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New Insights in Estrogen Receptor (ER) Biology and Implications for Treatment

  • Translational Research (TA King and EA Mittendorf, Section Editors)
  • Published:
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Abstract

Purpose of Review

Estrogen receptor-positive (ER+) breast cancer represents the majority of breast cancer diagnoses and is the leading cause of cancer death in women. Endocrine therapy is the principal treatment strategy for ER+ breast cancer. However, resistance to endocrine therapy, either de novo or acquired, is commonly observed, resulting in disease relapse and progression. This review will focus on recent progress in our understanding of ER biology and the implications for treatments.

Recent Findings

Advances in genomic technology and laboratory investigations have led to the identification of somatic mutations, including treatment-emergent ESR1 mutations, and aberrant activation of growth factor receptor signaling pathways and cell cycle machinery that are associated with estrogen-independent proliferation and resistance to endocrine therapy. A plethora of molecularly targeted agents are being developed to overcome these resistance mechanisms, among which inhibitors against the mammalian target of rapamycin (mTOR) and cyclin-dependent kinases (CDK) 4/6 are now in clinical use.

Summary

Advances in our understanding of ER biology have impacted the treatment landscape of ER+ breast cancer. Ongoing biomarker research on tumor specimens and cell-free tumor DNA will continue to generate important biological insight toward improving individualized treatment strategies for patients with ER+ breast cancer.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Beatson GW. On the treatment of inoperable carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet. 1896;2:104–7.

    Article  Google Scholar 

  2. Taylor CW, Green S, Dalton WS, Martino S, Rector D, Ingle JN, et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol. 1998;16(3):994–9.

    Article  CAS  PubMed  Google Scholar 

  3. • Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372(5):436–46. SOFT was a phase III trial that randomized premenopausal women with early stage hormone receptor positive breast cancer to receive either 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression as adjuvant endocrine therapy. This trial, in conjunction with the TEXT trial, established the use of ovarian suppression in combination with tamoxifen or exemestane as an adjuvant hormonal therapy for premenopausal with high risk hormone receptor positive breast cancer.

    Article  PubMed  Google Scholar 

  4. EBCTCG. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687–717.

    Article  Google Scholar 

  5. Early Breast Cancer Trialists’ Collaborative G. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341–52.

    Article  Google Scholar 

  6. • Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371(2):107–18. This paper describes the results of the TEXT trial, which demonstrated that adjuvant exemestane in combination with ovarian suppression significantly reduced breast cancer recurrences compared to tamoxifen in combination with ovarian suppression in premenopausal women with hormone-positive early-stage breast cancer. This trial, in conjunction with the SOFT trial, established the use of ovarian suppression in combination with exemestane as an adjuvant endocrine therapy in premenopausal with high risk hormone receptor positive breast cancer.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. JNCI. 2006;98(18):1285–91.

    Article  CAS  PubMed  Google Scholar 

  8. Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594–600.

    Article  PubMed  Google Scholar 

  9. Early Breast Cancer Trialists’ Collaborative G. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771–84.

    Article  Google Scholar 

  10. Hammond MEH, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):2784–95.

    Article  PubMed  PubMed Central  Google Scholar 

  11. • Yi M, Huo L, Koenig KB, Mittendorf EA, Meric-Bernstam F, Kuerer HM, et al. Which threshold for ER positivity? A retrospective study based on 9639 patients. Ann Oncol. 2014;25(5):1004–11. In this single institution retrospective review of over 9000 patients with early stage breast cancer, patients with tumors that are ER-positive 1–9% had survival rates similar to those with ER-negative tumors and did not appear to have derived benefit from endocrine therapy. Authors questioned the validity of using 1% as the threshold for ER positivity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. • Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 2015;15(5):261–75. This paper provided a comprehensive review on the topic of aromatase inhibitor resistance mechanisms.

    Article  CAS  PubMed  Google Scholar 

  13. Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW, et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature. 2012;486(7403):353–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. • Gellert P, Segal CV, Gao Q, Lopez-Knowles E, Martin LA, Dodson A, et al. Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation. Nat Commun. 2016;7:13294. In this pre-surgical study, exome sequencing of baseline biopsies, surgical core-cuts (post 2 weeks of aromatase inhibitor or control) and blood were performed for 60 patients (40 aromatase inhibitor treated and 20 controls) and targeted sequencing were performed for an additional 28 AI patients. Poor response to aromatase inhibitor treatment by Ki67 was associated with a significantly higher mutation load and mutations in TP53, data consistent with the finding from the previous study published by Ellis, et al. Nature 2012, 486(7403):353–360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Clinical pharmacology (http://www.clinicalpharmacology-ip.com/). In: Letrozole.

