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An overview of the recent progress in irinotecan pharmacogenetics
Recent developments in a number of molecular profiling technologies, including genomic/genetic testing, proteomic profiling and metabolomic analysis have allowed the development of ‘personalized medicine’. Irinotecan is one of the models for personalized medicine based on pharmacogenetics, and a number of clinical studies have revealed significant associations between UGT1A1*28 and irinotecan toxicity. Based on this cumulative evidence, the US FDA and pharmaceutical companies revised the irinotecan label in June 2005. However, a recommended strategy for irinotecan-dose adjustments based on individual genetic factors has not yet been fully established. This article provides an overview of recent progress in irinotecan pharmacogenetics and discusses the clinical significance of the UGT1A1 genotype/haplotype with regard to severe irinotecan toxicity.
KEYWORDS: ABCB1 n ABCC1 n ABCC2 n CES n CYP3A4 n ethnicity n irinotecan n pharmacogenomics n polymorphism n SNP n transporter n UGT

Yutaka Fujiwara? & Hironobu Minami
Author for correspondence: Medical Oncology/Hematology, Department of Medicine, Kobe University Hospital & Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan Tel.: +81 783 825 820 Fax: +81 783 825 821 yufujiwa@med.kobe-u.ac.jp
?

Irinotecan is an antineoplastic prodrug, approved worldwide for the treatment of a broad range of carcinomas, including colorectal and lung cancers. Irinotecan needs to be activated by systemic carboxylesterases to 7-ethyl-10-hydroxycamptotecin (SN-38), a topoisomerase I inhibitor. SN-38 is subsequently glucuronidated by uridine disphosphate glucuronosyltransferases (UGTs) to form an inactive metabolite, SN-38 glucuronide (SN-38G) [1–4] . Among the various UGT isozymes, UGT1A1 is a major enzyme that inactivates irinotecan to SN-38, and UGT1A7 and UGT1A9 are also involved in the inactivation of SN-38 [5–8] . While UGT1A9 is highly expressed in human liver, UGT1A7 is expressed in extrahepatic tissues and is potentially relevant to the enterohepatic circulation of SN-38 [9] . In addition to conversion to SN-38, irinotecan undergoes oxidation to metabolites, 7-ethyl-10-(4-N-[5-aminopentanoic acid]-1piperidino)-carbonyloxy-camptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino)-carbonyloxycamptothecin (NPC), by CYP3A4/5 enzymes [10] . Moreover, membrane transporters are responsible for the uptake of SN-38 from plasma into hepatocytes (e.g., OATP1B1) and the elimination of irinotecan and its metabolites into bile (e.g., ABCB1, ABCC2 and ABCG2). The ABCC1 transporter is responsible for the efflux of SN-38 from hepatocytes into the interstitial space (Figure?1) [11] . Dose-limiting toxicities of irinotecan are diarrhea and neutropenia [12] . A higher ratio of plasma SN-38:SN-38G has been shown to correlate with severe irinotecan
10.2217/PGS.10.19 ? 2010 Future Medicine Ltd

toxicities, suggesting that the efficiency of SN-38 glucuronidation is an important determinant of toxicity. Biliary SN-38G excreted into the small intestine is cleaved by bacterial glucuronidases in the colon to regenerate SN-38; therefore, this process is also assumed to be one of the mechanisms of late-onset diarrhea [13] . Although the pharmacokinetics of irinotecan are affected by many metabolic enzymes and transporters, the clinical relevance of lowered activity of UGT to severe irinotecan toxicity is well established, and UGT1A1 is the most prominent enzyme related to this [2,14,15] . Among UGT isoforms, UGT1A1 is abundant in both the liver and the intestine, and is thought to be mainly responsible for the inactivation of SN-38. Therefore, the association of UGT1A1 poly morphisms with irinotecan toxicities has been intensively studied. To date, a number of studies have demonstrated a significant association between UGT1A1*28, a repeat polymorphism in the TATA box (-54_-39A[TA] 6TAA>A[TA] 7TAA or -40_-39insTA), and reduced values of area under the time–concentration curve (AUC) of SN-38G and/or severe toxicities of irinotecan [16–20] . Patients who are homozygous for the UGT1A1*28 allele are at high risk of developing severe irinotecan toxicity, whereas heterozygous patients seem to be at intermediate risk [21] . The US FDA and pharmaceutical companies revised the irinotecan label in June 2005. The label now includes homozygosity for UGT1A1*28 genotype as one of the risk factors for severe neutropenia.
Pharmacogenomics (2010) 11(3), 391–406

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Blood Irinotecan

CES SN-38

ABCC2

SLCO1B1 Liver cell

Irinotecan

CES SN-38 UGT1A1 UGT1A7 UGT1A9

CYP3A4/5

ABCB1 APC NPC ABCC1 ABCC2

SN-38G

ABCC2

Irinotecan

SN-38 Intestinal epithelial cell

SN-38G

Pharmacogenomics ? Future Science Group (2010) s

Figure 1. Enzymes and transporters for the metabolism and disposition of irinotecan and its metabolites. ABCB1: Multidrug resistance protein B1 (P-glycoprotein); ABCC1: Multidrug resistance protein C1 (MRP1); ABCC2: Multidrug resistance-associated protein 2 (cMOAT); APC: 7-ethyl-10-(4-N-[5-aminopentanoic acid]-1-piperidino)-carbonyloxy-camptothecin; CES: Carboxylesterase isoforms; CYP3A4/5: Cytochrome P450 isoforms 3A4 and 3A5; NPC: 7-ethyl-10-(4-amino-1-piperidino)-carbonyloxycamptothecin; SLCO1B1: Solute carrier organic anion transporter family member 1B1 (OATP-C); SN-38: 7-ethyl-10-hydroxycamptothecin; SN-38G: SN-38 glucuronide; UGT1A1/9: UDP glucuronosyltransferase isoforms 1A1 and 1A9.

Although a genetic diagnostic kit for the *28 allele is available for clinical use in the USA, implementation of the genetic testing when using irinotecan is not mandatory. The irinotecan label states that a reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele. However, the appropriate dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment. Furthermore, several issues must be considered in clinical applications of the genetic test in each country, such as ethnic differences of genetic polymorphisms, the possible contribution of UGT1A7 and 1A9, and a balance between anti-tumor and adverse effects. Recent pharmacogenomics studies have suggested an
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advantage to the use of linked combinations of SNPs (haplotypes), rather than individual SNPs, to investigate the associations between genotypes and phenotypes [22] . Therefore, information on the haplotype structures covering the UGT1A1 gene complex in each ethnic population is particularly important for irinotecan pharmacogenetic research, and a number of recent studies with combinational haplotypes of UGT1A1, UGT1A7 and UGT1A9 have been instrumental in understanding irinotecan pharmacogenetics. In addition, transporters and other enzymes involved in the metabolism, distribution and excretion of irinotecan and its metabolites should be considered in pharmacogenomics research. SNPs in enzymes involved in the metabolism, distribution and excretion of irinotecan and its metabolites are listed in Table?1.
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An overview of the recent progress in irinotecan pharmacogenetics

