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A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genotyping platform

The Pharmacogenomics Journal volume 10, pages 191–199 (2010)Cite this article

Abstract

The anticancer agent docetaxel shows significant inter-individual variation in its pharmacokinetic and toxicity profile. Thalidomide is an active anticancer agent and also shows wide pharmacological variation. Past pharmacogenetic research has not explained this variation. Patients with prostate cancer enrolled in a randomized phase II trial using docetaxel and thalidomide versus docetaxel alone were genotyped using the Affymetrix DMET 1.0 platform, which tests for 1256 genetic variations in 170 drug disposition genes. Genetic polymorphisms were analyzed for associations with clinical response and toxicity. In all, 10 single-nucleotide polymorphisms (SNPs) in three genes were potentially associated with response to therapy: peroxisome proliferator-activated receptor-δ (PPAR-δ), sulfotransferase family, cytosolic, 1C, member 2 (SULT1C2) and carbohydrate (chondroitin 6) sulfotransferase 3 (CHST3). In addition, 11 SNPs in eight genes were associated with toxicities to treatment: spastic paraplegia 7 (pure and complicated autosomal recessive) (SPG7), CHST3, cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2), ATP-binding cassette, sub-family C (CFTR/MRP), member 6 (ABCC6), ATPase, Cu++ transporting, alpha polypeptide (ATP7A), cytochrome P450, family 4, subfamily B, polypeptide 1 (CYP4B1) and solute carrier family 10 (sodium/bile acid cotransporter family), member 2 (SLC10A2). Genotyping results between drug metabolizing enzymes and transporters (DMET) and direct sequencing showed >96% of concordance. These findings highlight the role that non-CYP450 metabolizing enzymes and transporters may have in the pharmacology of docetaxel and thalidomide.

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Abbreviations

CRPC:

castrate-resistant prostate cancer

DMET:

drug-metabolizing enzymes and transporters

SNP:

single-nucleotide polymorphism

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Acknowledgements

This work was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA. Partial findings contained in this article were initially presented at the 2007 Annual Convention of the American Society of Clinical Oncology.

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Authors and Affiliations

  1. Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    J F Deeken

  2. Affymetrix, Inc.,, Santa Clara, CA, USA

    T Cormier, K Tran & X Miao

  3. Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, MD, USA

    D K Price, T M Sissung, W L Dahut & W D Figg

  4. Biostatistics and Data Management Section, National Cancer Institute, NIH, Bethesda, MD, USA

    S M Steinberg & D J Liewehr

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  1. J F Deeken
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  2. T Cormier
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Correspondence to J F Deeken.

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Competing interests

TC, KT and XM are employees of Affymetrix, the manufacturer of the DMET platform. JFD serves as a consultant to Sanofi-Aventis, the manufacturer of docetaxel.

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Deeken, J., Cormier, T., Price, D. et al. A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genotyping platform. Pharmacogenomics J 10, 191–199 (2010). https://doi.org/10.1038/tpj.2009.57

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