The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer

Br J Cancer. 2010 Sep 7;103(6):765-71. doi: 10.1038/sj.bjc.6605800. Epub 2010 Aug 10.


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.

Conclusion: 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.

MeSH terms

  • Adult
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology
  • Cohort Studies
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Middle Aged
  • Neoplasm Metastasis / drug therapy*
  • Pharmacogenetics
  • Phenotype
  • Tamoxifen / therapeutic use*
  • Treatment Outcome


  • Antineoplastic Agents, Hormonal
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Enzyme Inhibitors
  • Tamoxifen
  • Cytochrome P-450 CYP2D6