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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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Metabolic profiling for tamoxifen (Tam) and five measured metabolites, N-desmethyltamoxifen (DM-Tam), N,N-didesmethyltamoxifen (DDM-Tam), (Z)-endoxifen, 4-hydroxytamoxifen [(Z)-4-OH-DDM-Tam] and norendoxifen [(Z)-4-OH-DDMT-Tam] in study cohorts from Singapore (Sing, N=164), Lebanon (Leb, N=78) and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH, N=345). Metabolite concentrations are presented as boxplots with whiskers defined by the 5th and 95th percentiles and extreme values outside the whiskers. The two dashed lines for Tam delineate putative non-compliant (⩽40 nM) and poorly compliant (40–150 nM) patients as defined from Tam plasma concentrations. Patients with Tam concentrations <150 nM were excluded from further analyses.
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fig2: Metabolic profiling for tamoxifen (Tam) and five measured metabolites, N-desmethyltamoxifen (DM-Tam), N,N-didesmethyltamoxifen (DDM-Tam), (Z)-endoxifen, 4-hydroxytamoxifen [(Z)-4-OH-DDM-Tam] and norendoxifen [(Z)-4-OH-DDMT-Tam] in study cohorts from Singapore (Sing, N=164), Lebanon (Leb, N=78) and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH, N=345). Metabolite concentrations are presented as boxplots with whiskers defined by the 5th and 95th percentiles and extreme values outside the whiskers. The two dashed lines for Tam delineate putative non-compliant (⩽40 nM) and poorly compliant (40–150 nM) patients as defined from Tam plasma concentrations. Patients with Tam concentrations <150 nM were excluded from further analyses.

Mentions: There was a strong interindividual variability for tamoxifen and the five metabolites in each ethnic group (Figure 2). According to two tamoxifen concentration splits, we defined non-compliant (⩽40 nM), poorly compliant (40–150 nM) and compliant (>150 nM) patients (Figure 2, dashed lines). Twenty-four POSH patients were non-compliant (7%) in their first-year serum sample, 10 patients were poorly compliant (2.9%). Of the other two cohorts, two patients were below 40 nM, whereas three patients were below 150 nM. There were no differences in CYP2D6 phenotype frequencies between poorly/non-compliant patients and the remaining patients, therefore subsequent genotype-phenotype correlations were not biased by excluding poorly/non-compliant patients (data not shown).


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)

Metabolic profiling for tamoxifen (Tam) and five measured metabolites, N-desmethyltamoxifen (DM-Tam), N,N-didesmethyltamoxifen (DDM-Tam), (Z)-endoxifen, 4-hydroxytamoxifen [(Z)-4-OH-DDM-Tam] and norendoxifen [(Z)-4-OH-DDMT-Tam] in study cohorts from Singapore (Sing, N=164), Lebanon (Leb, N=78) and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH, N=345). Metabolite concentrations are presented as boxplots with whiskers defined by the 5th and 95th percentiles and extreme values outside the whiskers. The two dashed lines for Tam delineate putative non-compliant (⩽40 nM) and poorly compliant (40–150 nM) patients as defined from Tam plasma concentrations. Patients with Tam concentrations <150 nM were excluded from further analyses.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Metabolic profiling for tamoxifen (Tam) and five measured metabolites, N-desmethyltamoxifen (DM-Tam), N,N-didesmethyltamoxifen (DDM-Tam), (Z)-endoxifen, 4-hydroxytamoxifen [(Z)-4-OH-DDM-Tam] and norendoxifen [(Z)-4-OH-DDMT-Tam] in study cohorts from Singapore (Sing, N=164), Lebanon (Leb, N=78) and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH, N=345). Metabolite concentrations are presented as boxplots with whiskers defined by the 5th and 95th percentiles and extreme values outside the whiskers. The two dashed lines for Tam delineate putative non-compliant (⩽40 nM) and poorly compliant (40–150 nM) patients as defined from Tam plasma concentrations. Patients with Tam concentrations <150 nM were excluded from further analyses.
Mentions: There was a strong interindividual variability for tamoxifen and the five metabolites in each ethnic group (Figure 2). According to two tamoxifen concentration splits, we defined non-compliant (⩽40 nM), poorly compliant (40–150 nM) and compliant (>150 nM) patients (Figure 2, dashed lines). Twenty-four POSH patients were non-compliant (7%) in their first-year serum sample, 10 patients were poorly compliant (2.9%). Of the other two cohorts, two patients were below 40 nM, whereas three patients were below 150 nM. There were no differences in CYP2D6 phenotype frequencies between poorly/non-compliant patients and the remaining patients, therefore subsequent genotype-phenotype correlations were not biased by excluding poorly/non-compliant patients (data not shown).

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