Clinical Relevance of CYP2D6 Genetics for Tamoxifen Response in Breast Cancer

Abstract

Tamoxifen is a standard endocrine therapy for the prevention and treatment of steroid hormone receptor-positive breast cancer. Tamoxifen requires enzymatic activation by CYP 450 enzymes for the formation of clinically relevant metabolites, 4-OH-tamoxifen and endoxifen, which both have a greater affinity to the estrogen receptor and ability to inhibit cell proliferation when compared to the parent drug. CYP2D6 is the key enzyme in this biotransformation, and recent mechanistic, pharmacologic, and clinical pharmacogenetic evidence suggests that genetic variants and drug interaction by CYP2D6 inhibitors influence plasma concentrations of active tamoxifen metabolites and outcome of patients treated with adjuvant tamoxifen. Particularly, non-functional (poor metabolizer) and severely impaired (intermediate metabolizer) CYP2D6 variants are associated with higher recurrence rates. Accordingly, CYP2D6 genotyping prior to treatment for prediction of metabolizer status and outcome may open new avenues for the individualization of endocrine treatment choice and benefit. Moreover, strong CYP2D6 inhibitors such as the selective serotonin reuptake inhibitor paroxetine should be avoided as co-medication.

Figures

Fig 1

Metabolic pathways leading to the formation of anti-estrogenic tamoxifen metabolites 4-OH-TAM and endoxifen as well as CYP 450 enzymes involved in these pathways. The size of the arrows symbolize the importance of the respective pathway in the tamoxifen metabolism. Adapted from [9].

Fig 2

Trimodal frequency distribution of the metabolic ratio (MR) of the probe drug spartein in a German population. MR reflects the drug metabolizing enzyme activity of CYP2D6. MR refers to the amount of parent drug excreted divided by the amount of metabolite excreted. Subjects with a very low MR have a very high metabolic capacity whereas subjects with a high MR have a low metabolic capacity. The antimode of MR greater than 20 defines PMs, whereas IMs have an antimode of greater 1.2 and smaller than 20. Adapted from [14].

Fig 3

Consequences of CYP2D6 genotypes for the plasma concentrations of active tamoxifen metabolites. Depending on the genotype, pronounced differences in the plasma concentration of active metabolites will be observed. PM = poor metabolizer; IM = intermediate metabolizer; EM = extensive metabolizer; UM = ultrarapid metabolizer. Frequency in Europeans: PM: 5-10%, IM: 5-10%; EM: 60-70%, and UM: 1-10%.

Fig 4

Kaplan-Meier probabilities of relapse-free time (RFT) for CYP2D6 metabolizer phenotypes predicted from genotypes: A Patients not treated with tamoxifen (noTAM); B Patients treated with adjuvant tamoxifen monotherapy (mTAM); C Carriers of one or two impaired CYP2D6 alleles predictive for ‘decreased’ enzyme activity were combined; EM, IM, PM, extensive, intermediate, poor metabolizer; hetEM, heterozygous extensive. (Reprinted with permission from the American Society of Clinical Oncology: Schroth et al. [23]).