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.