Endocrine treatment of advanced breast cancer: Selective Estrogen Receptor Modulators (SERMs).

I. ABSTRACT The ability of tamoxifen to antagonize estrogen-dependent growth factor by binding estrogen receptors (ERs) and inhibiting breast epithelial cell proliferation make it one of the most effective treatments for breast cancer. However, tamoxifen has estrogenic agonist effects in other tissues, such as bone and endometrium, where liganded ERs can activate target genes. Several novel antiestrogen compounds and older high-dose estrogens have been developed that are also selective ER modulators (SERMs). These SERMs have altered agonist profiles on breast and gynecological tissues and offer the potential for enhanced efficacy and reduced toxicity compared with tamoxifen. In advanced breast cancer, clinical data exist for four groups of SERMs. These are high-dose estrogens

[e.g., diethylstilbestrol (DES), ethinylestradiol], the triphenylethylene estrogen analogues in addition to tamoxifen (e.g., toremifene, droloxifene, idoxifene, GW5638), the “fixed ring” compounds (e.g., raloxifene, arzoxifene, EM-800, and ERA-923), and the “pure antiestrogen” [e.g., fulvestrant (ICI 182780), SR 16234, ZK 191703]. High-dose estrogens show similar response rates to tamoxifen and are active after tamoxifen failure. In phase II trials of the other triphenylethylene SERMs, 263 patients resistant to tamoxifen have been treated. The median objective response rate to these SERMs was 5% (range 0 to 15%), with stable disease for ≥ 6 months in an additional 18% (range 9 to 23%). As first-line therapy for advanced breast cancer, the median response rate was 31% (range 20 to 51%), with a median time to progression of 7 months. Randomized phase III trials in over 1500 patients for toremifene and idoxifene showed no significant difference compared with tamoxifen. Fewer clinical data exist for the fixed-ring SERMs (raloxifene, arzoxifene, EM-800, and ERA-923), although a similarly low median response rate of 6% (range 0 to 14%) was seen in phase II trials in tamoxifen-resistant patients. It remains unclear whether any clinical advantage exists for the fixed-ring SERMs over tamoxifen as first-line therapy.