Irinogenetics: How Many Stars Are There in the Sky?
Authors: Ron H.J. Mathijssen, Howard Gurney
Journal: Journal of Clinical Oncology (2009)

“Personalizing cancer care” is the theme of the 2009 ASCO Annual Meeting. 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 al 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. Several phase I and II enzymes are involved in its metabolism, as are a variety of uptake and efflux transporters. 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). Patients with two variant alleles for UGT1A1*28 seemed more prone to neutropenia or diarrhea compared with patients with one variant or none. Then came conflicting results from a meta-analysis by Hoskins et al, 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/m per week). Moreover, another UGT1A1 gene mutation, UGT1A1*6, rather than UGT1A1*28, was found to better explain irinotecan exposure and toxicity in Asians. Recently, a plethora of pharmacogenetic studies related to irinotecan has come to the fore, for which the term irinogenetics has been coined. 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. 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. The pharmacogenetic pathway assessment of irinotecan by Innocenti et al 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. 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? UGT1A1*28 kits are commercially available but have not been adopted worldwide, as we await the results of genotypedirected trials of dose on the basis of UGT1A1*28 genotype. However, Innocenti et al, 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 al 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. 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. Using toxicity as a drug exposure surrogate (ie, toxicity-adjusted dosing) has also been JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 16 JUNE 1 2009