Roles ofUGT1A1 Genotypes Haplotypes

Until now, much attention has focused on the possible relevance of UGT1A1 polymorphisms to irinotecan toxicities (Table 3). The first clinical evidence showing a role for UGT1A1*28 in irinotecan toxicities was reported by Ando et al. (14). In this study, associations of UGT1A1 genotypes with irinotecan severe toxicities (grade 4 leucopenia and/or grade 3 or 4 diarrhea) were retrospectively evaluated in 118 Japanese cancer patients who received irinotecan therapy with various regimens. Among 26 patients who experienced severe toxicities, 4 homozygous (15%) and 8 heterozygous (31%) *28-bearing patients were observed, while 3 homozygous (3%) and 10 heterozygous (11%) *28 patients were detected in the 92 patients who did not experience severe toxicities. Multivariate analysis also suggested that the genotype of UGT1A1*28 was a risk factor for the irinotecan toxicities (odds ratio, 7.23, confidence interval, 2.52-22.3). Although no statistically significant relevance of 1A1*6 or *27 alone to toxicity was obtained, an additive contribution of these alleles to the toxicities was suggested when

Table 3

Association of UGT1A Polymorphisms with Severe Irinotecan Toxicities: Depencency on Ethnicity and Combination Therapy

Table 3

Association of UGT1A Polymorphisms with Severe Irinotecan Toxicities: Depencency on Ethnicity and Combination Therapy

Reference (No.)

Toxicity

Responsible UGT1A polymorphisms

Ethnicity

Tumor type

Combination therapy

Ando Y et al.. (2000) (14)

Neutropenia and/or t UGT1A1*28

Japanese (N=118)

Various

Monotherapy and

Diarrhea

Combination (various)

Iyer Let al. (2002) (15)

Neutropenia

t UGT1A1*28

Caucasian (N=18) and Other ethnics (N=2)

Various

Monotherapy

Innocenti F et al. (2004) (16)

Neutropenia

t UGT1A1*28

Caucasian (N=50) and Other ethnics (N=16)

Various

Monotherapy

Marcuello E et al. (2004) (17)

Diarrhea

t UGT1A1*28

Caucasian (N=95)

CRC

Monotherapy and Combination (5-FU or raltitrexed)

Rouits E et al. (2004) (18)

Neutropenia

t UGT1A1*28

Caucasian (N=75)

CRC

Combination (5-FU)

Carlini LE et al. (2005) (43)

-1A9*1[-118(T)9]

Caucasian (N=55) and Other ethnics (N=11)

CRC

Combination (capecitabine)

Han JY et al. (2006) (41)

Neutropenia

t UGT1A1*6

Korean (N=81)

NSCLC

Combination (cisplatin)

Minami H et al. (2007) (47)

Neutropenia

t UGT1A1*6 and *28

Japanese (N=55)

Various

Monotherapy

CRC, colorectal cancer; NSCLC, non-small cell lung cancer; f, increases toxicity; decreases toxicity.

CRC, colorectal cancer; NSCLC, non-small cell lung cancer; f, increases toxicity; decreases toxicity.

they were combined with *28. However, recent UGT1A1 haplotype analysis revealed that the *27 allele is linked to the *28 allele (38,40).

Clinical significance of UGT1A1*28 in irinotecan therapy was further demonstrated in a prospective study in 20 patients (including 18 Caucasians) who received irinotecan monotherapy (15). This study showed that patients with the *28 allele had significantly lower rates of SN-38 G formation (AUC ratio of SN-38 G to SN-38) than those with the wild-type (TA)6/6, and that grade 3 or 4 diarrhea and neutropenia were observed only in the patients bearing *28. A significant correlation was found between the absolute neutrophil counts at nadir and the number of the *28 alleles present. Innocenti et al. also showed that the 1A1*28 allele was an important factor in grade 4 neutropenia in 66 cancer patients (including 50 Caucasians) who received irinotecan monotherapy (16). This study revealed that grade 4 neutropenia was much more frequent in the *28 homozygotes [(TA)7/7] (50%) than in heterozygotes [(TA)7/6](12.5%) and wild-type [(TA)6/6] (0%) subjects, and that the relative risk for homozygotes was 9.3-fold higher than that in the other genotypes. In addition, the -3156 G>A mutation, a variation closely linked to the *28 allele, was suggested as a better predictor for UGT1A1 status than the *28 allele in Caucasians (16), but further clinical studies are needed.

