Irinogenetics: What Is the Right Star?
Authors: Federico Innocenti, Everett E. Vokes, Mark J. Ratain
Journal: Journal of Clinical Oncology (2006)

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) indicate that a common polymorphism in the uridine diphosphateglucuronosyltransferase 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 al 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, 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, 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. 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, and concerns have been expressed regarding an excessive rate of early deaths in colorectal cancer patients receiving irinotecan/fluorouracil regimens. Despite this discouraging scenario, recent studies have shown that irinotecan is an active drug with an important role in standard-of-care treatment regimens for colorectal cancer. Overall survival of metastatic colorectal cancer patients can be excellent if patients receive all active drugs, including irinotecan, during their course of treatment. 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, 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. 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 15 MAY 2