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Antiestrogen hormonal therapy is the cornerstone of endocrine treatment of hormone-receptor positive breast cancer.

Current antiestrogen treatment options for hormone-receptor positive breast cancer include selective estrogen-receptor modulators (SERMs), selective estrogen-receptor downregulators (SERDs), and aromatase inhibitors (AIs).


The SERMs are chemically diverse compounds that lack the steroid structure of estrogen but possess a tertiary structure that allows them to bind to estrogen receptors. Depending on the specific end-organ, they exert selective agonist and/or antagonist effects (1).

There are three currently approved SERMS: raloxifene, toremifene, and tamoxifen (Figure 11-1). The most widely used SERM for treatment of ER positive breast cancer is tamoxifen.


Chemical structure of selective estrogen receptor modulators: tamoxifen, raloxifene, and toremifene.


Mechanism of action. Tamoxifen is a competitive inhibitor of estradiol binding to the ER. In addition to its estrogen antagonist effects on the breast and breast cancer, tamoxifen exerts estrogenic effects on non-breast tissues which influence its overall therapeutic index. Tamoxifen exerts agonist or antagonist effects in part related to ambient estrogen levels. For example on bone metabolism it exerts a partial agonist action in postmenopausal women whereas in premenopausal women its effect on bone is antagonistic (1).

Clinically in women with ER positive disease, 5 years of post-operative adjuvant tamoxifen reduces the annual odds of recurrence of breast cancer by 39% and the annual odds of death by 31%, with comparable effects regardless of age as well as menopausal and nodal status (2).

Absorption, fate, and excretion. Tamoxifen is readily absorbed following oral administration, with peak concentrations measurable after 3–7 h and steady-state levels being reached at 4–6 weeks. It is a prodrug with little affinity for the estrogen receptor and requires metabolization into its active form endoxifen (4-hydroxy N-desmethyltamoxifen) by the sequential action of CYP2D6 and CYP3A4. A second metabolite, N-desmethyltamoxifen, also has strong antiestrogenic activity. Some selective serotonin reuptake inhibitors (SSRIs) like fluoxetine, paroxetine, and sertraline are potent inhibitors of CYP2D6, and may impair tamoxifen's activation.

It is hypothesized that certain CYP2D6 genotypes and phenotypes are associated with lower endoxifen concentrations and worse breast cancer outcome. However, two published retrospective studies with the largest sample size thus far found no statistically significant association between the presence of poor or intermediate metabolizer phenotype and breast cancer outcome (3, 4). Given the limited and conflicting data, CYP2D6 testing is not recommended as a tool to define the optimal endocrine strategy.

The half-lives of N-desmethyltamoxifen and endoxifen are 14 days or longer. After ...

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