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It is desirable to identify the most effective sequence of endocrine therapies for the treatment of postmenopausal women with advanced, hormone-responsive breast cancer. In a retrospective analysis of two large, randomized, comparative Phase III trials in this patient population, the Tamoxifen or 'Arimidex' Randomized Group Efficacy and Tolerability (TARGET) trial and the North American trial, we ascertained that tumors responding to anastrozole as first-line therapy may subsequently respond to tamoxifen as second-line therapy. In a double-blind cross-over trial, the SAKK 21/95 sub-trial (including patients from the Swiss centres in the TARGET trial), we further investigated the clinical impact of anastrozole followed by tamoxifen compared with that of tamoxifen followed by anastrozole. Patients with locally advanced or metastatic breast cancer who had continued on randomized treatment until objective disease progression and were still considered suitable for endocrine therapy, could continue on blinded therapy crossing-over to the alternative treatment. They were assessed for time to progression (TTP) from treatment randomization, TTP after crossing-over treatments, time from randomization to progression after crossing-over treatments and overall survival. Median TTP from randomization for patients receiving first-line treatment with anastrozole (n = 31) and tamoxifen (n = 29) was 11.3 and 8.3 months, respectively, p = 0.75. Median TTP from treatment cross-over was 6.7 months for tamoxifen after progression on anastrozole (n = 19) and 5.7 months for anastrozole after progression on tamoxifen (n = 18), while median time from randomization to second progression was 28.2 and 19.5 months, respectively. Overall survival from randomization for the anastrozole-tamoxifen sequence and the tamoxifen-anastrozole sequence was 69.7 versus 59.3 months, respectively, p = 0.10. The relative risk of death was higher for the tamoxifen followed by anastrozole sequence (1.63; 95% confidence interval [CI] 0.89-2.98). Tamoxifen is an effective second-line therapy after anastrozole. Our data, together with the better tolerability profile of anastrozole compared with tamoxifen, support the use of anastrozole as first-line therapy for advanced breast cancer in postmenopausal women with hormone receptor-positive tumors. Treatment with tamoxifen may still be useful upon subsequent progression.