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Molecular characterization of ESR1 variants in breast cancer

  • Preclinical study
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Abstract

Purpose

Estrogen receptor 1 (ESR1) mutations and fusions typically arise in patients with hormone receptor-positive breast cancer after aromatase inhibitor therapy, whereby ESR1 is constitutively activated in a ligand-independent manner. These variants can impact treatment response. Herein, we characterize ESR1 variants among molecularly profiled advanced breast cancers.

Methods

DNA next-generation sequencing (592-gene panel) data from 9860 breast cancer samples were retrospectively reviewed. Gene fusions were detected using the ArcherDx fusion assay or whole transcriptome sequencing (n = 344 and n = 4305, respectively). Statistical analyses included Chi-square and Fisher’s exact tests.

Results

An ESR1 ligand-binding domain (LBD) mutation was detected in 8.6% of tumors evaluated and a pathogenic ESR1 fusion was detected in 1.6%. Most ESR1 LBD mutations/fusions were from estrogen receptor (ER)-positive samples (20.1% and 4.9%, respectively). The most common ESR1 LBD mutations included D538G (3.3%), Y537S (2.3%), and E380Q (1.1%) mutations. Among biopsy sites, ESR1 LBD mutations were most observed in liver metastases. Pathogenic ESR1 fusions were identified in 76 samples (1.6%) with 40 unique fusion partners. Evaluating co-alterations, ESR1 variant (mutation/fusion) samples more frequently expressed androgen receptor (78.0% vs 58.6, P < 0.0001) and less frequently immune checkpoint proteins than ESR1 wild-type (PD-1 20.0% vs 53.4, P < 0.05; immune cell PD-L1 10.0% vs 30.2, P < 0.0001).

Conclusion

We have described one of the largest series of ESR1 fusions reported. ESR1 LBD mutations were commonly identified in ER-positive disease. Limited data exists regarding the clinical impact of ESR1 fusions, which could be an area for future therapeutic exploration.

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Data availability

The datasets generated during and/or analyzed during the current study are not publicly available but may be available from the corresponding author upon reasonable request.

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Authors and Affiliations

  1. Department of Solid Tumor Oncology and Investigational Therapeutics, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA

    Arielle L. Heeke, Hazel F. O’Connor & Antoinette R. Tan

  2. Caris Life Sciences, Phoenix, AZ, USA

    Andrew Elliott, Rebecca Feldman, Daniel Magee, Matthew J. Oberley, Jeffrey Swenson & W. Michael Korn

  3. University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Paula R. Pohlmann

  4. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Filipa Lynce

  5. Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA

    Sandra M. Swain & Claudine Isaacs

  6. Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    Maria R. Nunes

  7. West Cancer Center and Research Institute, Memphis, TN, USA

    Gregory Vidal & Lee Schwartzberg

  8. University of Tennessee Health Science Center, Memphis, TN, USA

    Gregory Vidal & Lee Schwartzberg

  9. University of California in San Francisco, San Francisco, CA, USA

    W. Michael Korn

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  1. Arielle L. Heeke
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Contributions

ALH: corresponding/first author, material preparation, data analysis, manuscript writing and editing. AE: material preparation, data collection and analysis, manuscript writing and editing. RF: project conceptualization, data collection and analysis, manuscript editing. HFO’: material preparation, data analysis, manuscript writing and editing. PRP: data analysis, manuscript editing. FL: data analysis, manuscript editing. SMS: data analysis, manuscript editing. MRN: data analysis, manuscript editing. DM: data collection and analysis, manuscript editing. MJO: data collection and analysis, manuscript editing. JS: data collection and analysis, manuscript editing. GV: data analysis, manuscript editing. CI: data analysis, manuscript editing. LS: data analysis, manuscript editing. WMK: data collection and analysis, manuscript editing. ART: project conceptualization, data analysis, manuscript editing.

Corresponding author

Correspondence to Arielle L. Heeke.

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Competing interests

Arielle L. Heeke: Consulting (Caris Life Sciences). Andrew Elliott: Employee of Caris Life Sciences. Rebecca Feldman: Employee of Caris Life Sciences. Hazel F. O’Connor: No relevant conflicts of interest to disclose. Paula R. Pohlmann: Stock/ownership (Immunonet BioSciences), consulting (Heron, Immunonet BioSciences, OncoPlex Diagnostics, Personalized Cancer Therapy, Pfizer, Xcenda, SEAGEN, AbbVie, BOLT), education (Genentech/Roche), research funding (Advanced Cancer Therapeutics, Caris Centers for Excellence, Cascadian/Seattle Genetics, Fabre-Kramer, Genentech/Roche, Pfizer, Pieris, Byondis, BOLT). Filipa Lynce: Advisory board (Pfizer, Astra Zeneca, Chugai), research funding to institution (Astra Zeneca, BMS, CytomX, Inivata). Sandra M. Swain: Consulting/advisory board/speaking (AstraZeneca, Athenex, Daiichi-Sankyo, Genentech/Roche, Exact Sciences, Natera, Lilly Pharmaceuticals, Merck, bioTheranostics), research funding to institution (Genentech/Roche, Kailos Genetics). Maria R. Nunes: Research funding to institution (bioTheranostics, Biovica). Daniel Magee: Employee of Caris Life Sciences. Matthew J. Oberley: Employee of Caris Life Sciences. Jeffrey Swenson: Employee of Caris Life Sciences. Gregory Vidal: No relevant conflicts of interest to disclose. Claudine Isaacs: Consulting (Genentech/Roche, PUMA, Seattle Genetics, AstraZeneca, Novartis, Pfizer, ESAI, Sanofi, ION), royalties (Wolters Kluwer, McGraw Hill), research funding to institution (Tesaro/GSK, Seattle Genetics, Pfizer, Az, BMS, Genentech/Roche, Novartis), medical director SideOut Foundation. Lee Schwartzberg: Consulting (BMS, Pfizer, Helsinn, Spectrum, AstraZeneca, Amgen, Genentech, Myriad, Napo, Odonate, Lilly, Beyond Spring). W. Michael Korn: Employee of Caris Life Sciences, consultant (Merck). Antoinette R. Tan: Meeting travel and accommodations (Caris Life Sciences).

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Heeke, A.L., Elliott, A., Feldman, R. et al. Molecular characterization of ESR1 variants in breast cancer. Breast Cancer Res Treat 196, 279–289 (2022). https://doi.org/10.1007/s10549-022-06740-y

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