic tests for UGT1A1*28. The study by Han et al2 provides evidence that the UGT1A1*6 polymorphism can be considered a biomarker of severe toxicity of irinotecan in Asians. The impact of this variant on efficacy in irinotecan-containing regimens should be prospectively investigated in patients of Asian descent. The study by Han et al2 is a great example of the complexity of the application of pharmacogenetics to cancer treatment. Author Contributions
Author’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
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