title: Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study.
abstract: The overall goal of this study was to provide evidence for the clinical validity of nine genetic variants in five genes previously associated with irinotecan neutropenia and pharmacokinetics. Variants associated with absolute neutrophil count (ANC) nadir and/or irinotecan pharmacokinetics in a discovery cohort of cancer patients were genotyped in an independent replication cohort of 108 cancer patients. Patients received single-agent irinotecan every 3 weeks. For ANC nadir, we replicated UGT1A1*28, UGT1A1*93 and SLCO1B1*1b in univariate analyses. For irinotecan area under the concentration-time curve (AUC0-24), we replicated ABCC2 -24C>T; however, ABCC2 -24C>T only predicted a small fraction of the variance. For SN-38 AUC0-24 and the glucuronidation ratio, we replicated UGT1A1*28 and UGT1A1*93. In addition to UGT1A1*28, this study independently validated UGT1A1*93 and SLCO1B1*1b as new predictors of irinotecan neutropenia. Further demonstration of their clinical utility will optimize irinotecan therapy in cancer patients.
authors: University of North Carolina Center for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, NC, USA.
authors: D J
authors: DJ
authors: Crona
authors: University of Chicago, Department of Medicine, Chicago, IL, USA.
authors: J
authors: J
authors: Ramirez
authors: MD Anderson Cancer Center, The University of Texas, Division of Quantitative Sciences, Houston, TX, USA.
authors: W
authors: W
authors: Qiao
authors: Erasmus University Medical Center, Erasmus MC Cancer Institute, Department of Medical Oncology, Rotterdam, The Netherlands.
authors: A-J
authors: AJ
authors: de Graan
authors: University of Chicago, Department of Medicine, Chicago, IL, USA.
authors: M J
authors: MJ
authors: Ratain
authors: Erasmus University Medical Center, Erasmus MC Cancer Institute, Department of Clinical Chemistry, Rotterdam, The Netherlands.
authors: R H N
authors: RH
authors: van Schaik
authors: Erasmus University Medical Center, Erasmus MC Cancer Institute, Department of Medical Oncology, Rotterdam, The Netherlands.
authors: R H J
authors: RH
authors: Mathijssen
authors: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, MD, USA.
authors: G L
authors: GL
authors: Rosner
authors: University of North Carolina Center for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, NC, USA.|University of Chicago, Department of Medicine, Chicago, IL, USA.|University of North Carolina Lineberger Comprehensive Cancer Center, School of Medicine, Chapel Hill, NC, USA.
authors: F
authors: F
authors: Innocenti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015331:Cohort Studies; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics
chemical_list: C000715087:ABCC2 protein, human; D000970:Antineoplastic Agents; D005819:Genetic Markers; D000089762:Multidrug Resistance-Associated Protein 2; D000077146:Irinotecan; D002166:Camptothecin