  16. 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. JNCI. 2004;96(12):926–35.

    Article  CAS  PubMed  Google Scholar 

  17. Arpino G, Green SJ, Allred DC, Lew D, Martino S, Osborne CK, et al. HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group Study. Clin Cancer Res. 2004;10(17):5670–6.

    Article  CAS  PubMed  Google Scholar 

  18. 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(5):2085–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. •• Rugo HS, Vidula N, Ma C. Improving response to hormone therapy in breast cancer: new targets, new therapeutic options. Am Soc Clin Oncol Educ Book Am Soc Clin Oncol Meet. 2016;35:e40–54. This review summarized various endocrine resistance mechanisms that are being targeted therapeutically to improve hormonal therapy efficacy. These include ESR1 mutations, CDK4/6 activation, and cross talks between ER and growth factor receptors, including HER family members, FGFR, and IGF1R, and downstream signaling pathways, the PI3K/mTOR and MAPK, that promote estrogen independent tumor growth.

    Article  Google Scholar 

  20. • Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 2016;18(1):1–11. This review highlighted the current understanding of CDK signaling in normal and malignant breast tissues, and recent progress in the development of CDK4/6 inhibitors for the treatment of ER+ breast cancer.

    Article  Google Scholar 

  21. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, et al. The nuclear receptor superfamily: the second decade. Cell. 1995;83(6):835–9.

    Article  CAS  PubMed  Google Scholar 

  22. •• Jia M, Dahlman-Wright K, Gustafsson JA. Estrogen receptor alpha and beta in health and disease. Best Pract Res Clin Endocrinol Metab. 2015;29(4):557–68. This paper reviewed the current understanding of ERα and ERβ, and aberrations in ER signaling in breast cancer.

    Article  CAS  PubMed  Google Scholar 

  23. Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, et al. Mechanisms of estrogen action. Physiol Rev. 2001;81(4):1535–65.

    CAS  PubMed  Google Scholar 

  24. Treeck O, Juhasz-Boess I, Lattrich C, Horn F, Goerse R, Ortmann O. Effects of exon-deleted estrogen receptor beta transcript variants on growth, apoptosis and gene expression of human breast cancer cell lines. Breast Cancer Res Treat. 2008;110(3):507–20.

    Article  CAS  PubMed  Google Scholar 

  25. Treeck O, Lattrich C, Springwald A, Ortmann O. Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells. Breast Cancer Res Treat. 2010;120(3):557–65.

    Article  CAS  PubMed  Google Scholar 

  26. Cotrim CZ, Fabris V, Doria ML, Lindberg K, Gustafsson JA, Amado F, et al. Estrogen receptor beta growth-inhibitory effects are repressed through activation of MAPK and PI3K signalling in mammary epithelial and breast cancer cells. Oncogene. 2013;32(19):2390–402.

    Article  CAS  PubMed  Google Scholar 

  27. Chang EC, Frasor J, Komm B, Katzenellenbogen BS. Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells. Endocrinology. 2006;147(10):4831–42.

    Article  CAS  PubMed  Google Scholar 

  28. Omoto Y, Inoue S, Ogawa S, Toyama T, Yamashita H, Muramatsu M, et al. Clinical value of the wild-type estrogen receptor beta expression in breast cancer. Cancer Lett. 2001;163(2):207–12.

    Article  CAS  PubMed  Google Scholar 

  29. Hopp TA, Weiss HL, Parra IS, Cui Y, Osborne CK, Fuqua SA. Low levels of estrogen receptor beta protein predict resistance to tamoxifen therapy in breast cancer. Clin Cancer Res. 2004;10(22):7490–9.

    Article  CAS  PubMed  Google Scholar 

  30. Parker MG. Structure and function of estrogen receptors. Vitam Horm. 1995;51:267–87.

    Article  CAS  PubMed  Google Scholar 

  31. Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev. 1999;20(3):358–417.

    Article  CAS  PubMed  Google Scholar 

  32. Weigel NL, Zhang Y. Ligand-independent activation of steroid hormone receptors. J Mol Med (Berlin). 1998;76(7):469–79.

