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. 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.

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Keywords Adult, Antineoplastic Agents, Hormonal/*therapeutic use, Breast Neoplasms/*drug therapy/enzymology/pathology, Cohort Studies, Cytochrome P-450 CYP2D6/antagonists & inhibitors/genetics/*metabolism, Enzyme Inhibitors/therapeutic use, Female, Humans, Middle Aged, Neoplasm Metastasis/*drug therapy, Pharmacogenetics, Phenotype, Tamoxifen/*therapeutic use, Treatment Outcome
Persistent URL dx.doi.org/10.1038/sj.bjc.6605800, hdl.handle.net/1765/22063
Lammers, L.A, Matthijsen, R.H.J, van Gelder, T, Bijl, M.J, de Graan, A.J.M, Seynaeve, C.M, … van Schaik, R.H.N. (2010). The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer. British Journal of Cancer, 103(6), 765–771. doi:10.1038/sj.bjc.6605800