Hormonal Therapy: Current Status in the Treatment of Metastatic

Introduction
Hormonal therapy is generally attractive because there are a variety of effective options available and the toxicities are generally mild. For patients with estrogen receptor/progesterone receptor-positive breast cancer, hormonal therapy is the preferred treatment if possible. For patients with rapidly progressive tumors or those in visceral crises, chemotherapy may be preferred because of its rapid rate of response, although even in this situation, hormone therapy may be feasible.

Tamoxifen
Despite the effectiveness of tamoxifen in most patients with estrogen receptor/progesterone receptor-positive metastatic breast cancer, these patients eventually experience relapse. Over the last several years, new hormonal agents have become available and have now challenged tamoxifen as the gold standard for the treatment of patients with hormone receptor-positive metastatic breast cancer.

Aromatase Inhibitors
A meta-analysis of multiple trials comparing several aromatase inhibitors with tamoxifen or progestins in metastatic breast cancer has shown a survival benefit with third-generation aromatase inhibitors. The benefit of the third-generation AIs in the first-line setting was identical to their benefit in the second-line and subsequent-line settings.

Fulvestrant
Fulvestrant is in essence a "pure anti-estrogen" that downregulates the estrogen receptor and has no agonistic effect. The agent has received approved in many countries as second-line therapy in the treatment of postmenopausal estrogen receptor/progesterone receptor-positive metastatic breast cancer.

Ovarian Ablation/Ovarian Suppression
Ovarian ablation was the original systemic therapy for breast cancer but has largely been replaced with ovarian suppression by luteinizing hormone releasing hormone analogues. The combination of LHRH analogues and tamoxifen is accepted as standard hormonal treatment in premenopausal and perimenopausal patients with metastatic breast cancer.

Conclusions
Aromatase inhibitors have supplanted tamoxifen as the gold standard in the treatment of estrogen receptor/progesterone receptor-positive metastatic breast cancer in postmenopausal women. Fulvestrant is yet another available hormonal option for postmenopausal patients. For premenopausal and perimenopausal patients, ovarian suppression with an LHRH analogue and tamoxifen is considered a standard hormonal treatment. In lieu of an LHRH analogue, ovarian ablation via surgery or irradiation is acceptable.

Future Directions
In the era of biologic therapies, trastuzumab combined with anastrozole has been found to be superior to anastrozole alone upfront. Other targeted agents being evaluated with aromatase inhibitors include the antiangiogenic agents bevacizumab, sunitinib, and sorafenib (Nexavar) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.