Implications of ESR1 Mutations in Hormone Receptor-Positive Breast Cancer

Breast Cancer (ML Telli, Section Editor)
  • 4 Downloads
Part of the following topical collections:
  1. Topical Collection on Breast Cancer

Opinion Statement

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.

Keywords

Breast cancer Endocrine therapy ESR1 ESR1 mutations Aromatase inhibitors 

Notes

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

  1. 1.
    Josefsson M, Leinster S. Aromatase inhibitors versus tamoxifen as adjuvant hormonal therapy for estrogen sensitive early breast cancer in post-menopausal women: meta-analyses of monotherapy, sequenced therapy and extended therapy. Breast. 2010;19:76–83.CrossRefPubMedGoogle Scholar
  2. 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. 3.
    Huang B, Warner M, Gustafsson J. Estrogen receptors in breast carcinogenesis and endocrine therapy. Mol Cell Endocrin. 2014.Google Scholar
  4. 4.
    Reinert T, Saad ED, Barrios CH, Bines J. Clinical implications of ESR1 mutations in hormone receptor-positive advanced breast Cancer. Front Oncol. 2017;7:26.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 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
  6. 6.
    Osborne CKSR. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233–47.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Schiff RMS, Shou J, et al. Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin Cancer Res. 2004;10:331S–6S.CrossRefPubMedGoogle Scholar
  8. 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
  9. 9.
    Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004;96:926–35.CrossRefPubMedGoogle Scholar
  10. 10.
    Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010;70:2085–94.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Cavazzoni ABM, Fumarola C, et al. Overcoming acquired resistance to letrozole by targeting the PI3K/Akt/mTOR pathway in breast cancer cell clones. Cancer Lett. 2012;323:77–87.CrossRefPubMedGoogle Scholar
  12. 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
  13. 13.
    Reinert T, Barrios C. Overall survival and progression-free survival with endocrine therapy for hormone receptor-positive, HER2-negative advanced breast cancer: review. Ther Adv Med Oncol. 2017;9:693–709.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 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.
  15. 15.
    Rugo HSRB, Macrae E, Barton DL, Connoly HK, Dickler MN, et al. Endocrine therapy for hormone receptor–positive metastatic breast cancer: American Society of Clinical Oncology guideline. J Clin Oncol. 2016;34:3069–103.CrossRefPubMedGoogle Scholar
  16. 16.
    Zhang QX, Borg A, Wolf DM, Oesterreich S, Fuqua SA. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 1997;57:1244–9.PubMedGoogle Scholar
  17. 17.
    Weis KE, Ekena K, Thomas JA, Lazennec G, Katzenellenbogen BS. Constitutively active human estrogen receptors containing amino acid substitutions for tyrosine 537 in the receptor protein. Mol Endocrinol. 1996;10:1388–98.PubMedGoogle Scholar
  18. 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. 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
  20. 20.
    Li S, Shen D, Shao J, Crowder R, Liu W, Prat A, et al. Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep. 2013;4:1116–30.CrossRefPubMedGoogle Scholar
  21. 21.
    Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45:1439–45.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45:1446–51.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, Dvir A, Soussan-Gutman L, Jeselsohn R, et al. D538G mutation in estrogen receptor-alpha: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 2013;73:6856–64.CrossRefPubMedGoogle Scholar
  24. 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. 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
  26. 26.
    Veeraraghavan J, Tan Y, Cao XX, et al. Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers. Nat Commun. 2014;5:4577.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.CrossRefGoogle Scholar
  28. 28.
    Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M, et al. Droplet digital polymerase chain reaction assay for screening of ESR1 mutations in 325 breast cancer specimens. Transl Res. 2015;166:540–53 e2.CrossRefPubMedGoogle Scholar
  29. 29.
    Wang P, Bahreini A, Gyanchandani R, Lucas PC, Hartmaier RJ, Watters RJ, et al. Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions, and cell-free DNA of breast Cancer patients. Clin Cancer Res. 2016;22:1130–7.CrossRefPubMedGoogle Scholar
  30. 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. 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
  32. 32.
    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;34:2961–8.CrossRefPubMedGoogle Scholar
  33. 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
  34. 34.
    Spoerke JM, Gendreau S, Walter K, Qiu J, Wilson TR, Savage H, et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun. 2016;7:11579.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Niu J, Andres G, Kramer K, Kundranda MN, Alvarez RH, Klimant E, et al. Incidence and clinical significance of ESR1 mutations in heavily pretreated metastatic breast cancer patients. Onco Targets Ther. 2015;8:3323–8.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Dawson SJ, Tsui DW, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199–209.CrossRefPubMedGoogle Scholar
  37. 37.
