Abstract PS9-07: Epigenomic Characterization of ER Transcriptional Activation via Liquid Biopsy

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Abstract Background: Endocrine therapies (ET) are a cornerstone treatment for estrogen receptor-positive (ER+) breast cancer (BC). ET’s efficacy depends on the transcriptional addiction of the cancer cells to estrogen receptor signaling, for which there is no current clinical test. ER IHC and ESR1 mutations are insufficient proxies for ER transcriptional dependency. A blood-based biomarker for dynamic measurement of the ER transcriptional dependency of a tumor would greatly improve our ability to identify patients who would most benefit from continued ET. Methods: We profiled key epigenomic determinants of ER transcriptional activity in a broad array of ER+ BC cell lines, and then translated the resulting epigenomic signature into a form assayable in 1mL of plasma from BC patients. First, we profiled the epigenome of 8 breast cancer cell lines (MCF7, T47D, BT483, CAMA1, HCC1428, ZR-75-1, MDA-MB-361) in estrogen depleted media and in the presence of physiologically relevant levels of estradiol (E2, 0.1nM). Using ChIP-seq for histone modifications associated with active promoters and enhancers paired with enrichment-based DNA methylation we identified the epigenomic loci most associated with response to E2. The concurrent plating and treatment of these cell lines makes this a unique resource for the identification of enhancers, promoters, and DNA methylation marks associated with transcriptional response to estrogen signaling. We then employed the Precede multi-analyte liquid biopsy assay, which profiles these same epigenomic features from 1mL of patient plasma and used proprietary computational methods to combine information across analytes to create a patient-specific ER activity quantification algorithm robust to varying levels of circulating tumor DNA fraction (ctDNA%). We analyzed plasma from 38 patients with ER+ metastatic BC seen at the OHSU Knight Cancer Institute who had blood drawn within 1 week of tumor biopsy with ER and HER2 IHC. Additionally, we profiled 48 patient samples with the same characteristics sourced from commercial biobanks. Results: We identified an epigenomic signature that profiles ER activity in patient plasma samples. Through a paired genome-wide analysis of all cell lines’ response to E2, we identified 2320 E2-upregulated enhancers, 334 E2-upregulated promoters, and—intriguingly—0 DNA methylation loci that responded to E2 modulation. E2 responsive enhancers and promoters are linked to genes associated with estrogen response, cell cycle, and epithelial to mesenchymal transition. Many of these sites are located adjacent to known ESR1, FOXA1, and GATA3 binding sites. Computational refinement and aggregation of a subset of the E2-induced enhancers enabled the creation of an ER activity score that can be assayed in patient plasma and is robust to clinically relevant levels of ctDNA%. Patients with ER+ tumors displayed higher ER activity scores compared to patients with ER- tumors, and scores were consistently high for patients with ESR1 mutations. This plasma-based ER activity score is highly correlated with previously published RNA-based ER activity scores (Guan et al. 2019) which require biopsy tissue. Conclusions: ER transcriptional pathway activation correlates with changes to the epigenome that are detectable via Precede multi-analyte liquid biopsy assay, enabling a measurement of breast cancer dependence on endocrine signaling from 1mL of plasma through an ER activity score. This ER activity score is biologically interpretable and correlates with previous RNA-seq based predictors of ER activity. While ESR1 mutant patients score consistently high, a subset of ESR1 wildtype patients also demonstrate high ER activity scores, implying a potentially expanded patient population for treatment with novel anti-endocrine agents such as SERDs. Citation Format: Jonathan Beagan, Suzanne Wardell, Travis Clark, Justin Finkle, Anthony D’Ippolito, Mike Zhong, Jamey Guess, Kristian Cibulskis, Aparna Gorthi, Tyrone Tamakloe, Charlene O'Brien, Baovy Tran, Sarah Kieft, Mary McGillicuddy, Jayne M Stommel, Allison L Creason, Julian Egger, Gordon B Mills, Corrie Painter, Matthew Eaton, Donald McDonnell, J. Carl Barrett. Epigenomic Characterization of ER Transcriptional Activation via Liquid Biopsy [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 PS9-07.

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