Implications of ESR1 Mutations in Hormone Receptor-Positive Breast Cancer
- 4 Downloads
Endocrine treatment resistance eventually develops during adjuvant and even more often during hormonal treatment for advanced breast cancer (ABC). An ESR1 gene mutation, which encodes for the estrogen receptor (ER) protein, is one of the potential mechanisms of therapy resistance. The ESR1 mutations result in conformational changes in the ER leading to subsequent estrogen-independent transcriptional activity. These mutations are found at a lower level in early stage when compared to metastatic BC, more often through selective pressure after aromatase inhibitor (AI) treatment. Recent studies have explored the role of ESR1 mutations as potential prognostic and predictive biomarkers and showed that ESR1 mutations are likely associated with a more aggressive disease. However, definitive associations with outcome in order to make a specific treatment recommendation are yet to be found. The development of targeted therapy directed to ESR1-mutated clones is an appealing concept, and preclinical and clinical works are in progress. ESR1 mutations represent an exciting field with a rapidly increasing number of recent publications that will likely advance the knowledge of treatment resistance mechanisms and pave the way into more individualized patient endocrine treatment.
KeywordsBreast cancer Endocrine therapy ESR1 ESR1 mutations Aromatase inhibitors
Compliance with Ethical Standards
Conflict of Interest
Tomás Reinert, Rodrigo Gonçalves, and José Bines declare that they have no conflict of interest.
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.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 2.•• Ma C, Reinert T, Chmielewska I, Ellis M. Mechanisms of aromatase inhibitors resistance. Nat Rev Cancer. 2015;15:261–75. Comprehensive review of mechanisms of resistance to AIs cancer considering both genomic and cell biological explanatations as to why ER+ breast cancer cells progress and cause an incurable systemic disease.CrossRefPubMedGoogle Scholar
- 3.Huang B, Warner M, Gustafsson J. Estrogen receptors in breast carcinogenesis and endocrine therapy. Mol Cell Endocrin. 2014.Google Scholar
- 5.•• Jeselsohn R, Buchwalter G, De Angelis C, et al. ESR1 mutations: a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015;12:573–83. Very important publication that established the role of ESR1 as a mechanism of resistance present in AI-refractory patients but not as a mechanism of primary endocrine resistance.CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Rea S. Advanced concepts in oestrogen receptor biology and breast cancer endocrine resistance: implicated role of growth factor signalling and oestrogen receptor coregulators. Cancer Chemother Pharmacol. 2005;56:10–20.Google Scholar
- 12.• Reinert T, Barrios C. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Ther Adv Med Oncol. 2015;7:304–20. Review of the literature that discusses advances and challenges in current treatment of ER+ advanced breast cancer. Issues about optimal sequencing of agents, definition of patterns of endocrine resistance, and factors that should be taken into account when choosing the ideal ET for the individual patient are discussed.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Cruz M, Reinert T, Cristofanilli M. Emerging innovative therapeutic approaches leveraging cyclin-dependent kinase inhibitors to treat advanced breast cancer. Clin Pharmacol Ther. 2017; https://doi.org/10.1002/cpt.965.
- 18.Fanning SW, Mayne CG, Dharmarajan V, Carlson KE, Martin TA, Novick SJ, et al. Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. elife. 2016;5Google Scholar
- 19.Fanning S, Mayne C, Dharmajaran V, et al. Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. elife. 2016;5.Google Scholar
- 24.Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014;20:1757–67.CrossRefPubMedPubMedCentralGoogle Scholar
- 25.• Martin L, Ribas R, Simigdala N, Schuster E, Pancholi S, Tenev T, et al. Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance. Nat Commun. 2017;8:1–15. Recent data reporting naturally occuring ESR1m in cell lines implicating that a minor fraction of mutant clones may be present in the primary tumor and could be responsible for primary endocrine resistance.CrossRefGoogle Scholar
- 30.•• Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol. 2016;2:1310–5. Evaluation of ESR1m pattenrs in AI-refractory patients enrolled in the BOLERO2 trial. ESR1m are associated with both prognostic and predictive implications. Additionally, heterogeneity among mutant clones affecting different codons is described.CrossRefPubMedPubMedCentralGoogle Scholar
- 31.• Clatot F, Perdrix A, Augusto L, et al. Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor. Oncotarget. 2016;7:74448–59. This study demonstrates the potential role of ESR1m as a biomarker for tracking disease evolution using sequencial liquid biopsies.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.•• Schiavon G, Hrebien S, Garcia-Murillas I, et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med. 2015;7:313ra182. Evaluation of the role of ESR1m as a prognostic and predicitve factor in a cohort of AI-refractory patients enrolled in the PALOMA3 trial.CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Fribbens C, Garcia Murillas I, Beaney M, et al. Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer. Ann Oncol. 2017;Google Scholar
- 45.Augusto L, Sarafan-Vasseur N, Perdrix A, et al. Prognostic and predictive value of circulating ESR1 mutations in metastatic breast cancer patients (mBC) progressing under aromatase inhibitor (AI) treatment. J Clin Oncol. 2016;34Google Scholar
- 46.Clatot F, Perdrix A, Augusto L, Beaussire L, Delacour J, Calbrix C, et al. Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor. Oncotarget. 2016;7:74448–59. https://doi.org/10.18632/oncotarget.12950.CrossRefPubMedPubMedCentralGoogle Scholar
- 49.Fribbens C, O’Leary B, Kilburn L, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol 2016;34:ahead of print.Google Scholar
- 56.Mayer Iea. Phase I study of ARN-810, a novel selective estrogen receptor degrader, in postmenopausal women with locally advanced or metastatic estrogen receptor positive breast cancer [abstract]. In: CTRC-AACR san Antonio breast Cancer symposium OT3-2-07; 2013.Google Scholar
- 57.Joseph J, Darimont B, ZHou W. The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. eLife. 2016;5. doi: https://doi.org/10.7554/eLife.15828.
- 64.Ng C, Schultheis A, Bidard F, Wigelt B, Reis-Filho J. Breast Cancer genomics from microarrays to massively parallel sequencing: paradigms and new insights. J Nat Cancer Inst. 2016;107Google Scholar