Endocrine manipulation in advanced breast cancer: Recent advances with SERM therapies

Tamoxifen is one of the most effective treatments for breast cancer through its ability to antagonize estrogen-dependent growth by binding estrogen receptors (ERs) and inhibiting breast epithelial cell proliferation. However, tamoxifen has estrogenic agonist effects in other tissues such as bone and endometrium because of liganded ER-activating target genes in these different cell types. Several novel antiestrogen compounds have been developed that are also selective ER modulators (SERMs) but that have a reduced agonist profile on breast and gynecological tissues. These SERMs offer the potential for enhanced efficacy and reduced toxicity compared with tamoxifen. In advanced breast cancer clinical data exist for three first-generation SERMs (toremifene, droloxifene, idoxifene), which are related to the triphenylethylene structure of tamoxifen. In Phase II trials in a total of 263 patients resistant to tamoxifen, the median objective response rate to these SERMs was only 5 % (range, 0-15%), with stable disease for greater than or equal to6 months in an additional 18% (range, 9-23%). As first-line therapy for advanced breast cancer, the median response rate was 31% (range, 20-68%) with a median time to progression of 7 months. Randomized Phase III trials for toremifene and idoxifene in more than 1500 patients showed no significant difference compared with tamoxifen. Fewer clinical data exist for the structurally distinct second- and third-generation SERMs (raloxifene, arzoxifene, EM-800, and ERA-923), although a similarly low median response rate of 6% (range, 0-14%) was seen in Phase II trials in tamoxifen-resistant patients. It remains unclear whether any clinical advantage exists for second- and third-generation SERMs over tamoxifen as first-line therapy. With the emergence of potent aromatase inhibitors (AIs) that are superior to tamoxifen, the clinical questions in advanced disease have shifted to which antiestrogen (including SERMs) may be effective following failure of AIs, and whether any merit exists for combined AI/SERM therapy. The main advantage for SERM therapy probably remains in early stage-disease (adjuvant therapy or prevention), in which the estrogenic effects on bone and reduced gynecological side effects may prove more beneficial than either tamoxifen or AI. The issue is whether the current clinical data for SERMs in advanced breast cancer are sufficiently strong to encourage that further development.