Tamoxifen: Biological activities and therapeutic outcomes

Tamoxifen is the most widely used adjuvant endocrine therapy for breast cancer in pre- and postmenopausal women. Long-term studies have shown tamoxifen therapy to reduce the occurrence and reoccurrence of breast cancer and to prolong survival of patients with breast cancer and those predisposed to breast cancer. Early research with tamoxifen and other triphenylethylene compounds demonstrated their partial estrogenic activity but, perhaps more importantly, identified their antiestrogenic properties. On the basis of this antiestrogenic activity, tamoxifen was approved in 1977 by the US Food and Drug Administration as adjuvant therapy in postmenopausal women with node positive breast cancer. Tamoxifen has also been approved to help reduce the risk for invasive breast cancer in women with ductal carcinoma in situ and to help reduce the incidence of breast cancer in women at high risk for such cancers. The demonstrated efficacy of tamoxifen in ER-positive breast cancers has led to the development and approval of aromatase inhibitor drugs, as well as to the conductance of large clinical trials comparing the two adjuvant hormonal therapies. Clinical guidelines now recommend tamoxifen for premenopausal breast cancer patients and sequential aromatase inhibitor and tamoxifen therapies in postmenopausal patients especially those with high risk of recurrence. Long-term studies of tamoxifen have led to multiple discoveries: that to be optimally active tamoxifen must be metabolized to 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen) by cytochrome P450 systems, that CYP2D6 polymorphisms affect tamoxifen metabolism and may affect clinical outcomes, and that not all ER-positive breast cancer patients respond to tamoxifen. Tamoxifen, as a selective estrogen receptor modulator, has direct estrogenic activities in that it preserves bone mineral density and has favorable effects on serum lipids. However, concerns with the drug include the invariable acquired resistance, a small but significant risk of developing uterine cancer, and in patients who took the drug for at least five years, the increased risk of developing ER-negative and perhaps more difficult to treat contralateral breast cancers. Tamoxifen continues to be studied in preclinical and clinical settings and furthergenetic marker studies may identify populations that benefit most from adjuvant tamoxifen treatment.