The clinical importance of *28 was also demonstrated in Caucasian patients who received other regimens. Marcuello et al. investigated the relevance of 1A1*28 to severe toxicities in 95 Caucasian colorectal cancer patients who were treated with irinotecan-containing regimens (5-FU or raltitrexed) (17). Grade 3 or 4 diarrhea was more frequently observed in the *28 homozygous (70%) and heterozygous (33%) patients than in those with the wild-type genotype (17%) (p = 0.005). An association with severe neutropenia was also observed in the *28 homozygous patients, but it was not statistically significant. Rouits et al. investigated the relationship of 1A1*28 to severe toxicities in 75 Caucasian patients with colorectal cancer who received irinotecan plus 5-FU and showed high incidences of *28-dependent grade 3/4 neutropenia (18).

While the majority of the evidence implicating the clinical importance of *28 in irinotecan treatment has been obtained in Caucasian patients, recent studies for Asian patients show involvement of the low-activity 1A1 allele *6, which is specific to the East Asian population. Sai et al. (38) reported that the effect of *6 on the AUC ratio was comparable and additive to that of *28, suggesting its clinical importance (38). Han et al. demonstrated the clinical significance of 1A1*6 for irinotecan pharmarcoki-netics and pharmacodynamics in 81 Korean patients with non-small cell lung cancer (NSCLC) who received irinotecan plus cisplatin (41). In this population, the allele frequency of 1A1*6 (23.5%) was much more prevalent than 1A1*28 (7.3%). This study also showed a significant association between the homozygous 1A1*6 haplotype and grade 4neutropenia, and between the homozygous 1A9*1-1A7*3-1A1*6 diplotype and lowered AUC ratios (SN-38 G/SN-38). Due to the close linkage of 1A7*3 to 1A1*6 and/or 1A9*1 [-118(T)9], the benefit of genotyping of 1A1*6 was suggested for Korean patients. The clinical significance of *28 was not shown in this Korean population, which may be partially due to its low frequency in this study (Table 2A). The clinical impact of *6 haplotype as well as *28 was also demonstrated in Japanese patients where the frequencies of *6 and *28 were almost equivalent (13%-16%). Multivariate analysis confirmed a significant contribution of the genetic marker " *6 or *28" to the altered AUC ratio (Fig. 4) and severe neutropenia (47). A different pharmacokinetic study also

Fig. 4. Association of the UGT1A1 genetic marker "*6 or *28" with a reduced AUC ratio (SN-38 G/ SN-38) in 176 Japanese cancer patients who received irinotecan. A significant gene dose-dependent decrease in the AUC ratio was observed for "*6 or *28" (p < 0.0001, Jonckheere-Terpestra test). The AUC ratios of the "*6 or *28" homozygotes were mostly distributed below the mean value of all patients.

Fig. 4. Association of the UGT1A1 genetic marker "*6 or *28" with a reduced AUC ratio (SN-38 G/ SN-38) in 176 Japanese cancer patients who received irinotecan. A significant gene dose-dependent decrease in the AUC ratio was observed for "*6 or *28" (p < 0.0001, Jonckheere-Terpestra test). The AUC ratios of the "*6 or *28" homozygotes were mostly distributed below the mean value of all patients.

suggested the clinical importance of 1A1*6 in addition to *28 for irinotecan treatment of Japanese patients (48).

The *60 allele (-3279 T>G) in PBREM is partially linked with the *28 allele; namely, the *60 haplotype without the *28 allele is also found (37,38,39) (Fig. 3). Trends of *60 haplotype-dependent decrease in SN-38 G formation (38,47) and increase in total bilirubin levels (38) have been observed in Japanese; however, contribution to irinotecan severe toxicities of the *60 allele alone was not clearly demonstrated (41,47,49).

As for the Block C (exons 2-5) haplotype *IB, its significant associations with reduced AUC ratios and neutropenia were not clearly demonstrated, but a possible contribution under co-occurrence with haplotype *60 was suggested (38, 47). In fact, the combinatorial haplotype *60 -*IB increased bilirubin levels in healthy Japanese subjects (50). Because the frequency of *IB homozygotes is rather low in Asians (39), further studies in other ethnic populations would clarify the role of *60-*IB in irinotecan treatment.

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