TY - JOUR
T1 - Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels
T2 - Effect on active metabolite isomers and the antiestrogenic activity score
AU - Barginear, M. F.
AU - Jaremko, M.
AU - Peter, I.
AU - Yu, C.
AU - Kasai, Y.
AU - Kemeny, M.
AU - Raptis, G.
AU - Desnick, R. J.
PY - 2011/10
Y1 - 2011/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80052971654&partnerID=8YFLogxK
U2 - 10.1038/clpt.2011.153
DO - 10.1038/clpt.2011.153
M3 - Article
C2 - 21900890
AN - SCOPUS:80052971654
SN - 0009-9236
VL - 90
SP - 605
EP - 611
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 4
ER -