Breast Cancer Research and Treatment

, Volume 125, Issue 1, pp 279–287 | Cite as

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

  • Alastair M. Thompson
  • Andrea Johnson
  • Philip Quinlan
  • Grantland Hillman
  • Marcel Fontecha
  • Susan E. Bray
  • Colin A. Purdie
  • Lee B. Jordan
  • Roberta Ferraldeschi
  • Ayshe Latif
  • Kirsten D. Hadfield
  • Robert B. Clarke
  • Linda Ashcroft
  • D. Gareth Evans
  • Anthony Howell
  • Michele Nikoloff
  • Jeffrey Lawrence
  • William G. Newman
Brief Report

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.

Keywords

Adherence Cytochrome P450 CYP2D6 Pharmacogenetics Tamoxifen 

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

Supplementary material

10549_2010_1139_MOESM1_ESM.doc (156 kb)
Supplementary material 1 (DOC 156 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Alastair M. Thompson
    • 1
    • 2
  • Andrea Johnson
    • 3
  • Philip Quinlan
    • 1
  • Grantland Hillman
    • 3
  • Marcel Fontecha
    • 3
  • Susan E. Bray
    • 1
  • Colin A. Purdie
    • 4
  • Lee B. Jordan
    • 4
  • Roberta Ferraldeschi
    • 5
    • 6
  • Ayshe Latif
    • 5
  • Kirsten D. Hadfield
    • 5
  • Robert B. Clarke
    • 7
  • Linda Ashcroft
    • 6
  • D. Gareth Evans
    • 5
  • Anthony Howell
    • 6
  • Michele Nikoloff
    • 3
  • Jeffrey Lawrence
    • 3
  • William G. Newman
    • 5
  1. 1.Department of Surgery and Molecular OncologyUniversity of DundeeDundeeUK
  2. 2.Department of Surgical OncologyMD Anderson Cancer CenterHoustonUSA
  3. 3.Roche Molecular DiagnosticsPleasantonUSA
  4. 4.Department of PathologyUniversity of DundeeDundeeUK
  5. 5.Genetic MedicineSt Mary’s Hospital, Manchester Academic Health Sciences Centre, University of ManchesterManchesterUK
  6. 6.Department of Medical OncologyChristie HospitalManchesterUK
  7. 7.Paterson Institute for Cancer Research, University of ManchesterManchesterUK

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