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Genetic polymorphisms & haplotypes of UGT1As Uridine disphosphate glucuronosyltransferases catalyze the transfer of a glucuronic acid from uridine diphosphoglucuronic acid to a variety

of endogenous and exogenous compounds. The UGT gene superfamily can currently be divided into four families, UGT1, UGT2, UGT3 and UGT8 [23] . The human UGT1 gene on chromosome 2q37 spans approximately 200 kb

Table 1. Genotype frequencies of enzymes and transporters involved in the metabolism, distribution and excretion of irinotecan and its metabolites.
Region
UGT1A1

dbSNP
rs8175347 rs3755319 rs887829 rs10929302 rs4148323 rs35350960 rs34993780 rs17868323 rs17863778 rs11692021 rs45625337 rs2741049 rs11075646 rs72547531 rs72547532 rs8192924 rs72547533 rs55785340 rs2740574 rs4986908 rs4987161 rs4986907 rs12721627 rs28371759 rs4986910 rs776746 rs1045642 rs1128503 rs2032582 rs10276036 rs2074087 rs3765129 rs35605 rs3740066 rs2273697 rs2804402 rs1885301 rs717620 rs2622604 rs2306283 rs4149056

Function
5’ near gene 5’ near gene 5’ near gene Intron Exon 1 Exon 1 Exon 5 Exon 1 Exon 1 Exon 1 5’ near gene Intron 1 5’ near gene Exon 1 Exon 2 Exon 4 Exon 5 Intron 8 Exon 7 5’ near gene Exon 6 Exon 7 Exon 6 Exon 7 Exon 10 Exon 12 Intron 3 Exon 27 Exon 13 Exon 22 Intron 10 Intron 18 Intron 11 Exon 13 Exon 28 Exon 10 5’ near gene 5’ near gene 5’ near gene Intron 1 Exon 5 Exon 6

Polymorphism
-40_-39insTA -3279T>G -3140G>A -3156G>A 211G>A 686C>A 1456T>G 387T>G 391C>A 622C>T -126_-118 IVS1+399C>T 830C>G 1A>T 100C>T 424G>A 617G>A IVS8–2A>G 664T>C -392A>G 520G>C 566T>C 485G>A 554C>G 878T>C 1334T>C 6986A>G 3435C>T 1236C>T 2677G>T/A IVS9–44A>G IVC18–30G IVS11–48C>T 1684T>C 3972C>T 1249G>A -1019A>G -1549A>G -24C>T Intron 388A>G 521T>C

Alleles
*28 *60 *93 *6 *27 *7 *2, *3 *2, *3 *3, *4 *1b – *5 *2 *3 *6 *4 *2 *1B *10 *17 *15 *16 *18B *3 *2 *2 *2

Variant allele frequency
European 0.30–0.40? 0.424 0.283 0.267 0.000 0.000 0.014 0.537 0.537 0.429 0.466 0.383 0.190 ND ND ND 0.000 ND ND 0.023 0.000 0.016 0.000 0.000 0.017 0.000 0.942 0.543 0.392 0.398/0.000 0.617 0.845 0.138 0.175 0.658 0.233 0.430 0.570 0.195 0.275 0.278 0.161 Asian 0.35–0.45? 0.233 0.089 0.089 0.211 0.006 ND ND ND 0.826 ND 0.633 0.000 0.002 0.002 0.002 0.000 0.002 ND 0.000 0.000 0.000 0.000 0.000 ND 0.000 0.667 0.400 0.689 0.522/0.152 0.311 0.756 0.111 0.278 0.733 0.078 0.100 0.900 0.100 0.083 0.622 0.156 African 0.07–0.16? 0.742 0.550 0.367 0.000 0.000 ND ND ND 0.771 ND 0.417 0.267 ND ND ND 0.000 ND ND 0.679 0.000 0.000 0.033 0.000 ND 0.033 0.150 0.110 0.123 0.000/0.000 0.850 0.836 0.000 0.075 0.725 0.217 0.365 0.515 0.060 0.178 0.733 0.008

UGT1A7

UGT1A9 CES2

CYP3A4

CYP3A5 ABCB1

ABCC1

ABCC2

ABCG2 SLCO1B1

C/T *1b *5, *15

Allele frequencies are based on the HapMap Project unless otherwise specified. ? Allele frequencies are obtained from data in [30,44–46]. dbSNP: SNP database; ND: Not determined.

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and consists of nine functional (UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A9, UGT1A8 and UGT1A10) and four pseudo-active (UGT1A2P, UGT1A11P, UGT1A12P and UGT1A13P) exon 1 segments and a shared set of common exons 2–5 [24,25] . UGT1A1, 1A3, 1A4, 1A6 and 1A9 are expressed in the liver as well as in extra hepatic tissues, including the GI tract, while UGT1A7, 1A8 and 1A10 are detected in extrahepatic tissues. There are large interindividual differences in UGT1A content and activities in various tissues, and UGT1A genetic polymorphisms in promoter or coding regions have been implicated as one of the sources of these variations. More than 100 polymorphisms of the UGT1A1 gene have been identified to date [101] . UGT1A1 also glucuronidates bilirubin, and some polymorphisms are related to mild, nonfatal hyperbilirubinemia, leading to Gilbert’s syndrome or Crigler–Najjar syndromes types I and II [26–29] . The number of TA repeats (A[TA]nTAA, n = 5–8) and the UGT1A1*60 allele (-3279T>G) are genetic variations that reportedly reduce transcriptional activity of UGT1A1 and have been associated with increased plasma bilirubin levels [30,31] . The wild-type allele contains six ([TA] 6) repeats in the TATA box. UGT1A1*28 ([TA]7), a common variation in Gilbert’s syndrome, has an in?vitro transcriptional activity that is 63% of that of the wild-type allele [30,32] . Minor TA variations include *36 (n = 5) and *37 (n = 8), which result in enhanced and reduced transcriptional in?vitro activity,? respectively. UGT1A1*6 (211G>A [G71R]) was found in Japanese patients with Crigler–Najjar type II and Gilbert’s syndrome [26,28] and results in reduced SN-38 glucuronidation activity [6,7] . UGT1A1*27 (686C>A [P229Q]) and UGT1A1*7 (1456T>G [Y486D]) are rare nonsynonymous polymorphisms that are associated with reduced or marginal in?vitro glucuronidation of SN-38 [6,7,28] . As the importance of the UGT1A haplotype in pharmacogenetics research has been recognized, analyses of ethnic differences have been conducted for irinotecan pharmacogenetics. The first haplotype analysis of the UGT1A1 enhancer (PBREM)/promoter region was conducted by Innocenti et? al. using hepatic samples from 55 Caucasians and 37 African–Americans [33] . This study revealed a close linkage among -3279T>G (*60), -3156G>A (*93) and (TA)7 (*28). The frequencies of the ten haplotypes identified in the study differed between the two ethnic groups (Table?2) [33–39] . Haplotype ana lysis of UGT1A1 in 195 Japanese subjects defined
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11 haplotypes in the 1A1 segment and classified them into four haplotype groups according to the *1, *60, *6 and *28 alleles. This study revealed that the *6 allele (211G>A [G71R]), specific for East Asians, and the *28 allele were present on mutually exclusive chromosomes, while the *27 allele (686C>A [P229Q]) was completely linked to the *28 allele. Among the common functional UGT1A7 polymorphisms, 1A7*2 (387T>G, 391C>A [129K, R131K]), 1A7*3 (387T>G, 391C>A, 622C>T [129K, R131K, W208R]) and 1A7*4 (622C>T [W208R]) were shown to cause reduced SN-38G formation in?vitro, but a consensus about a relationship between UGT1A7 polymorphisms and the toxicity of irinotecan was not achieved [6] . By contrast, a common variation in the UGT1A9 promoter region, 1A9*1b (originally named *22) (-126_-118 [T9>T10]) enhances transcriptional activity in?vitro [40–43] . Racial differences in the occurrence of UGT1A1 haplotypes were investigated among Caucasians, African–Americans and Asians. Allele frequency of the *28 group is several times higher in Caucasians (30–40%) and African–Americans (35–45%) than in Asian populations (7–16%) [30,44–46] . On the other hand, UGT1A1*6 or UGT1A1*27 polymorphisms have been identified only in Asians, with allele frequencies of 11–23% and less than 1–3%, respectively [20,29,47] . Both UGT1A1*6 and UGT1A1*27 have been known as risk factors for unconjugated hyperbilirubinemia among Asians, particularly among Japanese neonates, which indicates that the genetic basis for hyperbilirubinemia differs among different ethnic populations [6,7,36,48] . The genetic basis for irinotecan-related toxicity differs among distinct ethnic populations. UGT1A1*28 primarily increases the risk of irinotecan toxicity in Caucasian patients, whereas UGT1A1*6 and possibly UGT1A1*27, in addition to UGT1A1*28, increases the risk of irinotecan toxicity in Asian patients [35,49] . Furthermore, haplotype analyses across the UGT1A1 gene have revealed close linkages among the functional polymorphisms of 1A9, 1A7 and 1A1, and that their combinational haplotype structures vary by ethnicity [35,40,42,50] . The data so far reported demonstrates that most 1A7*3-containing haplotypes are linked to 1A1*28 in Caucasians and to either 1A1*6 or 1A1*28 in Asians. The reported findings also indicate that observations based on 1A9 or 1A7 polymorphisms might reflect phenotypes of the 1A1 genotypes, and that distinguishing between the effects of 1A1 and 1A9 or 1A7
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An overview of the recent progress in irinotecan pharmacogenetics

