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Originally published as JCO Early Release 10.1200/JCO.2004.01.950 on March 8 2004 © 2004 American Society of Clinical Oncology.
Irinotecan Pharmacogenetics: Is It Time to Intervene?Departments of Medicine, Genetics, and Molecular Biology and Pharmacology, Washington University School of Medicine and the Siteman Cancer Center, St Louis, MO The development of unpredictable systemic toxicity while attempting to achieve tumor response has been a common observation for as long as there has been anticancer therapy. The narrow therapeutic index of most chemotherapeutic agents and the severe consequences of both undertreatment and overdosing have led to a pressing need for molecular predictors of the toxicity and efficacy of cancer treatments. In the days when there were few options for the treatment of most human malignancies, it was acceptable to tolerate grade 4 toxicities in as many as 10% of patients in the search for optimal dose-intensity. Better that a patient experience side effects than the tumor be undertreated. However, much progress has been made in treating human malignancies, and there are now multiple treatment options with similar efficacy for nearly every type of cancer. Ideally, patients should receive a regimen that offers optimal efficacy with minimal chance of severe side effects. This can only be accomplished if there are means to determine the relative risks of both patient benefit and toxicity. In the context of regimens demonstrating similar efficacy in large populations of patients, but showing no individual predictive markers of benefit, toxicity prediction would be a meaningful way to achieve the goal of better therapy for individual patients. Irinotecan is an excellent candidate for individualized therapy.1 The drug has demonstrated potent activity against many types of human cancer, in particular, gastrointestinal and pulmonary malignancies. Indeed, the addition of irinotecan to first-line therapy with fluorouracil and leucovorin has led to improved survival in patients with advanced colorectal cancer.2,3 However, irinotecan does have significant side effects, including both acute and delayed diarrhea, neutropenia, and a vascular syndrome.4 The gastrointestinal and vascular syndromes have been associated with a high mortality rate in patients receiving the combination of irinotecan with bolus fluorouracil and leucovorin during the first 60 days of therapy.4,5 There are now combination therapy regimens with equal or superior efficacy, such as infusional fluorouracil and leucovorin with irinotecan or oxaliplatin.6 Hence the conundrum: can we identify patients who will receive antitumor benefit from irinotecan without experiencing severe, life-threatening, or fatal toxicity? Irinotecan is among the camptothecin class of topoisomerase 1 inhibitors.7,8 It is a prodrug and must be converted to SN-38 by carboxylesterase 2, resulting in a greater than 1,000-fold enhancement of cytotoxic activity.9,10 Before activation, irinotecan must run a disposition gauntlet of oxidation by cytochrome p450 enzymes, and transport by adenosine triphosphate–binding cassette efflux pumps. SN-38 must also undergo one of three fates: binding to the cellular target topoisomerase 1, exclusion from the cell via efflux pumps, or inactivation by the addition of a glucuronide moiety. While each of these steps has the potential to substantially regulate irinotecan activity, it is glucuronidation by the protein UGT1A1 that has the clearest potential impact on patient care. The glucuronidation of lipophilic compounds is catalyzed in vertebrates by the uradine diphosphate–glucuronosyltransferases (UGTs). This catalytic reaction utilizes UDP-glucuronic acid as a cosubstrate for the formation of glucuronides from various substrates, such as bilirubin, hormones, drugs, and other xenobiotics. This reaction leads to the formation of hydrophilic glucuronides from lipophilic substrates, facilitating the transport of these molecules to aqueous compartments of the body, and leading to elimination through the bile and urine. UGT glucuronidation is consequently regarded as a "detoxification" reaction, and UGTs therefore represent major phase II drug metabolizing enzymes.11,12 More than 16 human UGTs have been characterized and divided into two families—UGT1 and UGT2. All known family-1 members are encoded by the UGT1A locus on chromosome 2q37, which has evolved with the potential to encode 13 separate UGT transcripts. This gene locus contains 13 first exons, each with its own promoter and enhancer regions, which are spliced to identical exons 2 to 5. However, only nine of these are currently thought to encode functional transcripts (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10).13 In contrast, the UGT2 locus consists of seven separate genes clustered on chromosome 4q13 (UGT2A1, 2B4, 2B7, 2B10, 2B11, 2B15, 2B17).14,15 In addition to the glucuronidation of SN-38 to the inactive metabolite SN-38G, UGT1A1 is also capable of forming bilirubin glucuronides. Observations of patients with physiological hyperbilirubinemias led to interest in bilirubin metabolism and were a major driving force behind the discovery of the UGT1A locus.16 In humans, three forms of heritable unconjugated hyperbilirubinemias exist: Crigler-Najjar syndrome type 1 and type 2 and Gilbert's syndrome. These heritable syndromes are all the result of low activity UGT1A1 gene or promoter alleles.17-20 To date, more than 30 variant UGT1A1 alleles have been identified.11,21 Thus, it is not surprising that Innocenti et al,22 in this issue of the Journal of Clinical Oncology, report an association between high pretreatment bilirubin levels and risk of developing grade 4 neutropenia after irinotecan therapy, as high steady-state bilirubin is indicative of low UGT1A1 activity.22 It is currently much easier to measure total bilirubin than to perform UGT1A1 DNA testing, though that may change in the near future. However, it is unclear whether bilirubin is reliable enough to use as a "poor man's" genetic test, especially in the context of the dynamic nature of the biliary tree in patients with liver metastasis. Of the known UGT1A1 genetic variants, a dinucleotide repeat in the promoter region associated with Gilbert's syndrome is known to influence gene expression.23,24 The presence of seven TA repeats, rather than the wild-type number of six, results in the variant allele UGT1A1*28. This allele is associated with reduced gene expression and reduced glucuronidation in human liver microsomes.23,25,26 In addition, recent studies have shown that the homozygous UGT1A1*28 genotype (7/7 genotype) leads to 1.8- to 3.9-fold lower glucuronidation of SN-38 compared with patients with the wild-type sequence (6/6 genotype; Table 1).
