title: The Evolving Role of the Estrogen Receptor Mutations in Endocrine Therapy-Resistant Breast Cancer.
abstract: Recurrent ligand-binding domain ESR1 mutations have recently been detected in a substantial number of patients with metastatic ER+ breast cancer and evolve under the selective pressure of endocrine treatments. In this review, we evaluate the current understanding of the biological and clinical significance of these mutations. The preclinical studies revealed that these mutations lead to constitutive ligand-independent activity, indicating resistance to aromatase inhibitors and decreased sensitivity to tamoxifen and fulvestrant. Retrospective analyses of ESR1 mutations in baseline plasma circulating tumor DNA from completed clinical trials suggest that these mutations are prognostic and predictive of resistance to aromatase inhibitors in metastatic disease. Currently, we are lacking prospective studies to confirm these results and to determine the optimal treatment combinations for patients with the ESR1 mutations. In addition, the clinical development of novel agents to overcome resistance engendered by these mutations is also needed.
authors.affiliation: Breast Oncology Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA. rinath_jeselsohn@dfci.harvard.edu.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02215, USA. rinath_jeselsohn@dfci.harvard.edu.
authors.forename: Rinath
authors.initials: R
authors.lastname: Jeselsohn
authors.affiliation: Smith Breast Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.|Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Carmine
authors.initials: C
authors.lastname: De Angelis
authors.affiliation: Breast Oncology Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02215, USA.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.affiliation: Smith Breast Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.|Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D011379:Prognosis; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D004273:DNA, Neoplasm; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol
keywords: Circulating tumor DNA; ESR1 mutations; Endocrine resistance; Estrogen receptor