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UGT1As haplotypes & adverse reactions of irinotecan To date, considerable research has focused on the possible relevance of UGT1A1 polymorphisms to irinotecan toxicity (Table?3) . The first clinical evidence showing a role for UGT1A1*28 in irinotecan toxicities was reported in Japanese patients by Ando et?al. [16] . In this study, associations of UGT1A1 genotypes with severe irinotecan toxicities (grade 4 neutropenia and/or grade 3 or 4 diarrhea) were retrospectively evaluated in 118 Japanese cancer patients who received irinotecan therapy. The frequency of the UGT1A1*28 variant allele was 3.5-fold higher in those patients who experienced severe toxicity compared with those who did not. Of the 26 patients who experienced toxicity, the UGT1A1*28 variant alleles were homozygous in 15% and heterozygous in 31%. These frequencies were 3 and 11%, respectively, among the 92 patients without toxicity. Multivariate ana lysis revealed that UGT1A1*28 was significantly associated with the development of irinotecan treatment-related toxicity. Three individuals who were heterozygous for UGT1A1*27 experienced severe toxicity. However, two of the three were also homozygous for UGT1A1*28, and the other was heterozygous for this allele. Furthermore, in another study, all *27 alleles were linked to *28 in Japanese patients, and it was suggested that the observed associations between the *27 allele and toxicities might be caused by the linkage [36] . The clinical significance of UGT1A1*28 in irinotecan therapy was demonstrated in a prospective study of 20 patients (including 18 Caucasians) who received irinotecan monotherapy [17] . The rate of SN-38 glucuronidation was 3.9-fold lower in patients with UGT1A1*28 compared with those with the wild-type allele. In addition, it was found that grade 3 or 4 diarrhea and neutropenia were observed only in patients bearing *28. A significant correlation was found between absolute neutrophil counts at nadir and the number of *28 alleles. Innocenti et?al. further assessed genetic variants of UGT1A1 in 66 cancer patients (including 50 Caucasians) who received irinotecan monotherapy [18] . This study revealed that grade 4 neutropenia was much more common in UGT1A1*28 homozygous patients (50%) than
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Chinese?

Koreans

Haplotype frequency

Japanese

Africans

n = 147? n = 132§ n = 149?

Caucasians

Table 2. UGT1A1 haplotypes frequencies and ethnic differences.

0.451 0.000 0.000 0.389 0.000 0.000 0.017 0.007 0.135
Areas marked with a cross (x) signify that each allele exists in the specific haplotype. Haplotype definition is based on Kaniwa et al. [34]. ? Zhang et al. [39]. ? Kaniwa et al. [34]. § Innocenti et al. [35]. ? Innocenti et al. [33]. # Sai et al. [36]. ?? Han et al. [37]. ?? Ki et al. [38].

211G>A 686C>A (G71R) (P229Q)

Exon 1

*27

*6

Nucleotide -3279T>G (TA) 5 (TA) 7 (TA) 8 (amino acid)

Promoter (TATA box)

*37

x x

x

*28

*36

x x x x x x *36 *37 *60 *28 *1 *6 *1a *6a *6d *28b *28c *28d *36b *37b *60a x x x x

Enhancer

Region

Marker allele

*60

x

0.558 0.000 0.000 0.340 0.000 0.000 – 0.000 0.102

0.150 0.000 0.000 0.446 0.000 0.000 0.044 0.065 0.296

0.150 ND ND 0.350 ND 0.000 0.040 0.120 0.330

0.610 0.141 0.003 0.097 0.003 0.000 0.000 0.000 0.145

0.582 0.151 0.000 0.121 0.005 0.005 0.000 0.000 0.136

0.518 0.235 0.000 0.061 ND 0.012 0.000 0.000 0.172

0.520 0.213 0.000 0.127 ND 0.000 0.000 0.000 0.140

0.495 0.178 0.000 0.095 0.001 0.000 0.000 0.000 0.180

0.479 0.090 0.000 0.121 0.020 0.000 0.000 0.000 0.263

polymorphisms may be difficult. Thus, information on haplotype structure covering these 1A segments in each ethnic population could be integral for the precise evaluation and selection of genetic markers for irinotecan therapy.

