Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.
OBJECTIVE
Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation.


METHODS
Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m(2) every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (-3279G>T, -3156G>A, promoter TA indel, 211G>A, 686C>A) were genotyped.


RESULTS
The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P =.001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P =.02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean +/- standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 +/- 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 +/- 0.03 mg/dL; P <.001). The -3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The -3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r(2) = 0.51).


CONCLUSIONS
UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the -3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.
Innocenti
Federico
F
Department of Medicine, University of Chicago, 5841 S Maryland Ave, MC2115, Chicago, IL 60637, USA.
Undevia
Samir D
SD
Iyer
Lalitha
L
Chen
Pei Xian
PX
Das
Soma
S
Kocherginsky
Masha
M
Karrison
Theodore
T
Janisch
Linda
L
Ramírez
Jacqueline
J
Rudin
Charles M
CM
Vokes
Everett E
EE
Ratain
Mark J
MJ
D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D001663:Bilirubin / Q000378:metabolism; D002166:Camptothecin / Q000009:adverse effects* / Q000031:analogs & derivatives*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D009503:Neutropenia / Q000139:chemically induced*; D011446:Prospective Studies; D012306:Risk; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; C019787:bilirubin glucuronoside glucuronosyltransferase; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D001663:Bilirubin; D002166:Camptothecin