UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients.
BACKGROUND
Gene polymorphisms of the UDP-glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) contribute to individual variations in adverse events among patients administered irinotecan, and the distribution of the polymorphisms shows large interethnic differences. Variation in the solute carrier organic anion-transporter family, member 1B1 (SLCO1B1) gene also has a significant effect on the disposition of irinotecan in Asian cancer patients. In the present study, we evaluated the association of genetic polymorphisms of UGT1A1 and SLCO1B1 with irinotecanrelated neutropenia in Japanese cancer patients.


METHODS
One hundred and thirty-five consecutive patients treated with irinotecan were enrolled. Genotypes of UGT1A1 (*60, *28, *6, and *27) and SLCO1B1 (*1b, *5, and haplotype *15) were determined by direct sequencing. Severe neutropenia refers to events observed during the first cycle of irinotecan treatment.


RESULTS
Severe neutropenia was observed in 29 patients (22%). Six patients were homozygous and 48 heterozygous for UGT1A1*6. Only 1 patient was homozygous for UGT1A1*28. Homozygosity for UGT1A1*6 was associated with a high risk of severe neutropenia (odds ratio [OR], 7.78; 95% confidence interval [CI], 1.36 to 44.51). No significant association was found between severe neutropenia and other UGT1A1 polymorphisms or SLCO1B1 polymorphisms.


CONCLUSIONS
These findings suggest that the UGT1A1*6 polymorphism is a potential predictor of severe neutropenia caused by irinotecan in Japanese cancer patients.
Onoue
Masahide
M
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
Terada
Tomohiro
T
Kobayashi
Masahiko
M
Katsura
Toshiya
T
Matsumoto
Shigemi
S
Yanagihara
Kazuhiro
K
Nishimura
Takafumi
T
Kanai
Masashi
M
Teramukai
Satoshi
S
Shimizu
Akira
A
Fukushima
Masanori
M
Inui
Ken-ichi
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D011110:Polymorphism, Genetic; D000099148:UGT1A1 Enzyme
D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D000099148:UGT1A1 Enzyme; C503999:SLCO1B1 protein, human