Tamoxifen and CYP2D6: A Controversy in Pharmacogenetics

Abstract

Tamoxifen reduces the rate of breast cancer recurrence by about one-half. It is converted to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6) and transported by ATP-binding cassette transporters. Genetic polymorphisms that confer reduced CYP2D6 activity or concurrent use of CYP2D6-inhibiting drugs may reduce the clinical efficacy of tamoxifen. The issue of the clinical utility of CYP2D6 genotype testing is subject to considerable and ongoing academic and clinical controversy. In this chapter, we outline tamoxifen's clinical pharmacology and give an overview of the research to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Based on the evidence to date, the impact of drug-induced and/or gene-induced inhibition of CYP2D6 activity is likely to be null or small, or at most moderate in subjects carrying two reduced function alleles. Future research should examine the effect of polymorphisms in genes encoding enzymes in tamoxifen's complete metabolic pathway, should comprehensively evaluate other biomarkers that affect tamoxifen effectiveness, such as the transport enzymes, and focus on subgroups of patients, such as premenopausal breast cancer patients, for whom tamoxifen is the only guideline approved endocrine therapy.

Metabolic Pathway Analysis and Effectiveness of Tamoxifen in Danish Breast Cancer Patients

“…We have made the statistical computing code for the pathway analysis publicly available [Am J Epidemiology, pending 2 nd review], and encourage others with relevant data on the pharmacogenetics of tamoxifen to apply the method to their data. Tables Table 1. Distribution of clinical and tumor characteristics by study population, ERα status, and receipt of tamoxifen among participants in population-based postmenopausal case-control and premenopausal cohort studies of Danish women diagnosed with a first primary breast cancer Progesterone receptor expression PR− PR+ Unknown 0 (0) / 0 (0) 0 (0) / 0 (0) 541 (100) / 541 (100) 383 (8.3) 2680 (58) 1537 (33) 1121 (83) 19 (1.4) 219 (16) HER2 expression HER2− HER2+ Unknown 0 (0) / 0 (0) 0 (0) / 0 (0) 541 (100) / 541 (100) 2887 (63) 619 (14) 1094 (24) 692 (51) 354 (26) 313 (23) Duration of intended tamoxifen therapy None 1 year 2 years 5 years 0 (0) / 0 (0) 247 (46) / 249 (46) 98 (18) / 92 (17) 196 (36) / 200 (37) 0 (0) 0 (0) 0 (0) 4600 (100) 1359 (100) 0 (0) 0 (0) 0 (0) BF=Bayes Factor. BFs >1 indicate the data more strongly support an effect on recurrence than no effect, and support increases with the magnitude of the BF.…”

“…[1][2][3] Nonetheless, the potential for women with reduced metabolic capacity to accrue less than the full benefit of tamoxifen adjuvant therapy has been an ongoing controversy. 3,[7][8][9][10][11][12][13][14] Tamoxifen is metabolized by phase1 reactions to active compounds primarily by hydroxylation and demethylation ( Figure 1). 15,16 The 4-hydroxylated metabolites bind the ER a hundred-fold more readily than the parent compound and its demethylated metabolite, 17 but have less than 10% the steady state concentration.…”

“…[22][23][24][25][26][27][28] CYP2D6 variants have therefore received the most attention in clinical epidemiology studies of gene-drug interactions that might reduce tamoxifen's effectiveness. 3,8,10,14,29,30 Multiple enzymes catalyze most steps in the metabolic pathway and multiple pathways yield the same metabolites, 15,[18][19][20][21] so focusing on a single enzyme is unlikely to capture the full importance of metabolism in achieving an optimal tamoxifen response. No earlier study of tamoxifen adjuvant therapy has taken a comprehensive analytic approach to determine the importance of the metabolic pathway.…”

Role of Genetic Variations in the Hepatic Handling of Drugs

“…CYP2D6 metabolizes tamoxifen into endoxyfen that binds to the receptor more efficiently than tamoxifen. Thus, cancer patients carrying allele variants *10, *3, *4 (variant c.1846G>A, rs3892097, MAF 18.4%) *41, *5 and *6 with a PM phenotype showed a greater risk of relapse [35]. The variants mentioned above also have a role in reducing the effect and increasing the risk of secondary effects of some antidepressants such as amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline and trimipramine.…”

Pharmacogenomics of anticancer drugs: Personalising the choice and dose to manage drug response

“…As such, guidelines have been developed that recommend that PMs receive an alternative therapy such as aromatase inhibitors or if contraindicated, an increase in tamoxifen dose to 40 mg/d should be considered 101 . There is, however, controversy due to the inconsistent evidence as to whether pre‐emptive CYP2D6 genotyping actually improves clinical outcomes with some large trials reporting conflicting results 6 …”