title: The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer.
abstract: BACKGROUND
  Cytochrome P450 2D6 (CYP2D6) has a crucial role in the metabolic conversion of tamoxifen into the active metabolite endoxifen. In this cohort study, the effect of CYP2D6-predicted phenotype, defined as the combined effect of CYP2D6 genetic variation and concomitant use of CYP2D6-inhibiting medication, on time to breast cancer progression (TTP) and overall survival (OS) in women who use tamoxifen for metastatic breast cancer (MBC) was examined.
  
  
  METHODS
  We selected patients treated with tamoxifen (40 mg per day) for hormone receptor-positive MBC from whom a blood sample for pharmacogenetic analysis (CYP2D6*3, *4, *5, *6, *10 and *41) was available. Patient charts (n=102) were reviewed to assess TTP and OS, and to determine whether CYP2D6 inhibitors were prescribed during tamoxifen treatment.
  
  
  RESULTS
  OS was significantly shorter in patients with a poor CYP2D6 metaboliser phenotype, compared with extensive metabolisers (HR=2.09; P=0.034; 95% CI: 1.06-4.12). Co-administration of CYP2D6 inhibitors alone was also associated with a worse OS (HR=3.55; P=0.002; 95% CI: 1.59-7.96) and TTP (HR=2.97; P=0.008; 95% CI: 1.33-6.67) compared with patients without CYP2D6 inhibitors.
  
  
  CONCLUSIONS
  CYP2D6 phenotype is an important predictor of treatment outcome in women who are receiving tamoxifen for MBC. Co-administration of CYP2D6 inhibitors worsens treatment outcome of tamoxifen and should therefore be handled with care.
authors.affiliation: Department of Hospital Pharmacy, Erasmus MC, University Hospital, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: L A
authors.initials: LA
authors.lastname: Lammers
authors.forename: R H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: T
authors.initials: T
authors.lastname: van Gelder
authors.forename: M J
authors.initials: MJ
authors.lastname: Bijl
authors.forename: A-J M
authors.initials: AJ
authors.lastname: de Graan
authors.forename: C
authors.initials: C
authors.lastname: Seynaeve
authors.forename: M A
authors.initials: MA
authors.lastname: van Fessem
authors.forename: E M
authors.initials: EM
authors.lastname: Berns
authors.forename: A G
authors.initials: AG
authors.lastname: Vulto
authors.forename: R H N
authors.initials: RH
authors.lastname: van Schaik
mesh_terms: D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D010597:Pharmacogenetics; D010641:Phenotype; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6