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Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy

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Abstract

The association between CYP2D6 genotype and outcome in breast cancer patients treated with adjuvant tamoxifen remains controversial. We assessed the influence of comprehensive versus limited CYP2D6 genotype in the context of tamoxifen adherence and co-medication in a large cohort of 618 patients. Genotyping of 33 CYP2D6 alleles used two archival cohorts from tamoxifen-treated women with invasive breast cancer (Dundee, n = 391; Manchester, n = 227). Estimates for recurrence-free survival (RFS) were calculated based on inferred CYP2D6 phenotypes using Kaplan–Meier and Cox proportional hazard models, adjusted for nodal status and tumour size. Patients with at least one reduced function CYP2D6 allele (60%) or no functional alleles (6%) had a non-significant trend for worse RFS: hazard ratio (HR) 1.52 (CI 0.98–2.36, P = 0.06). For post-menopausal women on tamoxifen monotherapy, the HR for recurrence in patients with reduced functional alleles was 1.96 (CI 1.05–3.66, P = 0.036). However, RFS analysis limited to four common CYP2D6 allelic variants was no longer significant (P = 0.39). The effect of CYP2D6 genotype was increased by adjusting for adherence to tamoxifen therapy, but not significantly changed when adjusted for co-administration of potent inhibitors of CYP2D6. Comprehensive genotyping of CYP2D6 and adherence to tamoxifen therapy may be useful to identify breast cancer patients most likely to benefit from adjuvant tamoxifen.

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Abbreviations

CYP450:

cytochrome p450

RFS:

recurrence-free survival

HR:

hazard ratio

CI:

confidence intervals

ER:

oestrogen receptor

PM:

poor metabolizer

IM:

intermediate metabolizer

EM:

extensive metabolizer

UM:

ultrametabolizer

HWE:

Hardy–Weinberg Equilibrium

DCIS:

ductal carcinoma in situ

DNA:

deoxyribonucleic acid

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Acknowledgments

We thank H McBurney for technical assistance, A Ashfield, L-J Birse-Stuart-Bell and C McCowan for clinical data acquisition and the patients for donating their tissue for cancer research. The DNA extractions, clinical data gathering, data analysis and report writing were supported by Breast Cancer Research Scotland, Cancer Research-UK, NHS Tayside and the Tayside Tissue Bank (in Dundee), the National Institutes for Health Research Manchester Biomedical Research Centre and Cancer Research-UK (in Manchester) where RF is supported by an ESMO Clinical Translational Fellowship.

Conflict of interest

AM Thompson, CA Purdie and W Newman have received reimbursements and research funding, respectively, from Roche within the last 5 years. Marcel Fontecha, Grant Hillman, Andrea Johnson, Jeffrey Lawrence and Michele Nikoloff were employed by Roche Molecular Systems at the time this study was conducted. The other authors declare that they have no competing interests. The authors have full control of all the primary data and agree to external review by the Journal if requested.

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Authors and Affiliations

  1. Department of Surgery and Molecular Oncology, University of Dundee, Dundee, DD1 9SY, UK

    Alastair M. Thompson, Philip Quinlan & Susan E. Bray

  2. Department of Surgical Oncology, MD Anderson Cancer Center, 1400 Holcombe Boulevard, Houston, TX, USA

    Alastair M. Thompson

  3. Roche Molecular Diagnostics, Pleasanton, CA, USA

    Andrea Johnson, Grantland Hillman, Marcel Fontecha, Michele Nikoloff & Jeffrey Lawrence

  4. Department of Pathology, University of Dundee, Dundee, UK

    Colin A. Purdie & Lee B. Jordan

  5. Genetic Medicine, St Mary’s Hospital, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK

    Roberta Ferraldeschi, Ayshe Latif, Kirsten D. Hadfield, D. Gareth Evans & William G. Newman

  6. Department of Medical Oncology, Christie Hospital, Manchester, UK

    Roberta Ferraldeschi, Linda Ashcroft & Anthony Howell

  7. Paterson Institute for Cancer Research, University of Manchester, Manchester, UK

    Robert B. Clarke

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  1. Alastair M. Thompson
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  2. Andrea Johnson
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  13. Linda Ashcroft
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  14. D. Gareth Evans
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  17. Jeffrey Lawrence
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  18. William G. Newman
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Correspondence to Alastair M. Thompson.

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Thompson, A.M., Johnson, A., Quinlan, P. et al. Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy. Breast Cancer Res Treat 125, 279–287 (2011). https://doi.org/10.1007/s10549-010-1139-x

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  • DOI: https://doi.org/10.1007/s10549-010-1139-x

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