Endocrine manipulation in XXXX : recent advances with SERM therapies.

@entity172 @entity28002 @entity1 @entity137 @entity23392 @entity0 @entity440 @entity42332 @entity70685 @entity39707 @entity46019 @entity441 @entity62782
@entity440 is one of the most effective treatments for @entity0 through its ability to antagonize @entity172 -dependent growth by binding @entity172 receptors (ERs) and inhibiting breast epithelial cell proliferation. However, @entity440 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 @entity137 compared with @entity440 . In @entity0 clinical data exist for three first-generation SERMs ( @entity23392 , @entity28002 , @entity46019 ), which are related to the @entity42332 structure of @entity440 . In Phase II trials in a total of 263 @entity1 resistant to @entity440 , the median objective response rate to these SERMs was only 5% (range, 0-15%), with stable disease for > or =6 months in an additional 18% (range, 9-23%). As first-line therapy for @entity0 , the median response rate was 31% (range, 20-68%) with a median time to progression of 7 months. Randomized Phase III trials for @entity23392 and @entity46019 in more than 1500 @entity1 showed no significant difference compared with @entity440 . Fewer clinical data exist for the structurally distinct second- and third-generation SERMs ( @entity441 , @entity39707 , @entity62782 , and @entity70685 ), although a similarly low median response rate of 6% (range, 0-14%) was seen in Phase II trials in @entity440 -resistant @entity1 . It remains unclear whether any clinical advantage exists for second- and third-generation SERMs over @entity440 as first-line therapy. With the emergence of potent aromatase inhibitors (AIs) that are superior to @entity440 , 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 @entity440 or AI. The issue is whether the current clinical data for SERMs in @entity0 are sufficiently strong to encourage that further development.