n = 37? n = 150? n = 195 # n = 81?? n = 324?? n = 539 n = 273 n = 264

0.582 0.111 0.000 0.042 0.006 0.000 0.000 0.000 0.177

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in heterozygous patients (12.5%), and that none of the patients with the normal alleles experienced toxicity. Those patients with the *28/*28 genotype had a 9.3-fold higher risk of developing severe neutropenia compared with the rest of the patients. In addition, there was an association between pretreatment bilirubin levels and the risk of developing toxicity following irinotecan therapy. Moreover, the -3156G>A mutation (UGT1A1*93), a variation closely linked to the *28 allele, was suggested as a better predictor for toxicities than the *28 allele in Caucasians. In 95 Caucasian colorectal cancer patients treated with irinotecan-containing regimens, the incidence of severe diarrhea was greater in individuals homozygous (70%) and heterozygous (33%) for the variant allele compared with wildtype patients (17%). In addition, the occurrence of severe hematological toxicity was higher, but the difference was not statistically significant [19] . Rouits et?al. similarly reported the relationship of 1A1*28 to severe toxicities in 75 Caucasians patients with colorectal cancer who received irinotecan plus 5-fluorouracil (5-FU), and showed a high incidence of *28 dependent grade 3 and 4 neutropenia [20] . Racial differences in the frequencies of pharmacogenetic variants were documented in the North Central Cancer Treatment Group trial N9741 [51] . Black (n = 116) and white (n = 1296) patients were treated with: irinotecan, 5-FU and leucovorin; irinotecan, 5-FU, leucovorin and oxaliplatin (FOLFOX); or irinotecan and capecitabine (IROX) as first-line chemotherapy for metastatic colorectal cancer. Across all treatment arms, overall survival (OS) time was slightly shorter in black patients than in white patients, with a median of 16.3 and 17.8 months for black and white patients, respectively. In patients treated with leucovorin, OS for black patients was reduced compared with white patients (12.2 vs 15.2 months). The frequency of grade 3 diarrhea was lower in black patients (5 vs 17%). This difference was observed across all treatment arms, and it was most profound in the two irinotecan-containing arms. A pharmacogenetic ana lysis was performed in 486 patients (36 black and 450 white). Baseline characteristics of these patients did not differ from the general study population. Multiple highly significant associations between genotypes and race were observed. The frequencies of genetic variants in four genes related to irinotecan metabolism (ABCB1, CYP3A4, CYP3A5 and UGT1A1) were significantly associated with race. In particular, the homozygous UGT1A1*28? genotype, which has been associated with higher
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risk of grade 3–4 neutropenia, was more common in black patients than white patients (14 vs?9%). While the majority of the evidence implicating the clinical importance of *28 has been obtained in Caucasian patients, recent studies in Asian patients show involvement of the lowactivity allele 1A1*6, which is specific to the East Asian population. Sai et?al. identified six UGT1A1 haplotype groups and investigated their association with irinotecan pharmacokinetics and serum bilirubin levels in 85 Japanese cancer patients [36] . In this study, *28- and *6-containing haplotypes were associated with a reduced AUC ratio (SN-38G:SN-38). Further investigation revealed that severe neutropenia depended on the number of *28-containing and *6-containing haplotypes [52] . Based on these observations, the irinotecan label in Japan was also revised to include the effect of *28/*6 on irinotecan pharmacokinetics and toxicity. Han et?al. demonstrated the clinical significance of 1A1*6 for irinotecan pharmacokinetics and pharmacodynamics in 81 Korean patients with non-small-cell lung cancer who received irinotecan plus cisplatin [37] . In this population, the allele frequency of 1A1*6 (23.5%) was much more prevalent than 1A1*28 (7.3%). This genotype–pharmacokinetics association analysis showed that UGT1A1*6/*6, UGT1A7*3/*3 and UGT1A9?-118(dT)9/9 were associated with significantly lower AUC ratio of SN-38G:SN-38. Patients with UGT1A1*6/*6 had lower tumor response and a higher incidence of severe neutropenia. UGT1A9? -118(dT)9/9 also showed a trend for a high incidence of severe diarrhea, but not tumor response. This survival ana lysis in non-small-cell lung cancer patients treated with irinotecan-based chemotherapy showed that patients with UGT1A1*6/*6 had significantly shorter progression-free survival and OS. A small number of patients with the *28?allele (12 heterozygotes and no homozygotes) might preclude the detection of associations between *28 and pharmacokinetics or toxicities in this study. Coadministration of cisplatin might also underscore the potential confounding influence of other drugs coadministered with irinotecan. Lara et?al. demonstrated the potential role of population-related pharmacogenomics in North American patients with extensive-stage smallcell lung cancer, showing that ABCB1?3435C>T and UGT1A1*93?were significantly associated with specific toxicities [53] . ABCB1?3435C>T was associated with an increased risk of grade 3–4 diarrhea. UGT1A1*93? was associated with
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Table 3. Association between gene polymorphism and clinical outcome in irinotecan-based chemotherapy.
Patients Genotype (n)
Response Grade 3 or 4 neutropenia in the first course 8.84 (1.38–56.49) 3.44 (0.76–15.62) 0.32 0.81 Italy (0.12–0.86) (0.45–1.44) Grade 3 or 4 diarrhea in the first course PFS Survival

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Study

Cancer type Regimen (stage)

Odds ratio of outcomes (95% CI)

Country

Ref.

CRC (IV)

FOLFIRI

250

UGT1A1*28 (7/7 vs 6/6)

2.95 (1.10–7.91)

[54,89]

CRC (IV) 89 103 109 56 58 4.33 (0.84–22.13) 3.00 (0.29–30.76) 2.59 (0.69–9.70) 2.20 (0.41–11.77) NS 8.84 (2.31–33.87) NS 3.76 (0.85–16.78)

44

0.97 (0.26–3.61)

5.00 (1.13–22.18) 1.12 (0.24–5.18)

France France USA USA Italy Italy

[90] [91] [92] [92] [93] [94]

CRC (III)

CRC (IV)

CRC (IV)

CRC (IV)

Cecchin et al. (2009); Toffoli et al. (2006) Rouits et al. (2008) Cote et al. (2007) McLeod et al. (2006) McLeod et al. (2006) Massacesi et al. (2006) Chiara et al. (2005) UGT1A1*28 (7 allele vs 6/6) UGT1A1*28 (7/7 vs 6 allele) UGT1A1*28 (7/7 vs 6 allele) UGT1A1*28 (7/7 vs 6 allele) UGT1A1*28 (7 allele vs 6/6) UGT1A1*28 (7/7 vs 6 allele) 40.83 (4.06–410.70) p = 0.3 2.48 (0.64–9.60) 6.68 (1.60–27.94) 21 vs 33 months (p = 0.09) 7.71 (2.03–29.35) 61

CRC (IV)

5-FU + irinotecan LV5FU2 + irinotecan Irinotecan + oxaliplatin 5-FU + irinotecan Irinotecan + ralitrexed Irinotecancontaining chemotherapy Irinotecan UGT1A1*28 (7/7 vs 6 allele) UGT1A1*28 (7/7 vs 6 allele) UGT1A1*28 (7/7 vs 6 allele)

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USA Spain

[18] [19]

Innocenti et al. (2004) Marcuello et al. (2004)

Solid tumor, lymphoma CRC (IV)

Rouits et al. (2004)

CRC (IV)

France

[20]

Irinotecan95 containing chemotherapy Irinotecan + 73 5-FU + l-folinic acid Irinotecan 20 250 1.45 (0.67–3.13) 4.69 (1.43–15.38)

USA 1.08 (0.17–6.76) Italy

[17]

