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Originally published as JCO Early Release 10.1200/JCO.2008.21.2480 on April 6 2009 © 2009 American Society of Clinical Oncology.
Irinogenetics: How Many Stars Are There in the Sky?Department of Medical Oncology, Erasmus MC – Daniel den Hoed Cancer Center, University Medical Center, Rotterdam, the Netherlands
Departments of Medical Oncology and Medicine, Westmead Hospital, University of Sydney, Westmead, Australia "Personalizing cancer care" is the theme of the 2009 ASCO Annual Meeting.1 This underscores the status of personalized medicine as a hot topic. However, in anticancer drug therapy for the individual patient, dose calculation remains an Achilles' heel. How do we ensure every patient receives a drug dose high enough to be effective without causing serious morbidity? Pharmacogenetics has been touted as a potential answer. In this issue of Journal of Clinical Oncology, Innocenti et al2 provide a comprehensive assessment of the genes involved in irinotecan disposition. Irinotecan has a narrow therapeutic window, sometimes necessitating dose reduction and hospital admission for diarrhea and neutropenia.3 Several phase I and II enzymes are involved in its metabolism, as are a variety of uptake and efflux transporters.4 Uridine-diphosphate glucuronosyltransferase (UGT) 1A1 and cytochrome P450 (CYP) 3A are generally considered to largely dictate the pharmacokinetic behavior of irinotecan. In the year 2000, the life of an irinotecan pharmacologist was fairly simple. A common genetic alteration in the promoter area of the UGT1A1 gene was found to predict toxicity, ultimately leading the US Food and Drug Administration to require a warning on the package insert of Camptosar (irinotecan hydrochloride; Pfizer, New York, NY).5–7 Patients with two variant alleles for UGT1A1*28 seemed more prone to neutropenia or diarrhea compared with patients with one variant or none.5–8 Then came conflicting results from a meta-analysis by Hoskins et al,9 showing a lack of relationship between UGT1A1*28 and diarrhea and suggesting the association with neutropenia was dose dependent; UGT1A1*28 had no effect in patients treated with a low dose of irinotecan (< 150 mg/m2 per week). Moreover, another UGT1A1 gene mutation, UGT1A1*6, rather than UGT1A1*28, was found to better explain irinotecan exposure and toxicity in Asians.10 Recently, a plethora of pharmacogenetic studies related to irinotecan has come to the fore, for which the term irinogenetics has been coined.11 Single-nucleotide polymorphisms (SNPs) and haplotypes have been studied in other UGT1A isoenzymes, carboxylesterases, CYP3As, and adenosine triphosphate binding cassette transporters and solute carriers, all of which are involved in irinotecan elimination.12–14 The complex interplay of the many proteins involved in irinotecan disposition make it extremely difficult to accurately predict the pharmacokinetic/dynamic profile in an individual.4 The pharmacogenetic pathway assessment of irinotecan by Innocenti et al2 is, to our knowledge, the largest of its kind so far, in which no fewer than 42 common genetic variants and some nongenetic variables were studied. A multivariate analysis showed that nearly 50% of the variations among individuals at the nadir of the neutrophil count after irinotecan monotherapy could be explained by a combination of genetic polymorphisms and nongenetic covariates, such as neutrophil baseline levels and sex. The gene combination attributed to 28% of these variations alone. Variations in ABCB1, ABCC1, ABCC2, SLCO1B1, HNF1A, and UGT1A1 correlated with irinotecan and SN-38 exposure, explaining 30% to 40% of the variations among individuals. Innocenti et al also confirmed their previous finding that UGT1A1*93 might be a better predictor of UGT1A1 status than is UGT1A1*28.7 However, one must question the validity of the findings because of the study size. To measure the influence of more than 40 genetic variants and a handful of nongenetic variables, 85 patients may be too few. In addition, the heterogeneity of the study population, in terms of ethnicity and dosing regimens, may have influenced the results. Where does the study leave us in the determination of irinotecan dose? Will a single polymorphism still be predictive for toxicity, or will its utility fade?15 UGT1A1*28 kits are commercially available but have not been adopted worldwide, as we await the results of genotype-directed trials of dose on the basis of UGT1A1*28 genotype.16 However, Innocenti et al,2 among others, question the validity of measuring a single polymorphism to predict drug elimination. It seems that new "stars" have appeared, with UGT1A1*93 and drug transporter SNPs (eg, ABCB1, -C1, and -C2 and SLCO1B1) showing their importance in irinotecan disposition. How many more new stars will be found to correlate with drug exposure for this and other drugs? Will we need to measure a panel of SNPs (a so-called "SNP-chip") before administering irinotecan, or any other drug? Is there a better alternative for dose individualization than genotyping? The flip side of the study by Innocenti et al2 is that the other half of the variation in toxicity and drug exposure is unexplained by genotype. Many nongenetic factors, such as smoking behavior and use of co-medication, are known to influence irinotecan disposition by altering the function of CYP3A or UGT1A.14,17,18 The study by Innocenti et al also raises a possible effect of sex on irinotecan toxicity (neutropenia occurred more often in women). Perhaps the sum of both genetic and environmental effects should be measured; in other words, the drug-elimination phenotype should be ascertained, rather than genotype alone. The use of probe drugs that mimic the metabolism of cytotoxic drugs, as well as therapeutic drug monitoring, has been tried with varying