    Article  CAS  Google Scholar 

  33. Björnström L, Sjöberg M. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol. 2005;19(4):833–42.

    Article  PubMed  Google Scholar 

  34. Levin ER. Elusive extranuclear estrogen receptors in breast cancer. Clin Cancer Res. 2012;18(1):6–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. • Ma CX, Bose R, Ellis MJ. Prognostic and predictive biomarkers of endocrine responsiveness for estrogen receptor positive breast cancer. Adv Exp Med Biol. 2016;882:125–54. This review summarized clinical and genomic biomarkers including various RNA based multi-gene assays and somatic mutations in ER+ breast cancer that predict relapse risk and responsiveness to endocrine therapy.

    Article  PubMed  Google Scholar 

  36. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.

    Article  CAS  PubMed  Google Scholar 

  37. Prat A, Cheang MC, Martin M, Parker JS, Carrasco E, Caballero R, et al. Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer. J Clin Oncol. 2013;31(2):203–9.

    Article  CAS  PubMed  Google Scholar 

  38. • Prat A, Pineda E, Adamo B, Galvan P, Fernandez A, Gaba L, et al. Clinical implications of the intrinsic molecular subtypes of breast cancer. Breast. 2015;24 Suppl 2:S26–35. This paper reviewed the clinical implications of the intrinsic molecular subtypes of breast cancer.

    Article  PubMed  Google Scholar 

  39. Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, et al. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype—ACOSOG Z1031. J Clin Oncol. 2011;29(17):2342–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Iwamoto T, Booser D, Valero V, Murray JL, Koenig K, Esteva FJ, et al. Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ER-positive by immunohistochemistry. J Clin Oncol. 2012;30(7):729–34.

    Article  PubMed  Google Scholar 

  41. Prat A, Parker JS, Fan C, Cheang MC, Miller LD, Bergh J, et al. Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen. Ann Oncol. 2012;23(11):2866–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Network TCGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.

    Article  Google Scholar 

  43. • Desmedt C, Zoppoli G, Gundem G, Pruneri G, Larsimont D, Fornili M, et al. Genomic characterization of primary invasive lobular breast cancer. J Clin Oncol. 2016;34(16):1872–81. This paper reported the results from the analysis of targeted sequencing of 360 cancer-related genes and genome-wide copy number alterations performed on 413 and 170 primary invasive lobular breast cancer samples which identified the high mutation frequency of CDH1 (65%), and mutations in PIK3CA/PTEN/AKT1 (over 50%), HER2 (5.1%), HER3 (3.6%), and FOXA1 (9%), as well as copy number gain of ESR1 (25%).

    Article  PubMed  Google Scholar 

  44. Kong SL, Li G, Loh SL, Sung WK, Liu ET. Cellular reprogramming by the conjoint action of ERalpha, FOXA1, and GATA3 to a ligand-inducible growth state. Mol Syst Biol. 2011;7:526.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ, et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell. 2005;122(1):33–43.

    Article  CAS  PubMed  Google Scholar 

  46. Kong SL, Li G, Loh SL, Sung W-K, Liu ET. Cellular reprogramming by the conjoint action of ER[alpha], FOXA1, and GATA3 to a ligand-inducible growth state. Mol Syst Biol. 2011;7.

  47. Cirillo LA, Lin FR, Cuesta I, Friedman D, Jarnik M, Zaret KS. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol Cell. 2002;9(2):279–89.

    Article  CAS  PubMed  Google Scholar 

  48. Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell. 2006;127(5):1041–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS. FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat Genet. 2011;43(1):27–33.

    Article  CAS  PubMed  Google Scholar 

  50. Lin CY, Vega VB, Thomsen JS, Zhang T, Kong SL, Xie M, et al. Whole-genome cartography of estrogen receptor alpha binding sites. PLoS Genet. 2007;3(6):e87.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Stender JD, Kim K, Charn TH, Komm B, Chang KC, Kraus WL, et al. Genome-wide analysis of estrogen receptor alpha DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in receptor-mediated transcriptional activation. Mol Cell Biol. 2010;30(16):3943–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chimge NO, Frenkel B. The RUNX family in breast cancer: relationships with estrogen signaling. Oncogene. 2013;32(17):2121–30.

