Tamoxifen (brand name Nolvadex) is a selective estrogen receptor modulator (SERM) that is commonly used in both the treatment and prevention of breast cancer. When taken for 5 years, tamoxifen almost halves the rate of breast cancer recurrence in individuals who have had surgery for estrogen-receptor–positive (ER+) breast cancer.
Tamoxifen is the endocrine therapy of choice for treatment of premenopausal women with ER+ breast cancer, and an important alternative, or sequential treatment for postmenopausal women with ER+ breast cancer. In addition, tamoxifen is the only hormonal agent approved by the FDA for the prevention of premenopausal breast cancer in women who are at high risk, and the treatment of premenopausal invasive breast cancer and ductal carcinoma in situ (DCIS).
The CYP2D6 enzyme metabolizes a quarter of all prescribed drugs and is one of the main enzymes involved in converting tamoxifen into its major active metabolite, endoxifen. Genetic variation in the CYP2D6 gene may lead to increased (“ultrarapid metabolizer”), decreased (“intermediate metabolizer”), or absent (“poor metabolizer”) enzyme activity. Individuals who are intermediate or poor metabolizers may have reduced plasma concentrations of endoxifen and benefit less from tamoxifen therapy.
At this time, the FDA-approved drug label for tamoxifen does not discuss genetic testing for CYP2D6 (Table 1) (1). The National Comprehensive Cancer Network (NCCN) Breast Cancer Panel does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy (Table 2), and this recommendation is consistent with the 2010 update of the American Society of Clinical Oncology (ASCO) Guidelines (the most recent update, 2014, does not discuss pharmacogenetic testing) (2, 3).
The Clinical Pharmacogenetics Implementation Consortium (CPIC) recently published updated guidelines for the dosing of tamoxifen based on CYP2D6 phenotype, with therapeutic recommendations for each metabolizer phenotype (Table 3). For CYP2D6 poor metabolizers, CPIC recommends using an alternative hormonal therapy, such as an aromatase inhibitor for postmenopausal women; or an aromatase inhibitor along with ovarian function suppression in premenopausal women. This recommendation is based on these approaches being superior to tamoxifen regardless of CYP2D6 genotype, and the knowledge that CYP2D6 poor metabolizers who switched from tamoxifen to anastrozole do not have an increased risk of recurrence. The CPIC recommendation also states that higher dose tamoxifen (40 mg/day) can be considered if there are contraindications to aromatase inhibitor therapy; however, the increased endoxifen concentration among CYP2D6 poor metabolizers treated with a higher tamoxifen dose does not typically reach the level as in normal metabolizers (4).
Recommendations from the Dutch Pharmacogenetics Working Group (DWPG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) also discuss using an alternative drug to tamoxifen in CYP2D6 poor metabolizers (Table 4) (5).