Figure 1.

Tamoxifen is used for the long-term adjuvant treatment of ER positive breast cancer. The tamoxifen (or metabolite) ER complex requires dimerized NCOR2 to bind to ER and recruit other inhibitors of cells signaling to prevent breast cancer growth. A splice variant of NCOR2, BQ, binds to NCOR2 and prevents dimerization. This imperfect corepressor cannot bind to the tamoxifen ER complex. As a result, the BQ variant prevents the emasculation of the tamoxifen ER complex. Recurrence results. An alternative endocrine therapy to the injectable SERD fulvestrant, is an orally active SERD, to advance from the treatment of metastatic breast cancer (MBC) to long-term adjuvant therapy. The compound ASD9496 has completed a phase I study. However, side effects may retard studies as an adjuvant therapy. The structure of AZD9496 contains an acrylic acid antiestrogen sidechain that destroys the ER. It is interesting to reflect that this same sidechain on the known SERM GW5638 could be transferred to a SERM such as lasofoxifene with a proven record of positive SERM properties. Not only is there potential in the future for a new oral SERD but also an oral super SERD, that has enhanced healthcare benefits for our aging population when ER positive breast cancer develops.