    Article  CAS  PubMed  Google Scholar 

  53. Wang L, Brugge JS, Janes KA. Intersection of FOXO- and RUNX1-mediated gene expression programs in single breast epithelial cells during morphogenesis and tumor progression. Proc Natl Acad Sci U S A. 2011;108(40):E803–812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. • Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R. ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015;12(10):573–83. This paper reviewed the discovery of genomic alterations in ESR1, especially the acquired ESR1 ligand binding domain (LBD) mutations in endocrine resistant breast cancers, and the functional and mechanistic studies demonstrating the ability of ESR1 LBD mutations in inducing estrogen independent ER transcriptional activity and tumor cell proliferation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45(12):1446–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 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(12):1439–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. • 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(7):1757–67. Targeted sequencing of ESR1 and an additional 182 cancer-related genes were performed for 249 tumors (58 primary ER+HER2−, 76 metastatic ER+HER2− and 115 ER−) from 208 breast cancer patients. Recurring somatic mutations in ESR1 LBD amino acids 537 and 538 were observed in 12% of metastatic ER+HER2− tumors, but not detected in primary or treatment naïve ER+ or any ER− disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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(23):6856–64.

    Article  CAS  PubMed  Google Scholar 

  59. 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(6):1116–30.

    Article  CAS  PubMed  Google Scholar 

  60. • Schiavon G, Hrebien S, Garcia-Murillas I, Cutts RJ, Pearson A, Tarazona N, et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med. 2015;7(313):313ra182. This study showed that ESR1 mutations can be identified using ctDNA, and may be clinically useful in predicting AI resistance. In this study, ESR1 mutations were identified only in patients who had previously received AI therapy, and were more prevalent in the metastatic setting.

    Article  PubMed  PubMed Central  Google Scholar 

  61. • Miller CA, Gindin Y, Lu C, Griffith OL, Griffith M, Shen D, et al. Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers. Nat Commun. 2016;7:12498. This study compared whole-genome sequencing of 22 ER+ primary breast tumors before (at baseline) and after 4 months (surgery time point) of neoadjuvant AI therapy. The study demonstrated a widespread spatial and temporal heterogeneity in the mutation profile of individual breast cancers. New or enriched mutations were identified after neoadjuvant therapy, including two ESR1 mutations acquired at the surgical time points.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 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(7):1244–9.

    CAS  PubMed  Google Scholar 

  63. Nettles KW, Bruning JB, Gil G, Nowak J, Sharma SK, Hahm JB, et al. NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. Nat Chem Biol. 2008;4(4):241–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. • Wardell SE, Ellis MJ, Alley HM, Eisele K, VanArsdale T, Dann SG, Arndt KT, Primeau T, Griffin E, Shao J, et al. Efficacy of SERD/SERM hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy resistant breast cancer. Clin Cancer Res. 2015. This study provided the preclinical evidence that the combinations of the CDK4/6 inhibitor palbociclib and selective estrogen receptor downregulators (SERDs) or selective estrogen receptor modulator (SERM)/SERD hybrids were effective in inhibiting the growth of endocrine resistant or ESR1 mutant ER+ breast cancer xenograft models.

  65. •• Fribbens C, O’Leary B, Kilburn L, Hrebien S, Garcia-Murillas I, Beaney M, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2016;34(25):2961–8. This paper reported the analysis of ESR1 mutations detected by ctDNA sequencing of blood samples obtained from patients enrolled in two randomized phase III trials, the SoFEA trial and the PALOMA-3 trial, in relation to PFS on treatment with either an AI, fulvestrant or fulvestrant plus AI, or palbociclib plus fulvestrant. This study demonstrated that ESR1 mutations render breast cancers resistant to AI therapy, but remain responsive to fulvestrant and the benefit of palbociclib to fulvestrant was regardless of ESR1 mutation status.

    Article  PubMed  Google Scholar 

  66. • 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(10):1310–5. ctDNA analysis of blood samples from the BOLERO-2 trial demonstrated that ESR1 Y537S and D538G were associated with shorter OS compared with WT ESR1. The D538G group derived PFS benefit from the addition of everolimus.

