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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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Kaplan–Meier analyses for an association between (Z)-endoxifen concentrations, metabolic ratio (MR) Desmethyltamoxifen (DM-Tam)/(Z)-endoxifen or CYP2D6 phenotype score and distant relapse-free survival (DRFS) in the POSH cohort. Kaplan–Meier analyses for DRFS and the three predictor variables classified into groups. (a) Steady-state endoxifen concentrations split into four equally-sized patient groups (<14.1, 14.1–24.7, 24.7–35 and >35 nM), (b) MR DM-Tam/(Z)-endoxifen classified by conditional inference trees into three splits (<31, 31–115 and >115), (c) CYP2D6 phenotypes grouped into EM (plus UM), hetEM and PM. Corresponding Mantel–Cox log-rank tests are stratified for ethnicity. EM, extensive metabolizer; hetEM/IM, heterozygous EM/IM; IM, intermediate metabolizer; PM, poor metabolizer; POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer; UM, ultra rapid metabolizer.
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fig5: Kaplan–Meier analyses for an association between (Z)-endoxifen concentrations, metabolic ratio (MR) Desmethyltamoxifen (DM-Tam)/(Z)-endoxifen or CYP2D6 phenotype score and distant relapse-free survival (DRFS) in the POSH cohort. Kaplan–Meier analyses for DRFS and the three predictor variables classified into groups. (a) Steady-state endoxifen concentrations split into four equally-sized patient groups (<14.1, 14.1–24.7, 24.7–35 and >35 nM), (b) MR DM-Tam/(Z)-endoxifen classified by conditional inference trees into three splits (<31, 31–115 and >115), (c) CYP2D6 phenotypes grouped into EM (plus UM), hetEM and PM. Corresponding Mantel–Cox log-rank tests are stratified for ethnicity. EM, extensive metabolizer; hetEM/IM, heterozygous EM/IM; IM, intermediate metabolizer; PM, poor metabolizer; POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer; UM, ultra rapid metabolizer.

Mentions: POSH outcome analysis (N=306) was performed excluding hormone receptor-negative and poorly/non-compliant patients. There was no association between endoxifen concentrations and DRFS given the lack of a significant trend (Table 4, Figure 5a). However, following Madlensky et al.,14 when we classified patients into percentiles, we observed that patients with low endoxifen concentrations (<14.15 nM) had higher risk for distant relapse or death compared with those with high concentrations (>35 nM, P=0.03, Figure 5a), and showed a trend by multivariate Cox regression analysis of an increased hazard ratio (HR) of 1.94; 95% confidence interval (CI) 0.96–3.93; P=0.064 (Table 4). We next explored the MR DM-Tam/endoxifen and observed an increased HR with increasing MR (decreasing endoxifen formation rate) in multivariate Cox regression: HRper 1 unit=1.007; 95% CI 1.000–1.014; P=0.036 (Table 4). Because the per unit effect of this HR is rather small on a linear scale, we applied two cutoff values demonstrating worse (MR>115), moderate (MR 31–115) and better DRFS (MR<31) by Kaplan–Meier analysis (Log-rank P=0.001; Figure 5b). This was confirmed in multivariate Cox regression with an increased HR for patients with MR>115 (low endoxifen formation rate) compared with patients with MR<31 (high endoxifen formation rate): HR=3.82; 95% CI 1.47–9.89; P=0.006 (Table 4).


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)

Kaplan–Meier analyses for an association between (Z)-endoxifen concentrations, metabolic ratio (MR) Desmethyltamoxifen (DM-Tam)/(Z)-endoxifen or CYP2D6 phenotype score and distant relapse-free survival (DRFS) in the POSH cohort. Kaplan–Meier analyses for DRFS and the three predictor variables classified into groups. (a) Steady-state endoxifen concentrations split into four equally-sized patient groups (<14.1, 14.1–24.7, 24.7–35 and >35 nM), (b) MR DM-Tam/(Z)-endoxifen classified by conditional inference trees into three splits (<31, 31–115 and >115), (c) CYP2D6 phenotypes grouped into EM (plus UM), hetEM and PM. Corresponding Mantel–Cox log-rank tests are stratified for ethnicity. EM, extensive metabolizer; hetEM/IM, heterozygous EM/IM; IM, intermediate metabolizer; PM, poor metabolizer; POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer; UM, ultra rapid metabolizer.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Kaplan–Meier analyses for an association between (Z)-endoxifen concentrations, metabolic ratio (MR) Desmethyltamoxifen (DM-Tam)/(Z)-endoxifen or CYP2D6 phenotype score and distant relapse-free survival (DRFS) in the POSH cohort. Kaplan–Meier analyses for DRFS and the three predictor variables classified into groups. (a) Steady-state endoxifen concentrations split into four equally-sized patient groups (<14.1, 14.1–24.7, 24.7–35 and >35 nM), (b) MR DM-Tam/(Z)-endoxifen classified by conditional inference trees into three splits (<31, 31–115 and >115), (c) CYP2D6 phenotypes grouped into EM (plus UM), hetEM and PM. Corresponding Mantel–Cox log-rank tests are stratified for ethnicity. EM, extensive metabolizer; hetEM/IM, heterozygous EM/IM; IM, intermediate metabolizer; PM, poor metabolizer; POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer; UM, ultra rapid metabolizer.
Mentions: POSH outcome analysis (N=306) was performed excluding hormone receptor-negative and poorly/non-compliant patients. There was no association between endoxifen concentrations and DRFS given the lack of a significant trend (Table 4, Figure 5a). However, following Madlensky et al.,14 when we classified patients into percentiles, we observed that patients with low endoxifen concentrations (<14.15 nM) had higher risk for distant relapse or death compared with those with high concentrations (>35 nM, P=0.03, Figure 5a), and showed a trend by multivariate Cox regression analysis of an increased hazard ratio (HR) of 1.94; 95% confidence interval (CI) 0.96–3.93; P=0.064 (Table 4). We next explored the MR DM-Tam/endoxifen and observed an increased HR with increasing MR (decreasing endoxifen formation rate) in multivariate Cox regression: HRper 1 unit=1.007; 95% CI 1.000–1.014; P=0.036 (Table 4). Because the per unit effect of this HR is rather small on a linear scale, we applied two cutoff values demonstrating worse (MR>115), moderate (MR 31–115) and better DRFS (MR<31) by Kaplan–Meier analysis (Log-rank P=0.001; Figure 5b). This was confirmed in multivariate Cox regression with an increased HR for patients with MR>115 (low endoxifen formation rate) compared with patients with MR<31 (high endoxifen formation rate): HR=3.82; 95% CI 1.47–9.89; P=0.006 (Table 4).

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