UGT1A1*28 has also been shown to be associated with a higher chance of developing severe diarrhea and leukopenia during irinotecan therapy (Table 1). In an initial retrospective study of 118 cancer patients treated with irinotecan, UGT1A1*28 was significantly associated with the development of treatment-related toxicity.27 In addition, in a prospective pilot study of 20 patients with solid tumors treated with irinotecan, severe toxicity was only observed in UGT1A1*28 carriers, and the presence of this allele was associated with lower absolute neutrophil count at nadir.26 These studies provided the first clear demonstration that determination of UGT1A1 genotypes may be clinically important for the prediction of irinotecan toxicity, and laid the groundwork for the study by Innocenti et al.22 This study administered irinotecan at a dose of 350 mg/m2 over 90 minutes to 66 patients. Genetic variants in UGT1A1 were assessed, including an interesting novel promoter single nucleotide polymorphism at base –3156 and the aforementioned TA repeat. UGT1A1 genotype and haplotype were then correlated with SN-38 pharmacology and incidence of severe toxicity. Patients with the 7/7 genotype (UGT1A1*28 homozygous) had a 9.3-fold greater risk of grade 4 neutropenia compared with the patients with a 6/6 or 6/7 genotype.
The study by Innocenti et al raises many clinically important issues. It provides the first prospective trial with sufficient statistical power to demonstrate that patients with a UGT1A1*28 allele are at higher risk of grade 4 neutropenia. We can argue about the small number ( The predicament in which we now find ourselves is determining what to do about these findings, and when it should be done. Ideally, we would like data on whether there is a predictable, safe, and effective dose of irinotecan that can be administered to a patient with the UGT1A1*28 homozygous genotype, or whether clinicians must choose an alternate non–irinotecan-containing regimen, simply to avoid the issue. With only approximately 10% of all patients having this genotype, it would take a heroic effort to perform the requisite randomized trial to establish both tumor response and safety end points. There may be insufficient will to conduct such a trial, with the great existing burden on most major clinical trial systems. The choice of ignoring the high risk of neutropenia in a patient with the UGT1A1*28 homozygous genotype, while we wait for yet another cohort study or retrospective assessment of large randomized trials, seems unsatisfactory. At the least, we should not give irinotecan 300 to 350 mg/m2 every 3 weeks to patients with a known UGT1A1 7/7 genotype until more definitive guidelines are established. Trials are planned to address the impact of dose on irinotecan safety in patients with either the UGT1A1 6/6 or 6/7 genotype, which are the two most common genotypes in the general patient population. This is only the beginning for the development of molecular predictors of toxicity risk and, hopefully, in the future, antitumor efficacy.28,29 Therefore, we need to start preparing for the integration of these molecular data into our treatment algorithms. It will be yet another piece of data in the complex management of cancer patients, but it will be worthwhile if patients win. Authors' Disclosures of Potential Conflicts of Interest 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. Acted as a consultant within the last 2 years: Howard L. McLeod, Sanofi-Synthelabo.
Acknowledgment The comments of Richard M. Goldberg, MD, and Sharon Marsh, PhD, were greatly appreciated. Study supported in part by the National Institutes of Health Pharmacogenetics Research Network (GM63340). REFERENCES
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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10%) of patients in the general North American population with the 7/7 genotype (UGT1A1*28 homozygous), but we now have to take this finding seriously. Three studies, from two laboratories on two continents, all point to a high risk of grade 4 neutropenia in patients with a UGT1A1*28 homozygous genotype (
