Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan

Federico Innocenti, Samir D. Undevia, Lalitha Iyer, Pei Xian Chen, Soma Das, Masha Kocherginsky, Theodore Karrison, Linda Janisch, Jacqueline Ramírez, Charles M. Rudin, Everett E. Vokes, Mark J. Ratain

Research output: Contribution to journalArticle

Abstract

Purpose: 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. Patients and Methods: Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m2 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 In(absolute neutrophil count nadir; r2 = 0.51). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1382-1388
Number of pages7
JournalJournal of Clinical Oncology
Volume22
Issue number8
DOIs
StatePublished - 2004
Externally publishedYes

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irinotecan
Neutropenia
Genotype
Genes
Bilirubin
Neutrophils
Neoplasms
UGT1A1 enzyme

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Innocenti, F., Undevia, S. D., Iyer, L., Chen, P. X., Das, S., Kocherginsky, M., ... Ratain, M. J. (2004). Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. Journal of Clinical Oncology, 22(8), 1382-1388. https://doi.org/10.1200/JCO.2004.07.173

Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. / Innocenti, Federico; Undevia, Samir D.; Iyer, Lalitha; Chen, Pei Xian; Das, Soma; Kocherginsky, Masha; Karrison, Theodore; Janisch, Linda; Ramírez, Jacqueline; Rudin, Charles M.; Vokes, Everett E.; Ratain, Mark J.

In: Journal of Clinical Oncology, Vol. 22, No. 8, 2004, p. 1382-1388.

Research output: Contribution to journalArticle

Innocenti, F, Undevia, SD, Iyer, L, Chen, PX, Das, S, Kocherginsky, M, Karrison, T, Janisch, L, Ramírez, J, Rudin, CM, Vokes, EE & Ratain, MJ 2004, 'Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan', Journal of Clinical Oncology, vol. 22, no. 8, pp. 1382-1388. https://doi.org/10.1200/JCO.2004.07.173
Innocenti, Federico ; Undevia, Samir D. ; Iyer, Lalitha ; Chen, Pei Xian ; Das, Soma ; Kocherginsky, Masha ; Karrison, Theodore ; Janisch, Linda ; Ramírez, Jacqueline ; Rudin, Charles M. ; Vokes, Everett E. ; Ratain, Mark J. / Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. In: Journal of Clinical Oncology. 2004 ; Vol. 22, No. 8. pp. 1382-1388.
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abstract = "Purpose: 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. Patients and Methods: Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m2 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 In(absolute neutrophil count nadir; r2 = 0.51). Conclusion: 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.",
author = "Federico Innocenti and Undevia, {Samir D.} and Lalitha Iyer and Chen, {Pei Xian} and Soma Das and Masha Kocherginsky and Theodore Karrison and Linda Janisch and Jacqueline Ram{\'i}rez and Rudin, {Charles M.} and Vokes, {Everett E.} and Ratain, {Mark J.}",
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AU - Innocenti, Federico

AU - Undevia, Samir D.

AU - Iyer, Lalitha

AU - Chen, Pei Xian

AU - Das, Soma

AU - Kocherginsky, Masha

AU - Karrison, Theodore

AU - Janisch, Linda

AU - Ramírez, Jacqueline

AU - Rudin, Charles M.

AU - Vokes, Everett E.

AU - Ratain, Mark J.

PY - 2004

Y1 - 2004

N2 - Purpose: 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. Patients and Methods: Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m2 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 In(absolute neutrophil count nadir; r2 = 0.51). Conclusion: 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.

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