Microsoft word - catherino-sitrukware_abstract_5-28.doc

Are All SERMs the Same?

William H. Catherino, MD, PhD
Régine L. Sitruk-Ware, MD

Key Points
• In light of the Women’s Health Initiative, the development of therapies that have the beneficial effects of estrogens without deleterious estrogen action is in great demand. • Selective Estrogen Receptor Modulator (SERM) development has resulted in significant therapeutic advances for breast cancer, osteoporosis, and potentially other • Future SERMs may have a therapeutic profile that can be tailored to specific patient Compounds that can be described as SERMs have expanded dramatically over the past two decades. The ability of SERMs to act as estrogens in certain tissues, while remaining inert or acting as an anti-estrogen in other tissues, has opened up opportunities for treating specific estrogen-modulated diseases without accepting the risk of systemic estrogen activity. After publication of findings from the Women’s Health Initiative, interest in compound selectivity increased. A key question emerged: Is it possible to develop a compound that reduces menopausal symptoms while protecting bone, breast, The first SERM, tamoxifen, provided a glimpse into the potential of SERM therapy. Tamoxifen functions as an anti-estrogen in the breast, where it inhibits breast cancer formation and progression. At the same time, however, tamoxifen acts as an estrogen with regard to bone density and lipid profile. While these dual actions are encouraging, other SERM-like activity of tamoxifen diminished enthusiasm for this compound as an ideal peri- and postmenopausal therapy. Tamoxifen has demonstrated estrogen-like function on the endometrial lining, and prolonged treatment is linked with endometrial cancer development. Furthermore, it acts as an anti-estrogen centrally, resulting in an increased frequency of hot flashes. For many women, this therapeutic profile is not acceptable. Significant effort has been invested to design tamoxifen-like compounds with A second generation of compounds is represented by raloxifene. Raloxifene (originally investigated under the name keoxifene) was comparable or slightly inferior to tamoxifen as a breast cancer therapy in preclinical trials. Importantly, however, data showed notable benefit to bone maintenance. As a result, raloxifene was reintroduced as a therapy for osteoporosis and has been an effective addition to clinical therapies for this indication. Raloxifene also reduces breast cancer risk, and perhaps most importantly, does not have a tamoxifen-like stimulatory effect on the endometrium. Encouraged by this critical difference between the two main SERMs, significant investigation demonstrated evidence of beneficial effect on lipid profiles. However, climacteric symptoms were not alleviated by raloxifene, and thromboembolic events are increased to a similar extent as with tamoxifen. Continued investigations into raloxifene congeners have recently Suggested Readings
Cuzick J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet. 2003;361:296-300. Dorval M, Vallée MH, Plante M, Chiquette J, Gaudet M, Simard J. Effect of the Women's Health Initiative study publication on hormone replacement therapy use among women who have undergone BRCA1/2 testing. Cancer Epidemiol Biomarkers Prev. Gajdos C, Jordan VC. Selective estrogen receptor modulators as a new therapeutic drug group: concept to reality in a decade. Clin Breast Cancer. 2002;2:272-281. Jordan VC. The science of selective estrogen receptor modulators: concept to clinical practice. Clin Cancer Res. 2006;12:5010-5013. Palacios S. The future of the new selective estrogen receptor modulators. Menopause Int. Shelly W, Draper MW, Krishnan V, Wong M, Jaffe RB. Selective estrogen receptor modulators: an update on recent clinical findings. Obstet Gynecol Surv. 2008;63:163-181. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727-2741.


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