Limits...
Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer.

Saladores P, Mürdter T, Eccles D, Chowbay B, Zgheib NK, Winter S, Ganchev B, Eccles B, Gerty S, Tfayli A, Lim JS, Yap YS, Ng RC, Wong NS, Dent R, Habbal MZ, Schaeffeler E, Eichelbaum M, Schroth W, Schwab M, Brauch H - Pharmacogenomics J. (2014)

Bottom Line: Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013).Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064).Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

View Article: PubMed Central - PubMed

Affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tübingen, Tübingen, Germany.

ABSTRACT
Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R(2): 53%, P<10(-77)). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Show MeSH

Related in: MedlinePlus

Impact of CYP2C19, CYP2C9 and body mass index on tamoxifen metabolite ratios: (a) Metabolic ratio (MR) DDM-Tam/norendoxifen according to the loss-of-function alleles CYP2C19*2/*3 predicting EM, hetEM (heterozygous *2 or *3) and PM (homozygous *2 or *3). (b) MR tamoxifen/(Z)-4-OH-TAM according to CYP2C9 *2/*3 reduced activity alleles defining hetEM (heterozygous *2 or *3) and PM (homozygous *2 or *3) versus EM with normal activity (absence of *2 or *3). (c) MR tamoxifen/DM-Tam stratified by BMI (⩽30 or >30) in all patients, Caucasians and non-Caucasians. Data are presented as boxplots with whiskers defined by 5th and 95th percentiles and extreme values outside the whiskers. BMI, body mass index; DDM-Tam, DiDesmethyltamoxifen; DM-Tam, Desmethyltamoxifen; EM, extensive metabolizer; hetEM, heterozygous EM; PM, poor metabolizer; (Z)-4-OH-TAM, (Z)-4-hydroxytamoxifen.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4308646&req=5

fig4: Impact of CYP2C19, CYP2C9 and body mass index on tamoxifen metabolite ratios: (a) Metabolic ratio (MR) DDM-Tam/norendoxifen according to the loss-of-function alleles CYP2C19*2/*3 predicting EM, hetEM (heterozygous *2 or *3) and PM (homozygous *2 or *3). (b) MR tamoxifen/(Z)-4-OH-TAM according to CYP2C9 *2/*3 reduced activity alleles defining hetEM (heterozygous *2 or *3) and PM (homozygous *2 or *3) versus EM with normal activity (absence of *2 or *3). (c) MR tamoxifen/DM-Tam stratified by BMI (⩽30 or >30) in all patients, Caucasians and non-Caucasians. Data are presented as boxplots with whiskers defined by 5th and 95th percentiles and extreme values outside the whiskers. BMI, body mass index; DDM-Tam, DiDesmethyltamoxifen; DM-Tam, Desmethyltamoxifen; EM, extensive metabolizer; hetEM, heterozygous EM; PM, poor metabolizer; (Z)-4-OH-TAM, (Z)-4-hydroxytamoxifen.

Mentions: The formation of norendoxifen from DDM-Tam precursor and (Z)-4-OH-Tam converted from tamoxifen was decreased in patient carriers of CYP2C19*2 and/or *3 (Figure 4a, P<0.001) and CYP2C9*2 and/or*3 alleles (Figure 4b), P<0.001, respectively. Lower levels of DM-Tam were observed in patients with a BMI higher than 30, both in Caucasians and non-Caucasians (Figure 4c, P<0.001). Notably, DM-Tam formation did not depend on the CYP3A5*3 reduced-function allele. Multivariate regression analyses across all cohorts showed that the combined genetic (CYP2C9, CYP2C19, CYP3A5) and non-genetic factors (age, BMI) contributed to only 2.8% of DM-Tam/endoxifen ratio as compared with 53% by CYP2D6.


Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer.

Saladores P, Mürdter T, Eccles D, Chowbay B, Zgheib NK, Winter S, Ganchev B, Eccles B, Gerty S, Tfayli A, Lim JS, Yap YS, Ng RC, Wong NS, Dent R, Habbal MZ, Schaeffeler E, Eichelbaum M, Schroth W, Schwab M, Brauch H - Pharmacogenomics J. (2014)

Impact of CYP2C19, CYP2C9 and body mass index on tamoxifen metabolite ratios: (a) Metabolic ratio (MR) DDM-Tam/norendoxifen according to the loss-of-function alleles CYP2C19*2/*3 predicting EM, hetEM (heterozygous *2 or *3) and PM (homozygous *2 or *3). (b) MR tamoxifen/(Z)-4-OH-TAM according to CYP2C9 *2/*3 reduced activity alleles defining hetEM (heterozygous *2 or *3) and PM (homozygous *2 or *3) versus EM with normal activity (absence of *2 or *3). (c) MR tamoxifen/DM-Tam stratified by BMI (⩽30 or >30) in all patients, Caucasians and non-Caucasians. Data are presented as boxplots with whiskers defined by 5th and 95th percentiles and extreme values outside the whiskers. BMI, body mass index; DDM-Tam, DiDesmethyltamoxifen; DM-Tam, Desmethyltamoxifen; EM, extensive metabolizer; hetEM, heterozygous EM; PM, poor metabolizer; (Z)-4-OH-TAM, (Z)-4-hydroxytamoxifen.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4308646&req=5

fig4: Impact of CYP2C19, CYP2C9 and body mass index on tamoxifen metabolite ratios: (a) Metabolic ratio (MR) DDM-Tam/norendoxifen according to the loss-of-function alleles CYP2C19*2/*3 predicting EM, hetEM (heterozygous *2 or *3) and PM (homozygous *2 or *3). (b) MR tamoxifen/(Z)-4-OH-TAM according to CYP2C9 *2/*3 reduced activity alleles defining hetEM (heterozygous *2 or *3) and PM (homozygous *2 or *3) versus EM with normal activity (absence of *2 or *3). (c) MR tamoxifen/DM-Tam stratified by BMI (⩽30 or >30) in all patients, Caucasians and non-Caucasians. Data are presented as boxplots with whiskers defined by 5th and 95th percentiles and extreme values outside the whiskers. BMI, body mass index; DDM-Tam, DiDesmethyltamoxifen; DM-Tam, Desmethyltamoxifen; EM, extensive metabolizer; hetEM, heterozygous EM; PM, poor metabolizer; (Z)-4-OH-TAM, (Z)-4-hydroxytamoxifen.
Mentions: The formation of norendoxifen from DDM-Tam precursor and (Z)-4-OH-Tam converted from tamoxifen was decreased in patient carriers of CYP2C19*2 and/or *3 (Figure 4a, P<0.001) and CYP2C9*2 and/or*3 alleles (Figure 4b), P<0.001, respectively. Lower levels of DM-Tam were observed in patients with a BMI higher than 30, both in Caucasians and non-Caucasians (Figure 4c, P<0.001). Notably, DM-Tam formation did not depend on the CYP3A5*3 reduced-function allele. Multivariate regression analyses across all cohorts showed that the combined genetic (CYP2C9, CYP2C19, CYP3A5) and non-genetic factors (age, BMI) contributed to only 2.8% of DM-Tam/endoxifen ratio as compared with 53% by CYP2D6.

Bottom Line: Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013).Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064).Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

View Article: PubMed Central - PubMed

Affiliation: 1] Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany [2] University of Tübingen, Tübingen, Germany.

ABSTRACT
Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R(2): 53%, P<10(-77)). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Show MeSH
Related in: MedlinePlus