Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels: Effect on active metabolite isomers and the antiestrogenic activity score

Tamoxifen (Tam), the major drug for estrogen receptor (ER)-positive breast cancer, is converted to its active metabolites, Z-and Z′-endoxifen and 4-OH-Tam isomers, primarily by cytochrome P450 CYP2D6. In 117 patients taking 20mg/day of Tam, we determined CYP2D6 genotypes and measured the plasma levels of Tam metabolites. The Z-endoxifen levels increased while Z′-endoxifen levels decreased with increasing metabolizer phenotype activity (MPA) score (P 0.0004). The dosage in patients with endoxifen <40nmol/l and/or CYP2D6 MPA scores of 0 was increased to 30mg/day and their metabolite isomers were monitored for up to 90 days. Of the 24 patients on the increased dose, 90% showed an increase in active isomers by day 60; the rate of increase correlated with the MPA score. Notably, their antiestrogenic activity scores (AASs), which estimate total isomer biologic activity, increased from a baseline median of 17 to 26 at day 60. Further studies involving increasing/decreasing the Tam dosage based on the AAS may determine whether dose adjustment can optimize treatment and improve long-term survival.