    Chu D, Paoletti C, Gersch C, VanDenBerg DA, Zabransky DJ, Cochran RL, et al. ESR1 mutations in circulating plasma tumor DNA from metastatic breast Cancer patients. Clin Cancer Res. 2016;22:993–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Sefrioui D, Perdrix A, Sarafan-Vasseur N, Dolfus C, Dujon A, Picquenot JM, et al. Short report: monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer. Int J Cancer. 2015;137:2513–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Guttery DS, Page K, Hills A, Woodley L, Marchese SD, Rghebi B, et al. Noninvasive detection of activating estrogen receptor 1 (ESR1) mutations in estrogen receptor-positive metastatic breast cancer. Clin Chem. 2015;61:974–82.CrossRefPubMedGoogle Scholar
  40. 40.
    Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M, Inao T, Sueta A, Fujiwara S, et al. Clinical significance of monitoring ESR1 mutations in circulating cell-free DNA in estrogen receptor positive breast cancer patients. Oncotarget. 2016;7:32504–18.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M, Tomiguchi M, Sueta A, Murakami K, et al. Analysis of ESR1 and PIK3CA mutations in plasma cell-free DNA from ER-positive breast cancer patients. Oncotarget. 2017;8:52142–55.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M, Tomiguchi M, Sueta A, Murakami K, et al. Comparison of ESR1 mutations in tumor tissue and matched plasma samples from metastatic breast cancer patients. Transl Oncol. 2017;10:766–71.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 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
  44. 44.
    Toy W, Weir H, Razavi P, Lawson M, Goeppert A, Mazzola A, et al. Activating ESR1 mutations differentially impact the efficacy of ER antagonists. Cancer Discov. 2017;7:277–87.CrossRefPubMedGoogle Scholar
  45. 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. 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
  47. 47.
    Schiavon G, Hrebien S, Garcia-Murillas I, et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrated evolution during therapy for metastatic breast cancer. Sci Transl Med. 2015;7:182.CrossRefGoogle Scholar
  48. 48.
    Jeselsohn RYR, Buchwalter G, et al. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014;20:1757–67.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 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
  50. 50.
    Reinert T, Saad E, Barrios C, Bines J. Clinical implications of ESR1 mutations in hormone receptor-positive advanced breast cancer. Front Oncol. 2017;7:26.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, Dvir A, Soussan-Gutman L, Jeselsohn R, et al. D538G mutation in estrogen receptor-α: a novel mechanism for acquired endocrine resistance in breast Cancer. Cancer Res. 2013;73:6856–64.CrossRefPubMedGoogle Scholar
  52. 52.
    Chandarlapaty SCD, He W, Sung P, Samoila A, You D, Bhatt T, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Goss PEIJ, Pritchard KI, Robert NJ, Muss H, Gralow J, Gelmon K, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med. 2016;375:209–19.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Ladd B, Mazzola A, Bihani T, et al. Effective combination therapies in preclinical endocrine resistant breast cancer models harboring ER mutations. Oncotarget. 2016;7:54120–36.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Weir H, Bradbury R, Lawson M, et al. AZD9496: an oral estrogen receptor inhibitor that blocks the growth of ER-positive and ESR1-mutant breast tumors in preclinical models. Cancer Res. 2016;76:3307–18.CrossRefPubMedGoogle Scholar
  56. 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. 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.
  58. 58.
    Bihani T, Patel H, Arlt H. Elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), has anti-tumor activity in multiple ER+ breast cancer patient-derived xenograft models. Clin Cancer Res. 2017;23:4793–804.CrossRefPubMedGoogle Scholar
  59. 59.
    Wardell S, Nelson E, Chao C, McDonnell J. Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease. Clin Cancer Res. 2013;19:2420–31.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Wang T, et al. Bufalin is a potent small-molecule inhibitor of the steroid receptor co-activators SRC-3 and SRC-1. Cancer Res. 2014;74:1506–17.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Yu M, Bardia A, Aceto N, Bersani F, Madden MW, Donaldson MC, et al. Cancer therapy: ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science. 2014;345:216–20.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Spoerke J, Gendreau S, Walter K, et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun. 2016;7:11579.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Jeselson R. Are we ready to use ESR1 mutations in clinical practice? Breast Care. 2017;12:309–31.CrossRefGoogle Scholar
  64. 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
  65. 65.
    Niu J, Andres G, Kramer K, Kundranda MN, Alvarez RH, Klimant E, et al. Incidence and clinical significance of ESR1 mutations in heavily pretreated metastatic breast cancer patients. Oncotargets Ther. 2015;8:3323–8.CrossRefGoogle Scholar
  66. 66.
    Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M. Droplet digital polimerase chain reaction assay for screening of ESR1 mutations in 325 breast cancer specimens. Transl Res. 2015;166:540–53.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Tomás Reinert
    • 1
    • 2
  • Rodrigo Gonçalves
    • 3
  • José Bines
    • 4
  1. 1.Hospital do Câncer Mãe de DeusPorto AlegreBrazil
  2. 2.Programa de Pós-Graduação em Ciências MédicasUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Setor de Mastologia, Hospital das Clínicas, Disciplina de Ginecologia, Departamento de Obstetrícia e GinecologiaFaculdade de Medicina da Universidade de São PauloSão PauloBrazil
  4. 4.Instituto Nacional de Câncer (INCA-HCIII)Rio de JaneiroBrazil

Personalised recommendations