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The use of the 13C-dextromethorphan breath test for phenotyping CYP2D6 in breast cancer patients using tamoxifen: association with CYP2D6 genotype and serum endoxifen levels

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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

An Erratum to this article was published on 12 January 2013

Abstract

Purpose

Adjuvant therapy with tamoxifen significantly reduces breast cancer recurrence and mortality in estrogen receptor positive disease. CYP2D6 is the main enzyme involved in the activation of the prodrug tamoxifen into the anti-estrogen endoxifen. Endoxifen is thought to be a main determinant for clinical efficacy in breast cancer patients using tamoxifen. As the large interindividual variation in endoxifen levels is only partly explained by CYP2D6 genotype, we explored the use of the 13C-dextromethorphan breath test (DM-BT) for phenotyping CYP2D6 and to predict serum steady-state endoxifen levels as a marker for clinical outcome in breast cancer patients using tamoxifen.

Methods

In 65 patients with early breast cancer using tamoxifen, CYP2D6 phenotype was assessed by DM-BT. CYP2D6 genotype using Amplichip and serum steady-state levels of endoxifen were determined. Genotype was translated into the gene activity score and into ultrarapid, extensive, heterozygous extensive, intermediate or poor metabolizer CYP2D6 predicted phenotype.

Results

CYP2D6 phenotype determined by the DM-BT explained variation in serum steady-state endoxifen levels for 47.5 % (R 2 = 0.475, p < 0.001). Positive and negative predictive values for a recently suggested threshold serum level of endoxifen (5.97 ng/mL) for breast cancer recurrence rate were 100 and 90 %, respectively, for both CYP2D6 phenotype by DM-BT (delta-over-baseline at t = 50 min (DOB50) values of 0.7–0.9) and genotype (CYP2D6 gene activity score of 1.0).

Conclusion

DM-BT might be, along with CYP2D6 genotyping, of value in selection of individualized endocrine therapy in patients with early breast cancer, especially when concomitant use of CYP2D6 inhibiting medication alters the phenotype.

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Acknowledgments

We are grateful to Isotope Cambridge Labs, Inc. for supplying 13C-DM formulation, breath bags and POCone spectrophotometer for the study. We thank the nurse practitioners from the Leiden University Medical Center, Diaconessenhuis Leiden, and Medical Center of Alkmaar for recruitment of patients for this study. We thank the technicians from the pharmaceutical analytical laboratory of the Department of Clinical Pharmacy and Toxicology, for determination of serum levels of tamoxifen and metabolites. We thank Dr. H. Putter from the Departments of Medical Statistics for his contribution to statistical analyses.

Conflict of interest

Dr. A. M. has employment to disclose: Dr. A. S. Modak is Associate Director Medical Products R&D of Cambridge Isotope Laboratories Inc, Andover, Massachusetts, USA. All other authors state that they have no conflict of interest. There was no financial support of any company to this study.

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Authors and Affiliations

  1. Department of Clinical Oncology, K-1, Leiden University Medical Center, P.O. box 9600, 2300 RC, Leiden, The Netherlands

    F. L. Opdam, V. O. Dezentje, J. W. R. Nortier & H. Gelderblom

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

    F. L. Opdam, V. O. Dezentje, J. den Hartigh & H.-J. Guchelaar

  3. Cambridge Isotope Laboratories Inc., Andover, Massachusetts, USA

    A. S. Modak

  4. Surgery, Diaconessenhuis, Leiden, The Netherlands

    R. Vree

  5. Medical Center of Alkmaar, Alkmaar, The Netherlands

    C. H. Smorenburg

  6. Internal Medicine, Diaconessenhuis, Leiden, The Netherlands

    E. Batman

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  1. F. L. Opdam
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  2. V. O. Dezentje
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  8. J. W. R. Nortier
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  9. H. Gelderblom
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  10. H.-J. Guchelaar
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Correspondence to F. L. Opdam.

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Trial registration The Netherlands Trial Register (NTR1509).

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Opdam, F.L., Dezentje, V.O., den Hartigh, J. et al. The use of the 13C-dextromethorphan breath test for phenotyping CYP2D6 in breast cancer patients using tamoxifen: association with CYP2D6 genotype and serum endoxifen levels. Cancer Chemother Pharmacol 71, 593–601 (2013). https://doi.org/10.1007/s00280-012-2034-4

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