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ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer

Nature Reviews Clinical Oncology volume 12, pages 573583 (2015) | Download Citation

Abstract

Approximately 70% of breast cancers are oestrogen receptor α (ER) positive, and are, therefore, treated with endocrine therapies. However, about 25% of patients with primary disease and almost all patients with metastases will present with or eventually develop endocrine resistance. Despite the magnitude of this clinical challenge, the mechanisms underlying the development of resistance remain largely unknown. In the past 2 years, several studies unveiled gain-of-function mutations in ESR1, the gene encoding the ER, in approximately 20% of patients with metastatic ER-positive disease who received endocrine therapies, such as tamoxifen and aromatase inhibitors. These mutations are clustered in a 'hotspot' within the ligand-binding domain (LBD) of the ER and lead to ligand-independent ER activity that promotes tumour growth, partial resistance to endocrine therapy, and potentially enhanced metastatic capacity; thus, ER LBD mutations might account for a mechanism of acquired endocrine resistance in a substantial fraction of patients with metastatic disease. In general, the absence of detectable ESR1 mutations in patients with treatment-naive disease, and the correlation between the frequency of patients with tumours harbouring these mutations and the number of endocrine treatments received suggest that, under selective treatment pressure, clonal expansion of rare mutant clones occurs, leading to resistance. Preclinical and clinical development of rationale-based novel therapeutic strategies that inhibit these ER mutants has the potential to substantially improve treatment outcomes. We discuss the contribution of ESR1 mutations to the development of acquired resistance to endocrine therapy, and evaluate how mutated ER can be detected and targeted to overcome resistance and improve patient outcomes.

Key points

  • Over the past 18 months, recurrent activating mutations within the oestrogen receptor α (ER) LBD have been detected in 15–20% of patients with metastatic ER-positive endocrine-resistant breast cancer

  • The ER LBD mutations confer constitutive ligand-independent activity and are relatively resistant to tamoxifen and fulvestrant treatment

  • These mutations in the gene encoding the ER, ESR1, are detected mainly in metastatic tumours, implicating the clonal selection of these mutations as the mechanism of resistance to therapy

  • Structural studies have shown that the ER LBD mutations lead to ligand-independent stabilization of the LBD in the agonistic conformation

  • To study the clonal evolution and discern the full genetic complexity and clinical significance of the ESR1 mutations, new sensitive sequencing technologies will need to be applied

  • Potential strategies to overcome ER-related endocrine resistance include high-dose fulvestrant and tamoxifen, inhibitors of ER co-activator proteins, novel SERDs and SERMs, and other agents targeting the ER signalling axis

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Acknowledgements

R.S. has been funded in part by NCI grants P50 CA58183 and P50 CA186784-01 (SPORE) and P30 CA125123, as well as by the Susan G. Komen for the Cure Promise Grant PG12221410, and the Breast Cancer Research Foundation. C.D.A. has been funded by the Cancer Prevention and Research Institute of Texas (CPRIT) programme RP140102 and the Baylor College of Medicine Comprehensive Cancer Training Program. R.J. has been funded in part by the Claudia Adams Barr Award and by the NCI grant P50 CA168508 (SPORE) Career Development Award.

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Affiliations

  1. Breast Oncology Center, Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

    • Rinath Jeselsohn
    •  & Myles Brown
  2. Center for Functional Cancer Epigenetics, Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

    • Gilles Buchwalter
  3. Lester & Sue Smith Breast Center and Dan L. Duncan Cancer Center, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, BCM 600, Houston, TX 77030, USA.

    • Carmine De Angelis
    •  & Rachel Schiff

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Contributions

All authors contributed substantially to the discussion, content, writing, and review/editing of the manuscript.

Competing interests

M.B. has received a commercial research grant and is a consultant/advisory board member for Novartis Pharmaceuticals. R.S. has received research funding from AstraZeneca and GlaxoSmithKline. The other authors declare no competing interests.

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Correspondence to Rachel Schiff.

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https://doi.org/10.1038/nrclinonc.2015.117

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