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Genetic polymorphisms in ABCG2 and CYP1A2 are associated with imatinib dose reduction in patients treated for gastrointestinal stromal tumors

The Pharmacogenomics Journal volume 19, pages 473–479 (2019)Cite this article

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Abstract

Imatinib has a mild toxicity profile, although severe adverse events may develop. In this pharmacogenetic pathway analysis the need for dose reduction and cessation of therapy was tested for an association with single nucleotide polymorphisms (SNPs) in genes related to imatinib pharmacology. Retrospective data from 315 patients with a gastrointestinal stromal tumor who received imatinib 400 mg o.d. was associated with 36 SNPs. SNPs that showed a trend in univariate testing were tested in a multivariate model with clinical factors and correction for multiple testing was performed. Dose reduction was associated with carriership of the A-allele in rs2231137 in ABCG2 (OR 7.35, p = 0.0002) and two C-alleles in rs762551 in CYP1A2 (OR 7.12, p = 0.001). Results remained significant after correction for multiple testing. Therapy cessation did not show an association with any of the tested SNPs. These results may help identifying patients at increased risk for toxicity who could benefit from intensified follow-up.

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Acknowledgements

The authors wish to thank Inge Briaire-de Bruijn for her work on DNA isolation, and Tahar van der Straaten, Renee Baak-Pablo, and Daniëlle Klootwijk for their work on DNA isolation and SNP genotyping. This study was partly funded by unrestricted grants from Novartis and ‘Stichting Een Gift voor GIST’, which were used for SNP genotyping

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Authors and Affiliations

  1. Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands

    Michiel C. Verboom & Hans Gelderblom

  2. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Jacqueline S. L. Kloth, Stefan Sleijfer & Ron H. J. Mathijssen

  3. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

    Jesse J. Swen & Henk-Jan Guchelaar

  4. Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Anna K. L. Reyners

  5. Department of Medical Oncology and Clinical Pharmacology, Antoni van Leeuwenhoek - Netherlands Cancer Institute, Amsterdam, The Netherlands

    Neeltje Steeghs

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  1. Michiel C. Verboom
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Correspondence to Michiel C. Verboom.

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Verboom, M.C., Kloth, J.S.L., Swen, J.J. et al. Genetic polymorphisms in ABCG2 and CYP1A2 are associated with imatinib dose reduction in patients treated for gastrointestinal stromal tumors. Pharmacogenomics J 19, 473–479 (2019). https://doi.org/10.1038/s41397-019-0079-z

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