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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.

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Steady-state plasma concentrations of endoxifen and metabolic ratio DM-Tam/(Z)-endoxifen in premenopausal breast cancer patients according to genotype-based CYP2D6 activity score: (a) Endoxifen concentrations in Singapore (upper panel, N=160, R2=0.38; P<10−12), Lebanon (middle panel, N=77, R2=0.34; P<10−4) and POSH (lower panel, N=306, R2=0.33; P<10−21) cohorts. (b) Metabolic ratios of DMT/(Z)-endoxifen in Singapore (upper panel, R2=0.46; P<10−17), Lebanon (middle panel, R2=0.55; P<10−9) and POSH (lower panel, R2=0.55; P<10−46) cohorts. (c) Metabolic ratio DM-Tam/(Z)-endoxifen across all cohorts (N=548, R2=0.53; P<10−77). Data are presented as boxplots with whiskers defined by 5th and 95th percentiles and extreme values outside the whiskers. DM-Tam, N-desmethyltamoxifen. **P<10−3; ***P<10−5; ****P<10−10. POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer.
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fig3: Steady-state plasma concentrations of endoxifen and metabolic ratio DM-Tam/(Z)-endoxifen in premenopausal breast cancer patients according to genotype-based CYP2D6 activity score: (a) Endoxifen concentrations in Singapore (upper panel, N=160, R2=0.38; P<10−12), Lebanon (middle panel, N=77, R2=0.34; P<10−4) and POSH (lower panel, N=306, R2=0.33; P<10−21) cohorts. (b) Metabolic ratios of DMT/(Z)-endoxifen in Singapore (upper panel, R2=0.46; P<10−17), Lebanon (middle panel, R2=0.55; P<10−9) and POSH (lower panel, R2=0.55; P<10−46) cohorts. (c) Metabolic ratio DM-Tam/(Z)-endoxifen across all cohorts (N=548, R2=0.53; P<10−77). Data are presented as boxplots with whiskers defined by 5th and 95th percentiles and extreme values outside the whiskers. DM-Tam, N-desmethyltamoxifen. **P<10−3; ***P<10−5; ****P<10−10. POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer.

Mentions: The compliant patients from each cohort are shown according to genotype-predicted CYP2D6 activity scores (Table 3). There was a strong gene-dose effect for an association between the CYP2D6 activity score and endoxifen concentrations (P<10−40) in all ethnic cohorts (Figure 3a). The contribution of CYP2D6 to the interindividual variability of endoxifen formation via DM-Tam, as deduced from MR DM-Tam/(Z)-endoxifen, was 46% (Singapore, P<10−17), 55% (Lebanon, P<10−9) and 55% (POSH, P<10−46), respectively (Figure 3b). Altogether, 53% of the interindividual variability of endoxifen formation from DM-Tam was attributed to CYP2D6 (Figure 3c; R2=0.53; P<10−77).


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)

Steady-state plasma concentrations of endoxifen and metabolic ratio DM-Tam/(Z)-endoxifen in premenopausal breast cancer patients according to genotype-based CYP2D6 activity score: (a) Endoxifen concentrations in Singapore (upper panel, N=160, R2=0.38; P<10−12), Lebanon (middle panel, N=77, R2=0.34; P<10−4) and POSH (lower panel, N=306, R2=0.33; P<10−21) cohorts. (b) Metabolic ratios of DMT/(Z)-endoxifen in Singapore (upper panel, R2=0.46; P<10−17), Lebanon (middle panel, R2=0.55; P<10−9) and POSH (lower panel, R2=0.55; P<10−46) cohorts. (c) Metabolic ratio DM-Tam/(Z)-endoxifen across all cohorts (N=548, R2=0.53; P<10−77). Data are presented as boxplots with whiskers defined by 5th and 95th percentiles and extreme values outside the whiskers. DM-Tam, N-desmethyltamoxifen. **P<10−3; ***P<10−5; ****P<10−10. POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Steady-state plasma concentrations of endoxifen and metabolic ratio DM-Tam/(Z)-endoxifen in premenopausal breast cancer patients according to genotype-based CYP2D6 activity score: (a) Endoxifen concentrations in Singapore (upper panel, N=160, R2=0.38; P<10−12), Lebanon (middle panel, N=77, R2=0.34; P<10−4) and POSH (lower panel, N=306, R2=0.33; P<10−21) cohorts. (b) Metabolic ratios of DMT/(Z)-endoxifen in Singapore (upper panel, R2=0.46; P<10−17), Lebanon (middle panel, R2=0.55; P<10−9) and POSH (lower panel, R2=0.55; P<10−46) cohorts. (c) Metabolic ratio DM-Tam/(Z)-endoxifen across all cohorts (N=548, R2=0.53; P<10−77). Data are presented as boxplots with whiskers defined by 5th and 95th percentiles and extreme values outside the whiskers. DM-Tam, N-desmethyltamoxifen. **P<10−3; ***P<10−5; ****P<10−10. POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer.
Mentions: The compliant patients from each cohort are shown according to genotype-predicted CYP2D6 activity scores (Table 3). There was a strong gene-dose effect for an association between the CYP2D6 activity score and endoxifen concentrations (P<10−40) in all ethnic cohorts (Figure 3a). The contribution of CYP2D6 to the interindividual variability of endoxifen formation via DM-Tam, as deduced from MR DM-Tam/(Z)-endoxifen, was 46% (Singapore, P<10−17), 55% (Lebanon, P<10−9) and 55% (POSH, P<10−46), respectively (Figure 3b). Altogether, 53% of the interindividual variability of endoxifen formation from DM-Tam was attributed to CYP2D6 (Figure 3c; R2=0.53; P<10−77).

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