Iyer et al. Solid tumor, (2002) lymphoma Cecchin et al. CRC (IV) (2009) 250

FOLFIRI

50% vs 0% (p = 0.03) 9.00 (1.01–79.78)

[54]

Cecchin et al. CRC (IV) (2009) 169

FOLFIRI

2.60 (0.25–26.57)

1.27 (0.14–11.25)

Italy

[54]

Lara et al. (2009)

SCLC (ED)

Cisplatin + irinotecan

UGT1A1*28 (7/7 vs 6 allele) UGT1A1*60 3279T>G (GG vs TT) UGT1A1*93 -3156G>A (AA vs GG) UGT1A1*93 -3156G>A (AA vs G allele)

24 (2–282)

USA

[53]

Review

For columns in odds ratio of outcome, bolding indicate a significant difference (p < 0.05). 5-FU: 5-fluorouracil; CBDCA: Carboplatin; CRC: Colorectal cancer; ED: Extensive disease; FOLFIRI: Irinotecan, leucovorin, 5-FU; LV5FU2: Leucovorin, 5-FU; mm: Mutant type/mutant type; NS: Not significant; NSCLC: Non-small-cell lung cancer; PFS: Progression-free survival; SCLC: Small-cell lung cancer; ww: Wild-type/wild-type.

397

398 Patients Genotype (n)
Response Grade 3 or 4 neutropenia in the first course 7.0 (1.10–44.72) France Grade 3 or 4 diarrhea in the first course PFS Survival

Table 3. Association between gene polymorphism and clinical outcome in irinotecan-based chemotherapy (cont.).
Odds ratio of outcomes (95% CI) Country Ref.

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Study

Cancer type Regimen (stage)

Cote et al. (2007) 89 250 250 0.27 (0.03–2.29) 0.49 (0.05–4.56) 3.94 (1.05–14.82) 2.45 (0.47–12.67) Italy Italy

CRC (III)

LV5FU2 + irinotecan

[91]

FOLFIRI

[54] [54]

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Cecchin et al. CRC (IV) (2009) Cecchin et al. CRC (IV) (2009) 1.39 (0.65–2.98) 0.70 (0.32–1.50) 1.75 (0.41–7.35) p > 0.05 1.18 (0.30–4.66) 3.9 (1.1–13.8) 1.69 (0.58–4.85) p > 0.05 1.87 (0.39–8.89) p > 0.05 0.31 (0.03–2.85) 48 38 92 169 91 34 54

FOLFIRI

CRC (IV)

France USA France USA France USA USA

[90] [95] [91] [53] [91] [95] [96]

NSCLC (IV)

UGT1A1*93 -3156G>A (A/A vs G/G) UGT1A7*3 (mm vs ww) UGT1A9*22 (*22/*22 vs *1/*1) CES2 830C>G (C allele vs GG) CYP3A4*1B 2.5 (0.47–13.27) p > 0.05

Rouits et al. (2008) Pillot et al. (2006) Cote et al. (2007) Lara (2009)

CRC (III)

SCLC (ED)

CRC (III)

NSCLC (IV)

Pharmacogenomics (2010) 11(3)

Cote et al. (2007) Pillot et al. (2006) Rhodes et al. (2007)

CRC (IV)

5-FU + irinotecan CBDCA + irinotecan LV5FU2 + irinotecan Cisplatin + irinotecan LV5FU2 + irinotecan CBDCA + irinotecan 5-FU + leucovorin + irinotecan CYP3A5 -6986 (G/G vs A allele) ABCB1 -3435 (T/T vs C allele) ABCB1 -3435 (T/T vs C allele) ABCB1 -3435 (T/T vs C allele) SLCO1B1 -388A>G (GG vs AA)

For columns in odds ratio of outcome, bolding indicate a significant difference (p < 0.05). 5-FU: 5-fluorouracil; CBDCA: Carboplatin; CRC: Colorectal cancer; ED: Extensive disease; FOLFIRI: Irinotecan, leucovorin, 5-FU; LV5FU2: Leucovorin, 5-FU; mm: Mutant type/mutant type; NS: Not significant; NSCLC: Non-small-cell lung cancer; PFS: Progression-free survival; SCLC: Small-cell lung cancer; ww: Wild-type/wild-type.

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An overview of the recent progress in irinotecan pharmacogenetics

Review

increased risk of grade 3–4 neutropenia. UGT1A1*28?was observed in only four patients, and no correlations were detected. Cecchin et?al. investigated whether UGT1A haplotypes (UGT1A1*28, UGT1A1*60, UGT1A1*93, UGT1A7*3 and UGT1A9*22) might be better predictors of the outcome of FOLFIRI therapy in 267 patients with colorectal cancer [54] . This study demonstrated that UGT1A7*3 was the only marker of severe hematologic toxicity, and that UGT1A1*28 was a significant predictor of good response rate and time to progression. The clinical impact of the *6- and *28-containing haplotypes, was definitively demonstrated in Asian patients, in whom the frequencies of *6 and *28 were almost equivalent (13–16%) [48,52] . The *6 and *28 allele were mutually independent, and their effects on pharmacokinetics were comparable. Gene–dose effects of the number of *6 or *28 allele on pharmacokinetics and toxicity were observed. Multivariate ana lysis confirmed a significant contribution of the genetic marker ‘*6 or *28’ to the altered AUC ratio and severe neutropenia [52] . Esaki et?al. reported a dose escalation study of irinotecan to find an appropriate starting dose of irinotecan based on UGT1A1?*6 and *28 polymorphisms [55] . UGT1A1 polymorphisms were categorized into no variants (wild-type: *1/*1), heterozygous (*1/*28 or *1/*6 ) and homo zygous (*28/*28, *6/*6 or *28/*6 ). Irinotecan was administered biweekly in 90-min infusions. Starting doses were 150, 100 and 75 mg/m 2 in wild-type, heterozygous and homozygous patients, respectively. Among 82 patients (41 wild-type, 20 heterozygous and 21 homozygous) treated at 150 mg/m 2 , dose-limiting toxicities were observed in six homo zygous patients (grade 4 neutropenia in six patients and a grade 3 diarrhea in one). The incidences of grade 3/4 neutropenia at 150 mg/m 2 during the first cycle were 9.8, 18.8 and 62.5% in wild-type, heterozygous and homozygous patients, respectively. The second administration was delayed 7 days or more in most homozygous patients (63% at 150 mg/m 2 ). One homozygous patient for *28/*28 died of septic shock during the second cycle. SN-38 AUC (0–24 h, median) was 239, 237 and 410 ng*hr/ml in wild-type, heterozygous, and homozygous patients, respectively. Homozygous patients showed different pharmaco kinetics/pharmaco dynamics compared with wild-type and heterozygous patients. The AUC ratio (SN-38G:SN-38) tended to decrease in the order of wild-type,
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heterozygous and homozygous (median: 4.95, 3.09 and 1.36, respectively). Unfortunately, a limited number of homozygous patients were treated at the lower doses, and an appropriate starting dose for this group could not be determined. This study revealed that a dose of 150 mg/m 2 was safe for wild-type and heterozygotes, but may exceed the appropriate dosage for homozygotes. The genotype classification used was considered appropriate. Kim also reported a UGT1A1 genotypedirected Phase I study of irinotecan plus a fixed dose of capecitabine in Korean patients with metastatic colorectal cancer [56] . The dose of irinotecan was escalated from 200 to 380 mg/m 2 every 3 weeks. Capecitabine (1000 mg/m 2) was administered twice daily on days 2–15 every 3 weeks. Among 42 patients, 18 were wild-type (*1/*1), 18 were heterozygous (*1/*28 or *1/*6 ), and 6 were homozygous (*28/*28, *6/*6 or *28/*6 ), respectively. The maximum tolerated dose of irinotecan in combination with capecitabine was 350 mg/m 2 for wild-type and heterozygous patients, and 200 mg/m 2 for homozygous patients. Median SN-38G:SN-38 AUC was 10.45, 8.78 and 1.66 in wild-type, heterozygous and homozygous patients, respectively. In a meta-ana lysis, Hoskins reviewed data presented in nine studies that included a total of ten sets of patients (for a total of 821 patients) and assessed the association of irinotecan dose with the risk of irinotecan-related hematologic toxicities (grade 3–4) for patients with a UGT1A1*28/*28 genotype [57] . Patients received a variety of irinotecan-containing regimens, including commonly used higher doses (200–350 mg/m2) administered every 3 weeks, an intermediate dose (180 mg/m 2 ) every 2 weeks or a lower dose weekly (80–125 mg/m2). Irinotecan was given either alone or in combination with other anticancer agents. The risk of toxicity was higher among patients with a UGT1A1*28/*28 genotype than among those with UGT1A1*1/*1 or UGT1A1*1/*28 genotype at both medium (odds ratio [OR]: 3.22; 95% CI: 1.52–6.81; p = 0.008) and high (OR: 27.8; 95% CI: 4.0–195; p = 0.005) doses of irinotecan, while the risk was similar at lower doses (OR: 1.80; 95% CI: 0.37–8.84; p = 0.41). However, data from clinical studies conducted in Asian countries were not included in the metaanalysis. Stewart studied the association between UGT1A1 genotypes and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose irinotecan
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(15–75 mg/m2 daily for 5 days for 2 consecutive weeks) [58] . He demonstrated that patients with the *28/*28 genotype tended to have higher SN-38 AUC values and lower SN-38G:SN-38 AUC ratios, but that the UGT1A1*28?genotype was not associated with grade 3 and 4 neutropenia or diarrhea. Therefore, UGT1A1 genotype may not be a useful prognostic indicator of severe toxicity for pediatric patients treated with low-dose irinotecan. The risk of experiencing irinotecan-induced hematologic toxicity for patients with a UGT1A1*28/*28 genotype thus appears to be a function of the dose of irinotecan administered as well as ethnicity.