success.19,20 Using toxicity as a drug exposure surrogate (ie, toxicity-adjusted dosing) has also been proposed, whereby dose would be increased in absence of toxicity and vice versa.21 So far, none of these alternatives have proved practical or accurate. Despite this comprehensive assessment of irinotecan by Innocenti et al,2 we still do not have the holy grail for dose calculation, and we must question where pharmacogenetics is heading. It would be easy to conclude from the study by Innocenti et al that too many genes are involved in drug elimination, and pharmacogenetics is too complex to ever be of any practical clinical use. It could be argued that an explanation of only 50% of variability among individual patients is not good enough. However, most oncologists currently use a method for calculating irinotecan dose that explains only a fraction of variability among patients (ie, body-surface area).22 Surely we can do better than that. The sensible approach, as suggested by Innocenti et al,2 is to use this information and make a concerted effort to prospectively test—in a large number of patients—these candidate genes for irinotecan disposition to measure their true worth. Moreover, the general findings of their study are not specific to irinotecan. Almost all anticancer drugs have similarly complex elimination mechanisms. Rather, this study serves as a model for other drugs. If we can comprehensively predict drug elimination in individuals for a few drugs, it is possible that common gene patterns will be unmasked that hold true for many drugs. Individual Homo sapiens are pretty much like one another.23 The number of different drug elimination pathways in individual humans cannot be infinite. Clearly, many important questions need to be answered before true personalized dosing of irinotecan becomes common practice. But with its new stars, irinogenetics may illuminate the way forward to ultimately determining a drug elimination genotype that may well have relevance for many other drugs. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Ron H.J. Mathijssen, Howard Gurney Manuscript writing: Ron H.J. Mathijssen, Howard Gurney Final approval of manuscript: Ron H.J. Mathijssen, Howard Gurney REFERENCES 1. 2009 ASCO Annual Meeting. www.asco.org/ASCO/Meetings/ASCO+Annual+Meeting. 2. Innocenti F, Kroetz DL, Schuetz E, et al: Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. J Clin Oncol 27:2604–2614, 2009. 3. Fuchs CS, Marshall J, Mitchell E, et al: Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Results from the BICC-C study. J Clin Oncol 25:4779–4786, 2007. 4. Di Paolo A, Bocci G, Danesi R, et al: Clinical pharmacokinetics of irinotecan-based chemotherapy in colorectal cancer patients. Curr Clin Pharmacol 1:311–323, 2006.[CrossRef][Medline] 5. Ando Y, Saka H, Ando M, et al: Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: A pharmacogenetic analysis. Cancer Res 60:6921–6926, 2000. 6. Iyer L, Das S, Janisch L, et al: UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2:43–47, 2002.[CrossRef][Medline] 7. Innocenti F, Undevia SD, Iyer L, et al: Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382–1388, 2004. 8. Marcuello E, Altés A, Menoyo A, et al: UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer 91:678–682, 2004.[CrossRef][Medline] 9. Hoskins JM, Goldberg RM, Qu P, et al: UGT1A1*28 genotype and irinotecan-induced neutropenia: Dose matters. J Natl Cancer Inst 99:1290–1295, 2007. 10. Han JY, Lim HS, Shin ES, et al: Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non–small-cell lung cancer treated with irinotecan and cisplatin. J Clin Oncol 24:2237–2244, 2006. 11. Innocenti F, Ratain MJ: "Irinogenetics" and UGT1A: From genotypes to haplotypes. Clin Pharmacol Ther 75:495–500, 2004.[CrossRef][Medline] 12. Mathijssen RH, Marsh S, Karlsson MO, et al: Irinotecan pathway genotype analysis to predict pharmacokinetics. Clin Cancer Res 9:3246–3253, 2003. 13. Rosner GL, Panetta JC, Innocenti F, et al: Pharmacogenetic pathway analysis of irinotecan. Clin Pharmacol Ther 84:393–402, 2008.[CrossRef][Medline] 14. Kweekel D, Guchelaar HJ, Gelderblom H: Clinical and pharmacogenetic factors associated with irinotecan toxicity. Cancer Treat Rev 34:656–669, 2008.[CrossRef][Medline] 15. Toffoli G, Cecchin E, Corona G, et al: The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 24:3061–3068, 2006. 16. Innocenti F, Janisch L, Das S, et al: A genotype-directed phase I study of irinotecan in advanced cancer patients. J Clin Oncol 25:97s; 2007 (suppl) abstr 2502.[CrossRef] 17. van der Bol JM, Mathijssen RH, Loos WJ, et al: Cigarette smoking and irinotecan treatment: Pharmacokinetic interaction and effects on neutropenia. J Clin Oncol 25:2719–2726, 2007. 18. Corona G, Vaccher E, Sandron S, et al: Lopinavir-ritonavir dramatically affects the pharmacokinetics of irinotecan in HIV patients with Kaposi's sarcoma. Clin Pharmacol Ther 83:601–606, 2008.[CrossRef][Medline] 19. Kharasch ED, Thummel KE, Watkins PB: CYP3A probes can quantitatively predict the in vivo kinetics of other CYP3A substrates and can accurately assess CYP3A induction and inhibition. Mol Interv 5:151–153, 2005. 20. Mathijssen RH, de Jong FA, van Schaik RH, et al: Prediction of irinotecan pharmacokinetics by use of cytochrome P450 3A4 phenotyping probes. J Natl Cancer Inst 96:1585–1592, 2004. 21. Gao B, Klumpen HJ, Gurney H: Dose calculation of anticancer drugs. Expert Opin Drug Metab Toxicol 4:1307–1319, 2008.[CrossRef][Medline] 22. Mathijssen RH, Verweij J, de Jonge MJ, et al: Impact of body-size measures on irinotecan clearance: Alternative dosing recommendations. J Clin Oncol 20:81–87, 2002. 23. Levy S, Sutton G, Ng PC, et al: The diploid genome sequence of an individual human. PLoS Biol 5:e254; 2007.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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