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The Evolving Role of the Estrogen Receptor Mutations in Endocrine Therapy-Resistant Breast Cancer

  • Rinath Jeselsohn
  • Carmine De Angelis
  • Myles Brown
  • Rachel Schiff
Breast Cancer (B Overmoyer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on 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.

Keywords

Estrogen receptor ESR1 mutations Endocrine resistance Circulating tumor DNA 

Notes

Acknowledgements

This paper was supported by the NCI Grant K08 CA191058-02 (R.J.), the Breast Cancer Alliance Exceptional Award Grant (R.J.), the Breast Cancer Research Foundation (R.S.), NIH Breast Cancer Specialized Programs of Research Excellence Grants P50CA058183 and P50CA186784 (R.S.), NIH Cancer Center Grant P30CA125123, Susan G. Komen for the Cure Foundation Promise Grants PG12221410 (R.S.), and the Conquer Cancer Foundation (C.D.A., Breast Cancer Research Fellowship).

Compliance with Ethical Standards

Conflict of Interest

Rinath Jeselsohn declares no conflict of interest.

Carmine De Angelis declares that he has no conflict of interest.

Myles Brown declares that he has no conflict of interest.

Rachel Schiff has received research support through grants from Gilead and AstraZeneca.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Rinath Jeselsohn
    • 1
    • 2
  • Carmine De Angelis
    • 3
    • 4
    • 5
    • 6
  • Myles Brown
    • 1
    • 2
  • Rachel Schiff
    • 3
    • 4
    • 5
    • 6
  1. 1.Breast Oncology Center, Dana-Farber Cancer InstituteHarvard Medical SchoolBostonUSA
  2. 2.Center for Functional Cancer Epigenetics, Dana-Farber Cancer InstituteHarvard Medical SchoolBostonUSA
  3. 3.Smith Breast Cancer CenterBaylor College of MedicineHoustonUSA
  4. 4.Dan L. Duncan Cancer CenterBaylor College of MedicineHoustonUSA
  5. 5.Department of MedicineBaylor College of MedicineHoustonUSA
  6. 6.Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonUSA

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