Hormone therapy should generally be considered as initial treatment for a postmenopausal patient with newly diagnosed metastatic disease if the patient's tumor is ER-positive, PR-positive, or ER/PR-unknown. Hormone therapy is especially indicated if the patient's disease involves only bone and soft tissue and the patient has either not received adjuvant antiestrogen therapy or has been off such therapy for more than 1 year. While tamoxifen has been used in this setting for many years, several randomized trials suggest equivalent or superior response rates and progression-free survival (PFS) for the aromatase inhibitors (AIs) compared with tamoxifen.[24,25,26][Level of evidence: 1iiDiii] In a meta-analysis that included randomized trials in patients who were receiving an AI as either their first or second hormonal therapy for metastatic disease, those who were randomly assigned to a third-generation drug (anastrozole, letrozole, exemestane, or vorozole) lived longer (hazard ratio [HR] for death, 0.87; 95% confidence interval [CI], 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[Level of evidence: 1iA]
Several randomized but underpowered trials have tried to determine if combined hormone therapy (luteinizing hormone-releasing hormone [LHRH] agonists + tamoxifen) is superior to either approach alone in premenopausal women. Results have been inconsistent.[28,29,30] The best study design compared buserelin (an LHRH agonist) versus tamoxifen versus the combination in 161 premenopausal women with hormone receptor–positive tumors. Patients receiving buserelin and tamoxifen had a significantly improved median survival of 3.7 years compared with those receiving tamoxifen or buserelin who survived 2.9 and 2.5 years, respectively (P = .01).[Level of evidence: 1iiA] Very few women in this trial received adjuvant tamoxifen, which makes it difficult to assess whether these results are applicable to women who relapse after adjuvant tamoxifen.
Women whose tumors are ER-positive or unknown, with bone or soft tissue metastases only, who have received an antiestrogen within the past year, should be given second-line hormone therapy. Examples of second-line hormone therapy in postmenopausal women include selective AIs, such as anastrozole, letrozole, or exemestane; megestrol acetate; estrogens; androgens;[32,33,34,35,36,37,38,39,40] and the ER down-regulator, fulvestrant.[41,42] In comparison to megestrol acetate, all three currently available AIs have demonstrated, in prospective randomized trials, at least equal efficacy and better tolerability.[32,33,34,35,36,37,38,43] In a meta-analysis that included randomized trials of patients who were receiving an AI as either their first or second hormonal therapy for metastatic disease, those who were randomly assigned to a third-generation drug (e.g., anastrozole, letrozole, exemestane, or vorozole) lived longer (HRdeath 0.87; 95% CI, 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[Level of evidence: 1iA] Two randomized trials that enrolled 400 and 451 patients who had progressed after receiving tamoxifen demonstrated that fulvestrant yielded similar results to anastrozole in terms of its impact on PFS.[44,45] The proper sequence of these therapies is currently not known.[43,46] While there is a biologic rationale for combining fulvestrant with a third-generation AI for patients with recurrent or metastatic disease, the benefits of such combination therapy have not been established.