    Article  PubMed  Google Scholar 

  67. • McDonnell DP, Wardell SE, Norris JD. Oral selective estrogen receptor downregulators (SERDs) a breakthrough endocrine therapy for breast cancer. J Med Chem. 2015;58(12):4883–7. This review describes the discovery and development of the next generation SERDs for endocrine resistant ER+ breast cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. • Wang Y, Lonard DM, Yu Y, Chow D-C, Palzkill TG, Wang J, et al. Bufalin is a potent small-molecule inhibitor of the steroid receptor coactivators SRC-3 and SRC-1. Cancer Res. 2014;74(5):1506–17. This study reported the identification of bufalin, a small-molecular inhibitor against the steroid receptor co-activators SRC-3 and SRC-1 via a high-throughput screening effort. Bufalin was effective in inhibiting breast cancer xenograft tumor growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. • Yan F, Yu Y, Chow D-C, Palzkill T, Madoux F, Hodder P, et al. Identification of verrucarin A as a potent and selective steroid receptor coactivator-3 small molecule inhibitor. PLoS One. 2014;9(4):e95243. This study described the identification of verrucarin A as a potent and selective steroid receptor coactivator 3 small molecule inhibitor.

    Article  PubMed  PubMed Central  Google Scholar 

  70. • Ma Y, Ambannavar R, Stephans J, Jeong J, Dei Rossi A, Liu ML, et al. Fusion transcript discovery in formalin-fixed paraffin-embedded human breast cancer tissues reveals a link to tumor progression. PLoS One. 2014;9(4):e94202. This study demonstrated the feasibility to detect fusion transcripts from archived FFPE tissue as biomarkers, and that these transcripts correlated with poor outcomes. These findings support the potential prognostic value of detected fusion transcripts.

    Article  PubMed  PubMed Central  Google Scholar 

  71. • Veeraraghavan J, Tan Y, Cao XX, Kim JA, Wang X, Chamness GC, et al. Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers. Nat Commun. 2014;5:4577. This study identified recurrent rearrangements between ESR1 gene and neighboring CCDC170, which are associated with the more-aggressive luminal-B subset of ER+ breast cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Fox EM, Miller TW, Balko JM, Kuba MG, Sánchez V, Smith RA, et al. A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer. Cancer Res. 2011;71(21):6773–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Stephen RL, Shaw LE, Larsen C, Corcoran D, Darbre PD. Insulin-like growth factor receptor levels are regulated by cell density and by long term estrogen deprivation in MCF7 human breast cancer cells. J Biol Chem. 2001;276(43):40080–6.

    Article  CAS  PubMed  Google Scholar 

  74. Martin LA, Farmer I, Johnston SR, Ali S, Marshall C, Dowsett M. Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. J Biol Chem. 2003;278(33):30458–68.

    Article  CAS  PubMed  Google Scholar 

  75. Jeng MH, Yue W, Eischeid A, Wang JP, Santen RJ. Role of MAP kinase in the enhanced cell proliferation of long term estrogen deprived human breast cancer cells. Breast Cancer Res Treat. 2000;62(3):167–75.

    Article  CAS  PubMed  Google Scholar 

  76. Sanchez CG, Ma CX, Crowder RJ, Guintoli T, Phommaly C, Gao F, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res. 2011;13(2):R21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120(7):2406–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Roop RP, Ma CX. Endocrine resistance in breast cancer: molecular pathways and rational development of targeted therapies. Future Oncol. 2012;8(3):273–92.

    Article  CAS  PubMed  Google Scholar 

  79. Creighton CJ, Hilger AM, Murthy S, Rae JM, Chinnaiyan AM, El-Ashry D. Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors. Cancer Res. 2006;66(7):3903–11.

    Article  CAS  PubMed  Google Scholar 

  80. Oh AS, Lorant LA, Holloway JN, Miller DL, Kern FG, El-Ashry D. Hyperactivation of MAPK induces loss of ERalpha expression in breast cancer cells. Mol Endocrinol. 2001;15(8):1344–59.

    CAS  PubMed  Google Scholar 

  81. Lopez-Tarruella S, Schiff R. The dynamics of estrogen receptor status in breast cancer: re-shaping the paradigm. Clin Cancer Res. 2007;13(23):6921–5.

    Article  CAS  PubMed  Google Scholar 

  82. Bayliss J, Hilger A, Vishnu P, Diehl K, El-Ashry D. Reversal of the estrogen receptor negative phenotype in breast cancer and restoration of antiestrogen response. Clin Cancer Res. 2007;13(23):7029–36.

