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Genetic polymorphisms as predictive biomarker of survival in patients with gastrointestinal stromal tumors treated with sunitinib

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Abstract

This study aimed to identify single-nucleotide polymorphisms (SNPs) that are associated with outcome to treatment with sunitinib in patients with advanced gastrointestinal stromal tumors (GIST). Forty-nine SNPS involved in the pharmacokinetic and pharmacodynamic pathway of sunitinib were associated with progression-free survival (PFS) and overall survival (OS) in 127 patients with advanced GIST who have been treated with sunitinib. PFS was significantly longer in carriers of the TT genotype in POR rs1056878 (hazards ratio (HR) 4.310, 95% confidence interval (CI):1.457–12.746, P=0.008). The presence of the T-allele in SLCO1B3 rs4149117 (HR 2.024, 95% CI:1.013–4.044, P=0.046), the CCC-CCC alleles in SLC22A5 haplotype (HR 2.603, 95% CI: 1.216–5.573, P=0.014), and the GC-GC alleles in the IL4 R haplotype (HR 7.131, 95% CI:1.518–33.496, P=0.013) were predictive for OS. This shows that polymorphisms in the pharmacokinetic and pharmacodynamic pathways of sunitinib are associated with survival in GIST. This may help to identify patients that benefit more from treatment with sunitinib.

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Acknowledgements

This study was partially funded by Novartis and Stichting Gift for GIST.

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Author notes

  1. J S L Kloth and M C Verboom: These authors contributed equally to this work.

Authors and Affiliations

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

    J S L Kloth, S Sleijfer & R H J Mathijssen

  2. Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands

    M C Verboom & H Gelderblom

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

    J J Swen, T van der Straaten & H J Guchelaar

  4. Cancer Genomics Netherlands, Rotterdam, The Netherlands

    S Sleijfer

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

    A K L Reyners

  6. Department of Medical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    N Steeghs

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  1. J S L Kloth
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  2. M C Verboom
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  3. J J Swen
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  4. T van der Straaten
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  5. S Sleijfer
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  6. A K L Reyners
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  7. N Steeghs
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  8. H Gelderblom
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  9. H J Guchelaar
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  10. R H J Mathijssen
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Correspondence to J S L Kloth.

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Competing interests

JJ Swen, H Gelderblom and HJ Guchelaar have an unrestricted grant from Pfizer regarding pharmacogenetic research in patients treated with sunitinib.

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Kloth, J., Verboom, M., Swen, J. et al. Genetic polymorphisms as predictive biomarker of survival in patients with gastrointestinal stromal tumors treated with sunitinib. Pharmacogenomics J 18, 49–55 (2018). https://doi.org/10.1038/tpj.2016.83

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  • DOI: https://doi.org/10.1038/tpj.2016.83

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