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Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study

The Pharmacogenomics Journal volume 16, pages 54–59 (2016)Cite this article

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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.

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Acknowledgements

This study was supported by funding from NIH/NIGMS U01GM61393, NIH/NCI K07CA140390-01, NIH/NIGMS T32GM086330 and the American Foundation for Pharmaceutical Education. We would like to acknowledge Dr Lana Crona and Mrs Anna Crollman for their help in editing this manuscript, as well as Dr Eric Seiser for his input on the analysis of the liver data in relation to SLCO1B1*1b.

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Authors and Affiliations

  1. Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Center for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, Chapel Hill, NC, USA

    D J Crona & F Innocenti

  2. Department of Medicine, University of Chicago, Chicago, IL, USA

    J Ramirez, M J Ratain & F Innocenti

  3. Division of Quantitative Sciences, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA

    W Qiao

  4. Department of Medical Oncology, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    A-J de Graan & R H J Mathijssen

  5. Department of Clinical Chemistry, Erasmus University Medical Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    R H N van Schaik

  6. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    G L Rosner

  7. University of North Carolina Lineberger Comprehensive Cancer Center, School of Medicine, Chapel Hill, NC, USA

    F Innocenti

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  1. D J Crona
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Correspondence to F Innocenti.

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Competing interests

Dr Federico Innocenti and Dr Mark J Ratain disclose that they receive royalties from UGT1A1 genotyping. Dr Gary L Rosner discloses that he owns stock in Pfizer. The remaining authors state no conflict of interest.

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Crona, D., Ramirez, J., Qiao, W. et al. Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study. Pharmacogenomics J 16, 54–59 (2016). https://doi.org/10.1038/tpj.2015.23

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