Genetic polymorphisms of CES2 in irinotecan treatment Irinotecan is metabolized to an active compound, SN-38, by carboxylesterases. Two major families of carboxylesterases, CES1 and CES2, have been identified in human tissues. CES1 is highly expressed in the liver and lung, and CES2 is abundant in the small intestine, colon and kidney [59–61] . The activation of irinotecan is catalyzed by both human CES1 and CES2, but in?vitro hydrolytic activity toward irinotecan is much higher for CES2 than CES1 [62] . The activity of hepatic CES towards irinotecan varies threefold in microsomes obtained from a panel of human livers [63] . Polymorphisms of CES1 and CES2 genes have been reported, and some are defective or of low activity. Furthermore, large interethnic differences have been found in the frequencies of CES1 and CES2 polymorphisms [64,65] . In addition to functional human CES1 genes, including CES1A1 and CES1A2, recent studies identified a CES1A1 variant (varCES1A1), in which exon 1 was replaced with that of CES1A2, and a pseudogene CES1A3 was found instead of CES1A2. The CES1A3 sequence from the promoter region to exon 1 is the same as that of CES1A2, but there is a stop codon in exon 3. Ethnic differences in the CES1 genes have been reported [64,66] . Investigations into associations between these polymorphisms and the pharmacokinetics and toxicity of irinotecan are now ongoing. A comprehensive haplotype ana lysis of the CES2 gene using 21 SNPs has identified 20 haplotypes in 262 Japanese subjects [67] . In this study, the haplotypes harboring nonsynonymous SNPs, 100C>T (Arg34Trp), 424G>A (Val142Met), 1A>T (Met1Leu) and 617G>A (Arg206His) were assigned as haplotypes *2, *3, *5 and *6, respectively, and the
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haplotype harboring a SNP at a splice acceptor site of intron 8 (IVS8-2A>G) was assigned as haplotype *4. The SNPs of 100C>T (Arg34Trp) or 424G>A (Val142Met) are associated with little esterase activity toward irinotecan [68] , and the 1A>T (Met1Leu) haplotype yielded only 12% protein expression of the wild-type in an in? vitro functional ana lysis [67] . The IVS8-2A>G haplotype yielded mostly aberrantly spliced transcripts, including a deleted exon or a 32-bp deletion proximal to the 5? end of exon 9, which resulted in truncated CES2 [68] . A study of the association between these haplotypes and the pharmacokinetics of irinotecan in 176 cancer patients revealed that the AUC ratios (SN-38 + SN-38 glucuronide):irinotecan in patients who are heterozygotes for the *2 or *5 haplotypes were lower than those of wild-type patients. However, the frequency of both haplotypes was 0.2%, and the clinical significance of these haplotype in irinotecan chemotherapy remains to be clarified.

Genetic polymorphisms of CYP3A4 in irinotecan treatment CYP3A4 is the most abundant CYP enzyme in the liver, and is involved in the metabolism of a variety of drugs. Large interindividual differences in CYP3A4 activity have been observed, and various factors are considered to be responsible for the variability, including genetic factors. In addition to the activation to SN-38 by carboxylesterases, irinotecan is metabolized by CYP3A4 to inactive compounds, such as APC (a major CYP3A4-mediated product) and NPC (a minor product). Modulation of CYP3A4 activity alters the pharmacokinetics of irinotecan. Co-administration of ketoconazole, a potent CYP3A4 inhibitor, with irinotecan resulted in a decreased AUC of APC and increased AUC of SN-38 [69] . Co-administration of St John’s Wort, a CYP3A4 inducer, also alters the pharmacokinetics of irinotecan, and a close association between CYP3A4 activity and irinotecan clearance has been observed [70] . Various SNPs of CYP3A4 are known, and their frequencies depend on ethnicity. Relatively frequent SNPs are *2 (664T>C [Ser222Pro]), *10 (520G>C [Asp174His]), and *17 (566T>C [Phe189Ser]) in Caucasians and Mexicans (2–5%), *15 (485G>A [Arg162Gln]) in African–Americans (2–4%) and *16 (554C>G [Thr185Ser]) and *18?(878T>C [Leu293Pro]) in East Asians (1–10%). Interpatient variability in irinotecan pharmacokinetics may be caused by these polymorphisms of CYP3A4.
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An overview of the recent progress in irinotecan pharmacogenetics

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Among 65 patients treated with irinotecan in the Netherlands, heterozygotes for a rare allele, CYP3A4*3 (M445T), might have had a reduced clearance of irinotecan lactone, although the difference was not statistically significant [71] . In a comprehensive haplotype ana lysis of CYP3A4 in 416 Japanese subjects, 25 haplotypes were identified [72] , and associations between these haplotypes and the pharmacokinetics of irinotecan were then investigated in 177 Japanese cancer patients [73] . The *16B haplotype harboring 554C>G (Thr185Ser) and IVS10+12G>A was found only in male patients, and these patients had significantly lower AUC ratio of APC:irinotecan, an in?vivo parameter of CYP3A4 activity. This observation was in accordance with a reduced in?vitro activity on testosterone 6-b-hydroxylation and altered AUC ratios of metabolite:paclitaxel in cancer patients bearing *16B? [74,75] . However, no significant association was observed between the CYP3A4 genotypes and total clearance of irinotecan or toxicities. Therefore, the currently available data do not support genotyping for CYP3A4 before chemotherapy with irinotecan in the clinic.

