Abstract 881: Functional characterization and clinical prevalence of ESR1 fusions in advanced endocrine resistant breast cancer
Authors: Yates Megan E. , Liu Tiantong , Hooda Jagmohan , Atkinson Jennifer M. , Lee Adrian V. , Oesterreich Steffi 
Published: June 2022

Breast cancer is the most frequently diagnosed women’s cancer with one in eight women being diagnosed during her lifetime. Even within the era of novel therapeutics and improved diagnostic screening, mortality rates remain stable, with an estimated 43,600 deaths occurring in 2021 alone. Malignant transformation of breast cancer to advanced disease is the mainstay driver of mortality and is largely attributed to treatment resistance. Fortunately, identification of therapeutic resistance mechanisms has rapidly transformed our understanding of cancer evasion and is enabling personalized treatment guidance and regimens. Notably, mutations and amplifications of the estrogen receptor (ER, ESR1) remain a prominent source of endocrine therapy resistance. Two-thirds of all breast cancer are positive for ER, making it an attractive druggable target that has revolutionized patient care. Unfortunately, however, 30% of tumors exposed to endocrine therapy subsequently develop resistance. Recently identified ER fusion proteins, discovered in metastatic endocrine resistant disease, result in substitution of the C-terminal ER ligand binding domain with a variety of fused in-frame gene partners due to genomic translocations occurring at ESR1 intron 6. Our lab has demonstrated that ER fusion proteins drive robust ER hyperactivation and metastatic potential independent of ER ligand estradiol and in the presence of endocrine therapies such as Fulvestrant. Overexpression of ER fusion proteins, particularly ESR1-SOX9 and ESR1-YAP1, in invasive ductal and invasive lobular carcinoma models with endogenous ER knockdown, resulted in enhanced 3D growth, increased migration by wound scratch assay, enhanced colony formation as a proxy of survival and ER pathway hyperactivation. Targeted endogenous ER knockdown utilizing short hairpin RNA enhances fusion driven phenotypes that are unique to fusion partner proteins and cellular context. ER fusion prevalence in advanced breast cancer remains a challenge due to the promiscuous fusion partners disrupting traditional sequencing techniques. Our group has developed a novel method of ESR1 fusion detection, EnRich, which exploits the ESR1 fusion breakpoints. Importantly, we have assessed EnRich fusion discovery with the use of circulating tumor DNA (ctDNA) from non-invasive liquid biopsies. Our pilot study of 15 blood ctDNA samples detected three different ESR1 fusion gene products which have been further validated by PCR. EnRich will help us identify and monitor treatment resistance of known and novel ESR1 fusions in patient samples irrespective of treatment regime as well as in longitudinal samples collected from patients undergoing endocrine therapy. The in vitro resistant properties of fusion proteins emphasize the necessity to better detect these mutations in patients with advanced disease and determine more appropriate treatment measures.

Citation Format: Megan E. Yates, Tiantong Liu, Jagmohan Hooda, Jennifer M. Atkinson, Adrian V. Lee, Steffi Oesterreich. Functional characterization and clinical prevalence of ESR1 fusions in advanced endocrine resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 881.