Abstract 863: Differential activity and SERD sensitivity of clinical ESR1 mutations
Authors: Toy Weiyi , Weir Hazel , Razavi Pedram , Berger Michael , Wong Wai Lin , De Stanchina Elisa , Baselga Joœe , Chandarlapaty Sarat 
Published: July 2016

Abstract
Background: Mutations in the ligand binding domain of ESR1 have been identified as recurrent alterations in ER+ metastatic breast cancer patients previously treated with aromatase inhibitors. Selective estrogen receptor degraders (SERDs) such as fulvestrant have been speculated to be a rational therapeutic approach to inhibiting these mutants by promoting receptor inhibition and degradation. Whether such drugs can potently and durably inhibit the distinct ESR1 LBD mutants both in vitro and in vivo has not been well characterized. In this study, we investigated the activities of different SERDs against a set of ESR1 LBD mutants identified in the clinic.
Methods: The diversity of ESR1 LBD mutations was analyzed by next generation sequencing of metastatic breast tumors from over 900 patients treated at MSKCC. Laboratory models of these different mutants were generated to interrogate their activities and drug sensitivity. We utilized in vitro reporters of ER driven transcription, proliferation assays, and both cell line derived and patient derived models to characterize the different mutants.
Results: In addition to previously characterized mutations, D538G, Y537S/N/C, L536R, and E380Q, we identified a number of novel ESR1 LBD mutations in this series such as S432L, L469V, and Y537D among others. We found that while most ESR1 LBD mutations promoted estrogen independent ER function, some did not. We also found that different activating ER mutants had significant differences in the degree to which they induced estrogen independent signaling. Consistent with these findings, we found that while most SERDs could antagonize all of the mutant receptors, there were significant differences in potency. Whereas certain ESR1 mutants such as E380Q were inhibited at similar concentrations as wild type receptors, other mutants such as Y537S required higher concentrations. These differences appeared to impact the in vivo efficacy of the FDA approved SERD, fulvestrant, which is known to have poor pharmacokinetic properties. However, a SERD with high bioavailability and potency, AZD9496, was found to be sufficient to fully inhibit mutant driven tumor growth from WT, D538G and Y537S expressing tumors in vivo.
Conclusions: Altogether, the data suggest that clinical ESR1 LBD mutations have distinct effects in activating the receptor and differentially impact the efficacy of ER antagonists. In order to be broadly effective against different ESR1 LBD mutants, SERDs may require highly optimized pharmacokinetic properties.
Citation Format: Weiyi Toy, Hazel Weir, Pedram Razavi, Michael Berger, Wai Lin Wong, Elisa De Stanchina, Joœe Baselga, Sarat Chandarlapaty. Differential activity and SERD sensitivity of clinical ESR1 mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 863.