Abstract 2163: Establishment and characterization of an endocrine resistant ESR1D538G-mutant breast cancer PDX model

Background: Chronic endocrine therapy (ET) to treat luminal type breast cancer can result in acquired mutations in the ligand binding domain (LBD) of ERα (ESR1), primarily at residues Y537 and D538, leading to constitutive ER activation and hormone-independent progressive disease. While ESR1-mutated breast cancers are insensitive to endocrine therapy, agents including selective estrogen receptor degrader (SERD) or modulator (SERM) therapies may be effective. However, few preclinical models of ESR1-mutant breast cancer are available for preclinical evaluation. Previously we reported the establishment and characterization of several ER+ breast PDX models and a cell-derived xenograft representing ESR1Y537S-mutated breast cancer. Methods: We report here the establishment and characterization of ST2535 and ST2535/HI, ER+, ESR1D538G-mutated breast PDX models which are maintained in the presence (ST2535) or absence (ST2535/HI) of exogenous estradiol. We characterized these models using genomic analysis and evaluated both in vivo and compared efficacy results with those from ESR1Y537S-mutated models. Studies were performed evaluating model sensitivity to various test agents at standard dose and schedule regimens. Study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion. Results: Genomic analysis confirmed the identified ESR1-D538G mutation which was also reported in the donor patient. In addition, estrogen receptor expression (2+-3+) was confirmed in both models. Growth characteristics for both models were comparable with a doubling time of approximately 15 days after model stabilization in the F3 passage. Slight or no activity was reported in the ST2535/HI model with tamoxifen (T/C=90%) or fulvestrant (T/C>100%). Treatment with everolimus (T/C=92%) or palbociclib (T/C=90%) was ineffective. However, combination of fulvestrant and palbociclib reported a super additive effect in the study with a T/C=46%. Interestingly, all tested agents were notably less responsive in the ST2535/HI versus similar ESR1Y537S/HI models. Conclusion: Overall, we have established and characterized two models of ESR1D538G-mutant breast cancer and compared in vivo activity to previously developed ESR1Y537S-mutant hormone independent models, all of which can be utilized for development of targeted therapies. Citation Format: Megan Groves, Lizette Gamez, Alyssa Moriarty, Amanda Mangold, Melissa Rundle, Kyriakos P. Papadopoulos, Drew W. Rasco, Anthony W. Tolcher, Amita Patnaik, Michael J. Wick. Establishment and characterization of an endocrine resistant ESR1D538G -mutant breast cancer PDX model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2163.