Selective Estrogen-Receptor Modulators in 2001

Drs. O’Regan and Gradishar comprehensively review the selective estrogen-receptor modulators (SERMs) and other closely related drugs that are presently available or in phase II and III testing. This review is particularly important because, in the last few years, information from several large randomized trials shows the significant contribution of tamoxifen(Drug information on tamoxifen) (Nolvadex) as a preventive and adjuvant agent for breast cancer with hormone receptors. It is timely, as well, since we now have the results of randomized trials comparing tamoxifen with newer types of hormonal therapy for metastatic disease.

Two recently published trials compare the selective aromatase inhibitor anastrozole(Drug information on anastrozole) (Arimidex) with tamoxifen in postmenopausal patients with newly diagnosed metastatic disease. Both trials show equivalent efficacy and fewer complications (ie, thromboembolic events and vaginal bleeding) in patients who received anastrozole.[1,2] One of the trials demonstrates a significantly longer time to progression for patients treated with anastrozole.[2]

Osborne et al report that a randomized comparison of anastrozole with fulvestrant (Faslodex) in postmenopausal women with advanced breast cancer shows a longer duration of response in patients treated with fulvestrant.[3] A novel selective estrogen-receptor downregulator (SERD), fulvestrant acts as an antiestrogen in all tissues, competitively blocks estrogen binding to the estrogen receptor, and appears to reduce expression of the receptor. A second, similarly designed investigation found the two agents to be equivalent in efficacy and tolerability.[4] In addition, it appears that tumors resistant to tamoxifen may respond to fulvestrant.

New Possibilities for Treatment and Prevention

New SERMS, SERDS, and other related drugs not only offer alternatives for the treatment of metastatic disease, but also present the possibility of improved prevention and adjuvant therapy for primary breast cancer. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) study is an international randomized trial comparing 5 years of adjuvant anastrozole, alone or in combination with tamoxifen, with 5 years of tamoxifen alone. The trial has enrolled 9,300 postmenopausal women, but efficacy results are not yet available. Information from this trial may change our adjuvant treatment approach, and perhaps more importantly, may guide the design of future trials of adjuvant therapy in both pre- and postmenopausal women.

Dr. Richard Peto, PhD, in a plenary address delivered at the 23rd Annual San Antonio Breast Cancer Symposium, updated the results of meta-analyses by the Early Breast Cancer Trialists’ Collaborative Group, encompassing 300 randomized trials in which 200,000 women with breast cancer were treated. He reported that the death rate from breast cancer in the United Kingdom has fallen from 50% to 37% since the early 1990s. In the United States, breast cancer-associated death rates have fallen from 40% to 33%. He attributes these improvements to a number of things—such as better radiation, earlier detection, and more uniform adjuvant tamoxifen therapy—which improve disease-free survival results by 3% to 5%.

At present, with additional time and larger numbers of patients, we can recognize a significant overall benefit from these small to moderate improvements. Time may be particularly important in evaluating the efficacy of hormonal therapy. With 10 years of follow-up, the benefits of adjuvant tamoxifen appear to be almost twofold compared with the benefits assessed at 5 years. Hopefully, the newer agents described—coupled with the optimal timing, combinations, and/or sequencing of these agents with other therapies—will further improve the cure of breast cancer. We must, however, remain patient and analyze enough patients over enough time to be able to recognize those critical small and moderate improvements effected by our therapy.