Received on November 28, 2008
Accepted on June 8, 2009

Reviews

Pharmacogenomics of Tamoxifen Therapy

¹ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University Tübingen, Tübingen, Germany
² Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University Tübingen, Tübingen, Germany, and Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany

^* To whom correspondence should be addressed. E-mail: hiltrud.brauch{at}ikp-stuttgart.de.

BACKGROUND: Tamoxifen is a standard endocrine therapy for the prevention and treatment of steroid hormone receptor–positive breast cancer.

CONTENT: Tamoxifen requires enzymatic activation by cytochrome P450 (CYP) enzymes for the formation of active metabolites 4-hydroxytamoxifen and endoxifen, both of which have an affinity for the estrogen receptor and an ability to inhibit cell proliferation that are approximately 100-fold greater than the parent drug. The polymorphic CYP2D6 is the key enzyme in this biotransformation, and recent mechanistic, pharmacologic, and clinical evidence suggests that genetic variants and drug interaction by CYP2D6 inhibitors influence the plasma concentrations of active tamoxifen metabolites and the outcomes of tamoxifen-treated patients. In particular, nonfunctional (poor metabolizer) and severely impaired (intermediate metabolizer) CYP2D6 alleles are associated with higher recurrence rates.

SUMMARY: Accordingly, CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) genotyping before treatment to predict metabolizer status may open new avenues for individualizing endocrine treatment, with the maximum benefit being expected for extensive metabolizers. Moreover, strong CYP2D6 inhibitors such as the selective serotonin reuptake inhibitors paroxetine and fluoxetine, which are used to treat hot flashes, should be avoided because they severely impair formation of the active metabolites.