Molecular characterization of ESR1 variants in breast cancer.

Autor: Heeke AL; Department of Solid Tumor Oncology and Investigational Therapeutics, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA. arielle.heeke@atriumhealth.org., Elliott A; Caris Life Sciences, Phoenix, AZ, USA., Feldman R; Caris Life Sciences, Phoenix, AZ, USA., O'Connor HF; Department of Solid Tumor Oncology and Investigational Therapeutics, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA., Pohlmann PR; University of Texas MD Anderson Cancer Center, Houston, TX, USA., Lynce F; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Swain SM; Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA., Nunes MR; Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA., Magee D; Caris Life Sciences, Phoenix, AZ, USA., Oberley MJ; Caris Life Sciences, Phoenix, AZ, USA., Swenson J; Caris Life Sciences, Phoenix, AZ, USA., Vidal G; West Cancer Center and Research Institute, Memphis, TN, USA.; University of Tennessee Health Science Center, Memphis, TN, USA., Isaacs C; Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA., Schwartzberg L; West Cancer Center and Research Institute, Memphis, TN, USA.; University of Tennessee Health Science Center, Memphis, TN, USA., Korn WM; Caris Life Sciences, Phoenix, AZ, USA.; University of California in San Francisco, San Francisco, CA, USA., Tan AR; Department of Solid Tumor Oncology and Investigational Therapeutics, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.
Jazyk: angličtina
Zdroj: Breast cancer research and treatment [Breast Cancer Res Treat] 2022 Nov; Vol. 196 (2), pp. 279-289. Date of Electronic Publication: 2022 Sep 20.
DOI: 10.1007/s10549-022-06740-y
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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