Genetic polymorphisms & haplotypes of drug-transporting proteins In addition to metabolism by multiple drugmetabolizing enzymes, irinotecan and its metabolites are subject to transport by several members of the ATP-binding cassette (ABC) transporter superfamily. The ABC transporters play an important role in the pharmacology of irinotecan. The involvement of ABCB1 in irinotecan transport was demonstrated using ABCB1 knockout mice [11] . The biliary recovery of irinotecan was significantly lower in the knockout mice compared with wild-type animals, implying a role for ABCB1 in irinotecan biliary excretion, whereas that of SN-38 and SN-38G was unaffected. Of all the ABC drug transporters involved in irinotecan disposition, evidence for a pharmacogenetic association is most compelling for ABCB1. Several polymorphisms in the ABCB1 gene have been reported. Studies evaluating the effect of these polymorphisms on irinotecan pharmacokinetics have focused on the commonly occurring polymorphisms 1236C>T, 2677G>T/A and 3435C>T, which exist in strong linkage disequilibrium. In a study of 65 cancer patients treated with irinotecan, a significant association between the 1236C>T polymorphism and exposure to irinotecan and SN-38 was observed [70] . The AUC of irinotecan
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and SN-38 was significantly higher in homozygous patients compared with heterozygous and wild-type patients. A study of 49 Japanese cancer patients demonstrated a significant association between the ABCB1*2, which contains the three SNPs described, and reduced renal clearance of irinotecan, SN-38 and APC, possibly owing to reduced ABCB1 expression in renal proximal tubules [76] . Several polymorphisms in the ABCC1 gene have been reported. In a study of 65 cancer patients treated with irinotecan, no significant associations between 462C>T, 14008G>A and 34215C>G polymorphisms and the pharmacokinetics of irinotecan and SN-38 have been reported [71] . In this study, different variants of ABCC1 (IVS11 -48C>T and 1684T>C) were associated with the nadir of neutrophil counts, SN-38 AUC and SN-38G:SN-38 AUC. The clinical relevance of ABCC1 variation is relatively unexplored compared with that of ABCB1. Several rare variants of ABCC1 affect transport function, but their low allele frequency precludes a major role in humans. The biliary excretion of irinotecan carboxylate and SN-38 carboxylate, and both the lactone and carboxylate forms of SN-38G was lower in ABCC2-deficient rats [77,78] . Polymorphisms in ABCC2 have been found to influence irinotecan disposition. Innocenti et?al. demonstrated that the synonymous 3972T>C variant was correlated with irinotecan AUC, APC AUC and APC:irinotecan AUC ratios [18] . Some haplotypes of ABCC2 variants were associated with severe diarrhea in both Korean and European patients. However, no significant association between the 1249G>A or _24C>T variants and severe toxicity were observed. Organic anion-transporting polypeptide 1B1 (OATP1B1; gene SLCO1B1), expressed on the basolateral membrane in hepatocytes, has been reported to contribute to the hepatic uptake of SN-38 [79] . Some reports suggest the SLCO1B1*15 haplotype (388A>G and 521T>C) results in the decreased uptake activity of SN-38, leading to increased plasma concentration of irinotecan and SN-38 [80–82] . Takane et?al. reported that the combination of the UGT1A1*6,?*28 and SLCO1B1*15 variants was strongly associated with the excessive accumulation of SN-38, resulting in severe irinotecan-related toxicities [83] . Recently, Innocenti et? al. conducted a comprehensive pharmacogenetic ana lysis in advanced cancer patients treated with single-agent irinotecan every 3 weeks at doses of 300 and 350 mg/m 2 [84] . Almost 50% of the variation in the nadir for neutrophil
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counts was explained by UGT1A1*93, ABCC1? IVS11?-48C_T, SLCO1B1*1b, baseline neutrophil counts, sex and race. More than 40% of the variation in AUC of irinotecan was explained by ABCC2?-24C_T, SLCO1B1*5, HNF1A?79A_C, age and dose of irinotecan. Almost 30% of the variability in AUC of SN-38 was explained by ABCC1?1684T_C, ABCB1?IVS9?-44A_G and UGT1A1*93. This study demonstrated that common polymorphisms in genes encoding ABC and SLC transporters may have a significant impact on the pharmacokinetics and pharmacodynamics of irinotecan.

Conclusion Haplotype analyses across the UGT1A1 gene complex have revealed close linkages among the functional polymorphisms and interethnic variabilities of combinational haplotype structures. The accumulated evidence indicates the primary importance of UGT1A1 genetic polymorphisms, in particular the *28 promoter polymorphism, as a risk factor for severe irinotecan toxicities. Therefore, the label now includes homozygosity for the UGT1A1*28 genotype as one of the risk factors for severe neutropenia. A FDA-approved UGT1A1*28 genotyping method is also commercially available. Recent haplotype–phenotype analyses have also indicated that the genetic relevance to toxic events varies depending on ethnicity; UGT1A1*6 in East Asians is also an important risk factor for pharmacokinetics and severe neutropenia. Genotyping tests for UGT1A1*6 and *28 were approved in Japan and are currently used in oncology practice. The results of a randomized North American trial (Southwest Oncology Group [SWOG] S0124) that compared etoposide and cisplatin with irinotecan and cisplatin in patients with extensive smallcell lung cancer have failed to confirm the benefit of irinotecan, which had been demonstrated in a previous Japanese trial (JCOG 9511) [53,85] . SWOG S0124 and JCOG 9511 trials were conducted using virtually the same eligibility criteria and treatment regimens. Compared with Caucasian patients, Asian patients might respond favorably to irinotecan. To address the possibility that patients of the two different ethnic groups respond differently to irinotecan, genomic DNA was collected from patients in the SWOG S0124 trial and assayed for polymorphisms in genes involved in irinotecan metabolism and transport. Pharmacogenetic analyses showed that ABCB1? 3435C>T and UGT1A1*93?were significantly associated with specific toxicities. Recent trends toward ‘globalization’ of clinical trials critically
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highlight the presence of genetic differences associated with race and ethnicity, emphasizing the potential importance of pharmacogenomics in interpreting trials of cancer therapy. To date, most retrospective pharmacogenetic studies have revealed the primary importance of genetic polymorphisms with regard to severe irinotecan toxicities [86] . The influence of UGT1A genotypes on the anti-tumor effects to irinotecan treatment remains unclear. Prospective clinical studies based on genotypes in patients with colorectal cancer or lung cancer demonstrated that UGT1A1 genotype-guided dosing of irinotecan might establish individualized therapy with irinotecan [55,87,88] . Further prospective clinical studies are needed to evaluate the benefits of the genotyping of *28 and *6 or other genetic markers from the perspective of efficacy. In addition to the UGT1A genotypes, the genetic variants of other enzymes (i.e., CES and CYP3A4) and transporters (i.e., ABCB1, ABCC2, ABCG2 and SLCO1B1) responsible for irinotecan metabolism and disposition should be evaluated for their clinical impact. The clinical pharmacokinetic profile of irinotecan has been explored extensively in recent years, and various investigators have now independently confirmed that haplotypes significantly affect the pharmacokinetic profile of irinotecan, as well as treatment-related myelosuppression. Adequately powered prospective trials are needed to evaluate the clinical utility of genetic variant screening prior to chemotherapeutic treatment with irinotecan in order to identify patients who are genetically predisposed to severe side effects.

