Clinical Trial: CYP2D6 Related Dose Escalation of Tamoxifen in Breast Cancer Patients With Iranian Ethnic Background Resulted in Increased Concentrations of Tamoxifen and Its Metabolites

Zahra Khalaj; Zohreh Baratieh; Parvaneh Nikpour; Matthias Schwab; Elke Schaeffeler; Fariborz Mokarian; Hossein Khanahmad; Rasoul Salehi; Thomas E Mürdter; Mansoor Salehi

doi:10.3389/fphar.2019.00530

Clinical Trial: CYP2D6 Related Dose Escalation of Tamoxifen in Breast Cancer Patients With Iranian Ethnic Background Resulted in Increased Concentrations of Tamoxifen and Its Metabolites

Front Pharmacol. 2019 May 24:10:530. doi: 10.3389/fphar.2019.00530. eCollection 2019.

Authors

Zahra Khalaj¹, Zohreh Baratieh¹, Parvaneh Nikpour^{1

2}, Matthias Schwab^{3

4

5}, Elke Schaeffeler^{3

6}, Fariborz Mokarian⁷, Hossein Khanahmad¹, Rasoul Salehi^{1

2}, Thomas E Mürdter^{3

6}, Mansoor Salehi^{1

2

8}

Affiliations

¹ Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
² Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
³ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
⁴ Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.
⁵ Department of Pharmacy and Biochemistry, University Hospital Tübingen, Tübingen, Germany.
⁶ University of Tübingen, Tübingen, Germany.
⁷ Cancer Prevention Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
⁸ Cellular, Molecular and Genetics Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.

Abstract

Introduction: The polymorphic enzyme cytochrome P450 2D6 (CYP2D6) catalyzes a major step in the bioactivation of tamoxifen. Genotyping of clinically relevant CYP2D6 alleles and subsequent dose adjustment is a promising approach to individualize breast cancer therapy. The aim of this study was to investigate the relationship between the plasma levels of tamoxifen and its metabolites and different CYP2D6 genotypes under standard (20 mg/day) and dose-adjusted therapy (Registration ID in Iranian Registry of Clinical Trials: IRCT2015082323734N1). Materials and Methods: Using TaqMan^® assays common alleles of CYP2D6 (^∗1, ^∗2, ^∗4, ^∗5, ^∗6, ^∗10, ^∗17, and ^∗41) and gene duplication were identified in 134 breast cancer patients. Based on CYP2D6 genotypes patients with an activity score 1 (n = 15) and 0-0.5 (n = 2) were treated with tamoxifen adjusted dosage of 30 and 40 mg/day, respectively. The concentration of tamoxifen and its metabolites before and after 4 and 8 months of dose adjustment were measured using LC-MS/MS technology. Results: At baseline, (Z)-endoxifen plasma concentrations (33 ± 15.5, 28.1 ± 14, 26.6 ± 23.4, 14.3 ± 8.6, and 10.7 ± 5.5 nmol/l for EM/EM, EM/IM, EM/PM, IM/IM and PM/PM, respectively) and the metabolic ratio (Z)-Endoxifen/N-desmethyltamoxifen (0.0558 ± 0.02, 0.0396 ± 0.0111, 0.0332 ± 0.0222, 0.0149 ± 0.0026, and 0.0169 ± 0.0177 for EM/EM, EM/IM, EM/PM, IM/IM, and PM/PM, respectively) correlated with CYP2D6 genotype (Kruskal-Wallis p = 0.013 and p < 0.0001, respectively). Dose escalation to 30 and 40 mg/day in patients with a CYP2D6 activity score of 1 (n = 15) and 0-0.5 (n = 2) resulted in a significant increase in (Z)-endoxifen plasma levels (22.17 ± 24.42, 34.43 ± 26.54, and 35.77 ± 28.89 nmol/l at baseline, after 4 and 8 months, respectively, Friedman p = 0.0388) along with the plasma concentrations of tamoxifen and its other metabolites. No severe side effects were recorded during dose escalation. Conclusion: For the first time, we show the feasibility of dose escalation of tamoxifen in breast cancer patients with compromised CYP2D6 activity and Iranian ethnic background to increase the plasma concentrations of (Z)-endoxifen.

Keywords: CYP2D6; dose; endoxifen; genotype; metabolite; tamoxifen.