Rationale for salvage therapy with high-dose selective estrogen receptor modulator after treatment failure of aromatase inhibitors in breast cancer

Abstract

1129 Background: Aromatase inhibitors (AIs) are currently widely used for hormone responsive breast cancer patients as adjuvant therapy and first line treatment for metastatic breast cancer (MBC). Salvage therapy has become important to the patients failed these primary AIs. We explored the possible application of high-dose selective estrogen modulators (SERMs) in vitro and in vivo. Methods: As a model for treatment failure of AI, MCF-7 cells were cultured in estradiol (E2)-deficient medium for over 6 months. Survived cells were established as MCF-7 long term E2 deprived (LED) clone. Cell counting kit-8 was used for proliferation assay, and transcription activity of Estrogen Receptor (ER) on estrogen-responsive element (ERE) was measured with luciferase assay. HI-FAIR study (n=63) was conducted as a retrospective chart review from nine Japanese institutes for demonstrating the possible efficacy of high-dose toremifene (120mg/day p.o.) after AI treatment failure in MBC patients. Results: In western blotting, MCF-7 LED clone showed increased expression of ER and Her2, and reduction of Progesterone Receptor (PR) expression as compared to parent MCF-7 cell. Although addition of various concentration of E2 did not enhance the proliferation of LED cell, ERE-dependent transcription was still activated by E2 in same degree as parent MCF-7. Of note was 30-fold increase of basal transcriptional activity in LED cell due to phosphorylation of ER. Fulvestrant (FUL), 4-OH Tamoxifen (TAM) and Toremifene (TOR) all inhibited growth of LED cell. IC50 of FUL for parent MCF-7 and LED cell are identical, and maximum inhibition ratio was about 65%. Whereas, TAM and TOR showed more favorable response to LED cell than to parent MCF-7 cell. Growth capability of LED cell was reduced by about 90% by both TAM and TOR in dose dependent manner. In HI-FAIR study high-dose TOR showed 14.3% response rate, 34.9% clinical benefit and 7.4 months median TTF as the first (n=4), second to third (n=40) and fourth (n=19) lines MBC therapy after AI treatment. Conclusions: Although the efficacy of FUL in the patients previously treated with Ais has been already reported, this study demonstrated the possible contribution of high-dose SERM for these patients. No significant financial relationships to disclose.