Abstract P4-12-10: UNIQUE MECHANISM OF ACTION OF ELACESTRANT SENSITITIZES ESR1-MUTANT BREAST CANCER TO NOVEL THERAPEUTIC COMBINATIONS

Abstract Estrogen receptor (ER) signaling is the main driver of tumorigenesis in ER+ breast cancers by inducing proliferation and survival through genomic and non-genomic means. Therefore inhibition of ER signaling has been a mainstay of treatment for decades. While primary ER+ breast cancer has a relatively good initial prognosis, ∼30% of patients will develop treatment-refractory metastatic disease. In addition, up to 30% of advanced or metastatic tumors will acquire a mutation of ESR1, the gene which encodes ER. These mutations often make tumor cells less responsive to ER-targeting compounds. Elacestrant, a new-generation endocrine therapy, was found to out-perform the standard of care Fulvestrant in the EMERALD clinical trial [NCT03778931], specifically in patients with ESR1-mutant tumors. Preclinical studies have determined Elacestrant is a selective ER degrader, similar to Fulvestrant and it has been postulated that the increase in efficacy is the result of differences in affinity for mutated ER or increased bioavailability of Elacestrant. However, our studies determined that while Elacestrant reduces tumor burden in ESR1-mutant ER+ breast cancer Patient-Derived Xenograft (PDX) models, it does not reduce ER expression. Additionally, cells treated with Elacestrant in vivo demonstrate a unique transcriptomic profile, indicative of ER modulation rather than degradation. Elacestrant similarly reduced tumor burden in PDX models expressing only the wild-type ESR1 allele but exhibited a reduction in ER expression, consistent with previous reports. This suggests that the SERM-phenotype may be restricted to ESR1-mutant cells. High throughput screening of ESR1-mutant models with and without Elacestrant shows potentiation by compounds which target the cell cycle and the PI3K pathway, consistent with current clinical practices. Screening also determined topoisomerase inhibitors and Src family inhibitors to be synergistic with Elacestrant in ER-mutant cells. Ongoing studies include determining the mechanism of action of Elacestrant synergistic combinations and determining the role of SERM activity in treatment response in the metastatic setting. Citation Format: Emily Zboril, Julia E. Altman, Rachel K. Myrick, David C. Boyd, Amy L. Olex, Carson J. Walker, J. Chuck Harrell. UNIQUE MECHANISM OF ACTION OF ELACESTRANT SENSITITIZES ESR1-MUTANT BREAST CANCER TO NOVEL THERAPEUTIC COMBINATIONS [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-12-10.