    Article  CAS  PubMed  Google Scholar 

  83. Font de Mora J, Brown M. AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. Mol Cell Biol. 2000;20(14):5041–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SAW, et al. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. JCI. 2003;95(5):353–61.

    CAS  Google Scholar 

  85. • Ma CX, Bose R, Gao F, Freedman RA, Pegram M, Pegram MD, et al. Phase II trial of neratinib for HER2 mutated, non-amplified metastatic breast cancer (HER2mut MBC). J Clin Oncol. 2016;34(suppl):abstr 516. This phase II trial demonstrated that the irreversible pan-HER inhibitor neratinib was effective in treating patients with advanced HER2 mutated, non-amplified metastatic breast cancer. This study provided the proof of concept that HER2 mutation is a therapeutic target for HER2 non-amplified breast cancer.

    Google Scholar 

  86. Andre F, Bachelot T, Campone M, Dalenc F, Perez-Garcia JM, Hurvitz SA, et al. Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer. Clin Cancer Res. 2013;19(13):3693–702.

    Article  CAS  PubMed  Google Scholar 

  87. Ma CX, Crowder RJ, Ellis MJ. Importance of PI3-kinase pathway in response/resistance to aromatase inhibitors. Steroids. 2011;76(8):750–2.

    Article  CAS  PubMed  Google Scholar 

  88. Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM, et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 2009;69(9):3955–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Juric D, Argiles G, Burris HA, Gonzalez-Angulo AM, Saura C, Quadt C, et al. Phase I study of BYL719, an alpha-specific PI3K inhibitor, in patients with PIK3CA mutant advanced solid tumors: preliminary efficacy and safety in patients with PIK3CA mutant ER-positive (ER+) metastatic breast cancer (MBC). Cancer Res. 2012;72(24 Suppl):Abstract nr P6-10-07.

    Article  Google Scholar 

  90. Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal. 2009;2(67):e24.

    Article  Google Scholar 

  91. Campone M, Bachelot T, Gnant M, Deleu I, Rugo HS, Pistilli B, et al. Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study. Eur J Cancer. 2013;49(12):2621–32.

    Article  CAS  PubMed  Google Scholar 

  92. O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66(3):1500–8.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 2007;26(13):1932–40.

    Article  CAS  PubMed  Google Scholar 

  94. • Ma C. The PI3K pathway as a therapeutic target in breast cancer—see more at: http://www.gotoper.com/publications/ajho/2015/2015mar/the-pi3k-pathway-as-a-therapeutic-target-in-breast-cancer#sthash.lZMxeajc.dpuf. In 2015. This paper reviewed recent progress in the development of inhibitors against the PI3K/Akt/mTOR signaling pathway for the treatment of breast cancer.

  95. • Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S, Yardley DA, Melichar B, Forero-Torres A, Lee SC, et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17(6):811–821. This study evaluated the combination of pictilisib, a pan-PI3K inhibitor, with fulvestrant in patients with metastatic breast cancer.

  96. • Baselga J, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng L-M, et al. PIK3CA status in circulating tumor DNA (ctDNA) predicts efficacy of buparlisib (BUP) plus fulvestrant (FULV) in postmenopausal women with endocrine-resistant HR+/HER2− advanced breast cancer (BC): first results from the randomized, phase III BELLE-2 trial. In: San Antonio Breast Cancer Symposium: 2015; San Antonio, Texas; 2015: abstract S6-01. The BELLE-2 trial studied the combination of a pan-PI3K inhibitor, buparlisib, with fulvestrant in ER+/HER2− advanced breast cancer. The combination resulted in improved PFS.

  97. Mayer IA, Abramson VG, Isakoff SJ, Forero A, Balko JM, Kuba MG, et al. Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2014;32(12):1202–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. • Ma CX, Sanchez C, Gao F, Crowder R, Naughton M, Pluard T, et al. A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausal women with estrogen receptor positive metastatic breast cancer. Clin Cancer Res. 2016;22(11):2650–8. This study determined the recommended phase II treatment dose for the AKT inhibitor MK-2206 in combination with either anastrozole, or fulvestrant, or the combination of anastrozole and fulvestrant for the treatment of advanced hormone receptor positive breast cancer and provided a preliminary efficacy data for this patient population.

