Goss P et al. (2007) Phase III, double-blind, controlled trial of atamestane plus toremifene compared with letrozole in postmenopausal women with advanced receptor-positive breast cancer. J Clin Oncol 25: 4961–4966

Inhibition of estrogen synthesis with third-generation aromatase inhibitors (AIs) is standard first-line therapy in postmenopausal women with hormone-receptor-positive locally advanced or metastatic breast cancer. Combining an AI with a selective estrogen receptor modulator (SERM) could achieve complete estrogen blockade and be more effective than AI monotherapy. Adding tamoxifen to the AI anastrozole was unsuccessful; Goss et al. report success from combining tamoxifens less estrogenic analog toremifene, with the steroidal AI atamestane.

Postmenopausal women (n = 865) with advanced receptor-positive breast cancer, who had completed adjuvant hormonal therapy >12 months previously, were recruited across the US, Canada, Russia and the Ukraine; 434 patients were randomly assigned to atamestane 500 mg/day plus toremifene 60 mg/day, and 431 to the nonsteroidal AI letrozole 2.5 mg/day. Median time to progression was 11.2 months in both arms. Overall survival was slightly higher with the combination (3.01 vs 2.79 years), but objective response was lower (30% vs 36%). Disease progression and clinical benefit (objective response plus stable disease) were similar in the two arms, and the regimens were fairly equally tolerated.

This, say the authors, is the first evidence of an endocrine therapy comparable to letrozole in the treatment of advanced endocrine-responsive breast cancer; an antiestrogen can, therefore, be added to an AI without interfering with its action. Trials of more-potent SERMs and selective estrogen receptor downregulators are underway.