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

Study flow diagram of premenopausal study. co-med, co-medication; HR, hormone receptor; Leb, Lebanon; POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer; Sing, Singapore; Tam, tamoxifen.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Study flow diagram of premenopausal study. co-med, co-medication; HR, hormone receptor; Leb, Lebanon; POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer; Sing, Singapore; Tam, tamoxifen.

Mentions: Three ethnic groups of prospectively recruited hormone receptor-positive premenopausal breast cancer patients with adjuvant tamoxifen treatment were investigated (Figure 1). Of these, 164 Asian patients in part previously described31 (136 Chinese, 14 Malays and 14 Indians) have been provided by the Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, Singapore. Another 78 consecutively recruited patients (2009–2011) in part previously described32 have been provided by the Hematology-Oncology Division, Internal Medicine, American University of Beirut, Lebanon (Leb). Furthermore, 345 patients were selected from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort, an observational cohort study comprised mainly of Caucasian patients (2956 patients recruited between 2001 and 2007) by the Cancer Sciences Academic Unit and University of Southampton Clinical Trials Unit, University of Southampton, UK.33, 34 Selection of patients for our current study was based on the availability of tamoxifen steady-state serum and germline DNA. Patients taking CYP2D6 inhibitors were excluded from the Singapore cohort and comprised only seven patients who received weak CYP2D6 inhibitors, venlafaxine, escitalopram or clomipramine in the Lebanon cohort. For the POSH cohort, data on co-medication was not available. In total, 587 premenopausal patients were investigated for the quantitation of tamoxifen metabolites and genotyping. Figure 1 shows the patient inclusion scheme to explain the underlying rationale for the survival analyses, which was performed in the POSH cohort but not in the Singapore and Lebanon cohorts due to incomplete follow-up and delayed study entry of their patients, respectively (Figure 1).


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)

Study flow diagram of premenopausal study. co-med, co-medication; HR, hormone receptor; Leb, Lebanon; POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer; Sing, Singapore; Tam, tamoxifen.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Study flow diagram of premenopausal study. co-med, co-medication; HR, hormone receptor; Leb, Lebanon; POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer; Sing, Singapore; Tam, tamoxifen.
Mentions: Three ethnic groups of prospectively recruited hormone receptor-positive premenopausal breast cancer patients with adjuvant tamoxifen treatment were investigated (Figure 1). Of these, 164 Asian patients in part previously described31 (136 Chinese, 14 Malays and 14 Indians) have been provided by the Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, Singapore. Another 78 consecutively recruited patients (2009–2011) in part previously described32 have been provided by the Hematology-Oncology Division, Internal Medicine, American University of Beirut, Lebanon (Leb). Furthermore, 345 patients were selected from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort, an observational cohort study comprised mainly of Caucasian patients (2956 patients recruited between 2001 and 2007) by the Cancer Sciences Academic Unit and University of Southampton Clinical Trials Unit, University of Southampton, UK.33, 34 Selection of patients for our current study was based on the availability of tamoxifen steady-state serum and germline DNA. Patients taking CYP2D6 inhibitors were excluded from the Singapore cohort and comprised only seven patients who received weak CYP2D6 inhibitors, venlafaxine, escitalopram or clomipramine in the Lebanon cohort. For the POSH cohort, data on co-medication was not available. In total, 587 premenopausal patients were investigated for the quantitation of tamoxifen metabolites and genotyping. Figure 1 shows the patient inclusion scheme to explain the underlying rationale for the survival analyses, which was performed in the POSH cohort but not in the Singapore and Lebanon cohorts due to incomplete follow-up and delayed study entry of their patients, respectively (Figure 1).

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