Future perspective In the last decade, the knowledge of polymorphisms in genes involved in irinotecan metabolism and transport has increased dramatically. Many studies have revealed the linkage pattern of functional polymorphisms within their gene complex and their large ethnic variations. Recently, comprehensive pharmacogenetic studies showed that their genetic polymorphisms in addition to UGT1A1 were significantly associated with severe irinotecan toxicities. Prospective genotype-driven clinical studies in UGT1A1 are being conducted and the individualized irinotecan therapy is being realized. In addition to the UGT1A genotypes, the genetic variants of other biomolecules responsible for irinotecan metabolism and disposition, such as CES, CYP3A4, ABCB1 and SLCO1B1, should be evaluated for their clinical impact. In
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An overview of the recent progress in irinotecan pharmacogenetics

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the future, comprehensive genotype approaches would provide more effective dosing strategies in individualized irinotecan therapy.
Financial & competing interests disclosure
The? authors? have? no? relevant? affiliations? or? financial? involvement? with? any? organization? or? entity? with? a?

financial?interest?in?or?financial?conflict?with?the?subject? matter? or? materials? discussed? in? the? manuscript.? This? includes?employment,?consultancies,?honoraria,?stock?ownership? or? options,? expert? testimony,? grants? or? patents? received?or?pending,?or?royalties. No?writing?assistance?was?utilized?in?the?production?of? this?manuscript.

Executive summary
UGT1As haplotypes & adverse reactions of irinotecan ? The pharmacokinetics of irinotecan is affected by functional polymorphisms in UGT1As, and the clinical relevance of lowered activity of UGT1As to severe irinotecan toxicity is well established. ? The label of irinotecan was revised in the USA and Japan. The label in the USA now includes homozygosity for UGT1A1*28 genotype as one of the risk factors for severe neutropenia. The irinotecan label in Japan includes the effect of *28 and *6 on irinotecan pharmacokinetics and toxicity. Genetic polymorphisms of CES2 in irinotecan treatment ? The activation of irinotecan is catalyzed by human CES1 and CES2, but in vitro hydrolytic activity towards irinotecan is much higher for CES2. ? The activation of irinotecan was affected by some genotypes of CES2 in Japanese patients. However, their frequencies were low and the clinical significance in irinotecan chemotherapy remains to be clarified. Genetic polymorphisms of CYP3A4 in irinotecan treatment ? The currently available data do not support genotyping for CYP3A4 before chemotherapy with irinotecan in the clinic. Genetic polymorphisms and haplotypes of drug-transporting proteins ? Irinotecan and its metabolites are subject to transport by several ATP-binding cassette transporters. ? Polymorphisms in genes encoding transporters may have a significant impact on the pharmacokinetics and pharmacodynamics of irinotecan.

Bibliography
Papers of special note have been highlighted as: n of interest nn of considerable interest
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An overview of the recent progress in irinotecan pharmacogenetics

Review

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Nakajima M, Fukami T, Yamanaka H?et?al.: Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations. Clin.?Pharmacol.?Ther.?80(3), 282–297 (2006). Sai K, Kaniwa N, Itoda M?et?al.: Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotypedependent renal clearance of irinotecan. Pharmacogenetics?13(12), 741–757 (2003). Chu XY, Kato Y, Niinuma K, Sudo KI, Hakusui H, Sugiyama Y: Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J.?Pharmacol.?Exp.?Ther.?281(1), 304–314 (1997). Chu XY, Kato Y, Sugiyama Y: Multiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rats. Cancer? Res.?57(10), 1934–1938 (1997). Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I: Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in?vitro evidence and effect of single nucleotide polymorphisms. Drug?Metab.?Dispos.?33(3), 434–439 (2005). Xiang X, Jada SR, Li HH?et?al.: Pharmacogenetics of SLCO1B1 gene and the impact of *1B and *15 haplotypes on irinotecan disposition in Asian cancer patients. Pharmacogenet.?Genomics?16(9), 683–691 (2006). Takane H, Miyata M, Burioka N?et?al.: Severe toxicities after irinotecan-based chemotherapy in a patient with lung cancer: a homozygote for the SLCO1B1*15 allele. Ther.?Drug?Monit.?29(5), 666–668 (2007). Han JY, Lim HS, Shin ES?et?al.: Influence of the organic anion-transporting polypeptide 1b1 (OATP1B1) polymorphisms on irinotecan-pharmacokinetics and clinical outcome of patients with advanced non-small cell lung cancer. Lung?Cancer?59(1), 69–75 (2008). Takane H, Kawamoto K, Sasaki T?et?al.: Life-threatening toxicities in a patient with UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes after irinotecan-based chemotherapy. Cancer?Chemother.?Pharmacol.? 63(6), 1165–1169 (2009). Innocenti F, Kroetz DL, Schuetz E?et?al.: Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. J.?Clin.?Oncol.?27(16), 2604–2614 (2009). Comprehensive pharmacogenetic analysis of genetic variation of ABC transporters and SLCO1B1.

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Noda K, Nishiwaki Y, Kawahara M?et?al.: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N.?Engl.?J.?Med.? 346(2), 85–91 (2002). Funke S, Brenner H, Chang-Claude J: Pharmacogenetics in colorectal cancer: a systematic review. Pharmacogenomics?9(8), 1079–1099 (2008). Yamamoto N, Takahashi T, Kunikane H? et?al.: Phase I/II pharmacokinetic and pharmacogenomic study of UGT1A1 polymorphism in elderly patients with advanced non-small cell lung cancer treated with irinotecan. Clin.?Pharmacol.?Ther.?85(2), 149–154 (2009). Toffoli G, Cecchin E, Gasparini G?et?al.: Genotype-driven Phase I study of irinotecan administered in combination with fluorouracil/leucovorin in patients with metastatic colorectal cancer. J.?Clin.?Oncol. 28(5), 866–871 (2009). Prospective clinical study in UGT1A1 genotype-guided dosing of irinotecan. Toffoli G, Cecchin E, Corona G?et?al.: The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of

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