    Article  CAS  PubMed  Google Scholar 

  99. • Ma CX, Luo J, Naughton M, Ademuyiwa FO, Suresh R, Griffith M, et al. A phase 1 trial of BKM120 (buparlisib) in combination with fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer. Clin Cancer Res. 2015;22(7):1583–91. This trial determined the maximum tolerated dose (MTD) of the pan-PI3K inhibitor buparlisib in combination with fulvestrant in post-menopausal women with metastatic ER+ breast cancer and evaluated two dosing schedules of buparlisib, intermittent (5/7-day) and continuous daily, for their toxicity profiles and preliminary anti-tumor activity in this patient population.

    Article  PubMed  Google Scholar 

  100. Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, Burris HA, Campone M, Noguchi S, Perez AT, Deleu I, Shtivelband M, Provencher L, et al. Correlation of molecular alterations with efficacy of everolimus in hormone receptor-positive, HER2-negative advanced breast cancer: results from BOLERO-2. In: J Clin Oncol. Chicago, IL; 2013: abstract LBA509.

  101. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011;11(8):558–72.

    Article  CAS  PubMed  Google Scholar 

  102. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77.

    Article  PubMed  PubMed Central  Google Scholar 

  103. • O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13(7):417–30. This paper reviewed the mechanisms of action, preclinical rational, and the clinical development of CDK4/6 inhibitors for the treatment of ER+ breast cancer, and potential mechanisms of resistance to CDK4/6 inhibitors.

    Article  PubMed  Google Scholar 

  104. • Verma S, Bartlett CH, Schnell P, DeMichele AM, Loi S, Ro J, Colleoni M, Iwata H, Harbeck N, Cristofanilli M, et al. Palbociclib in combination with fulvestrant in women with hormone receptor-positive/HER2-negative advanced metastatic breast cancer: detailed safety analysis from a multicenter, randomized, placebo-controlled, phase III study (PALOMA-3). Oncologist 2016. This publication provided the detailed safety data of the PALOMA-3 trial and concluded that the combination of palbociclib with fulvestrant was well-tolerated. Asympatomatic neutropenia was the main toxicity, which could be effectively managed with dose-modification without sacrificing efficacy.

  105. • Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015. This study (PALOMA-3) established that palbociclib combined with fulvestrant resulted in a significant longer PFS than fulvestrant alone in patients with hormone receptor positive metastatic breast cancer who progressed on prior endocrine therapy. This data led to the FDA approval of palbociclib in combination with fulvestrant for this indication.

  106. • Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25–35. This randomized phase II trial demonstrated that the addition of palbociclib to letrozole as front line hormonal therapy improved PFS in patients with advanced ER+/HER− breast cancer. This data led to the accelerated FDA approval of palbociclib in combination with letrozole as the first line hormonal therapy for patients with hormone receptor positive breast cancer.

    Article  CAS  PubMed  Google Scholar 

  107. • Finn RS, Martin M, Rugo H, Jones SE, Im S-A, Gelmon KA, et al. PALOMA-2: primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2− advanced breast cancer (ABC). J Clin Oncol. 2016;34(supp):abstr 507. This phase III trial confirmed that palbociclib in combination with letrozole improved the PFS compared to letrozole alone as first line hormonal therapy for patients with advanced hormone receptor positive HER2 negative breast cancer.

    Google Scholar 

  108. • Hortobagyi GN, Stemmer SM, Burris HA, Yap Y-S, Sonke GS, Paluch-Shimon S, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Eng J Med. 2016;375(18):1738–48. This trial demonstrated improved PFS with the combination of ribociclib (a selective CDK4/6 inhibitor) and letrozole compared to placebo and letrozole as first-line therapy in patients with advanced ER+/HER2− breast cancer.

    Article  CAS  Google Scholar 

  109. Beaver JA, Amiri-Kordestani L, Charlab R, Chen W, Palmby T, Tilley A, et al. FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2015;21(21):4760–6.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Cynthia X. Ma.

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Aabha Oza has no conflict of interest to declare.

Cynthia X. Ma has received clinical trial support and an advisory fee from Pfizer, has received clinical trial support and an advisory fee from Novartis, received clinical trial support and an advisory fee from Puma, and has served as an advisor for AstraZeneca.

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Oza, A., Ma, C.X. New Insights in Estrogen Receptor (ER) Biology and Implications for Treatment. Curr Breast Cancer Rep 9, 13–25 (2017). https://doi.org/10.1007/s12609-017-0231-1

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