1932

Abstract

Estrogen receptor (ER) α is expressed in the vast majority of breast cancers and is one of the most successfully prosecuted drug targets in oncology, with multiple classes of endocrine therapies approved for the treatment of ER+ breast cancer. These existing agents are highly active, both as single agents and as combination partners for other targeted therapies, and have significantly benefited patients. However, each of these standard-of-care (SOC) therapies has liabilities that allow for the reengagement of ER signaling as a mechanism of resistance. Data supporting the continued dependence of tumors on ER signaling following exposure to SOC agents have underpinned an extraordinary reenergizing of academic, biotechnology, and pharmaceutical groups pursuing next-generation ER-targeted therapies. The hypothesis that there remains an opportunity to bring further meaningful benefit to patients through fully optimized ER-targeted therapies is currently being investigated in the clinic.

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2023-04-11
2024-10-16
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Literature Cited

  1. Aftimos PG, Cortés J, Bidard FC, Kaklamani V, Bardia A et al. 2022. 220P Elacestrant versus fulvestrant or aromatase inhibitor (AI) in phase III trial evaluating elacestrant, an oral selective estrogen receptor degrader (SERD), versus standard of care (SOC) endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC): subgroup analysis from EMERALD. Ann. Oncol. 33:S7S638 (Abstr.)
    [Google Scholar]
  2. Allen E, Doisy EA. 1923. An ovarian hormone. Preliminary report on its localization, extraction and partial purification, and action in test animals. JAMA 81:10819–21
    [Google Scholar]
  3. Bahreini A, Li Z, Wang P, Levine KM, Tasdemir N et al. 2017. Mutation site and context dependent effects of ESR1 mutation in genome-edited breast cancer cell models. Breast Cancer Res. 19:60
    [Google Scholar]
  4. Bardia A, Fernando TM, Fasching PA, Quiroga Garcia V, Park YH et al. 2022. 144P Neoadjuvant giredestrant (GDC-9545) + palbociclib (P) vs anastrozole (A) + P in postmenopausal women with oestrogen receptor-positive, HER2-negative, untreated early breast cancer (ER+/HER2– eBC): biomarker subgroup analysis of the randomised, phase II coopERA BC study. Ann. Oncol. 33:S605–6 (Abstr.)
    [Google Scholar]
  5. Beatson GT. 1896. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Trans. Med. Chir. Soc. Edinb. 15:153–79
    [Google Scholar]
  6. Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ et al. 2022. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. J. Clin. Oncol. 40:3246–56
    [Google Scholar]
  7. Bihani T, Patel HK, Arlt H, Tao N, Jiang H et al. 2017. Elacestrant (RAD1901), a selective estrogen receptor degrader (SERD), has antitumor activity in multiple ER+ breast cancer patient-derived xenograft models. Clin. Cancer Res. 23:4793–804
    [Google Scholar]
  8. Borras M, Laios I, el Khissiin A, Seo HS, Lempereur F et al. 1996. Estrogenic and antiestrogenic regulation of the half-life of covalently labeled estrogen receptor in MCF-7 breast cancer cells. J. Steroid Biochem. Mol. Biol. 57:203–13
    [Google Scholar]
  9. Breast Int. Group 1-98 Collab. Group, Thürlimann B, Keshaviah A, Coates AS, Mouridsen H et al. 2005. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N. Engl. J. Med. 353:2747–57. Erratum 2006. N. Engl. J. Med. 354:2200
    [Google Scholar]
  10. Brodie AM, Schwarzel WC, Shaikh AA, Brodie HJ. 1977. The effect of an aromatase inhibitor, 4-hydroxy-4-androstene-3,17-dione, on estrogen-dependent processes in reproduction and breast cancer. Endocrinol 100:1684–95
    [Google Scholar]
  11. Campone M, Dong Y, Ling B, Wang L, Herold CI 2022. AMEERA-4: a preoperative window-of-opportunity (WOO) study to assess the pharmacodynamic (PD) activity of amcenestrant or letrozole in postmenopausal patients with ER+/HER2− primary breast cancer. J. Clin. Oncol. 40:16 Suppl.528
    [Google Scholar]
  12. Chen YC, Yu J, Metcalfe C, De Bruyn T, Gelzleichter T et al. 2022. Latest generation estrogen receptor degraders for the treatment of hormone receptor-positive breast cancer. Expert Opin. Investig. Drugs 31:515–29
    [Google Scholar]
  13. Chong S, Dugast-Darzacq C, Liu Z, Dong P, Dailey GM et al. 2018. Imaging dynamic and selective low-complexity domain interactions that control gene transcription. Science 361:eaar2555
    [Google Scholar]
  14. Coombes RC, Hughes SW, Dowsett M. 1992. 4-Hydroxyandrostenedione: a new treatment for postmenopausal patients with breast cancer. Eur. J. Cancer 28:A1941–45
    [Google Scholar]
  15. Damodaran S, Plourde PV, Moore HCF, Anderson IC, Portman DJ. 2022. Open-label, phase 2, multicenter study of lasofoxifene (LAS) combined with abemaciclib (Abema) for treating pre- and postmenopausal women with locally advanced or metastatic ER+/HER2− breast cancer and an ESR1 mutation after progression on prior therapies. J. Clin. Oncol. 40:1022
    [Google Scholar]
  16. Fasching PA, Bardia A, Quiroga V, Park YH, Blancas I et al. 2022. Neoadjuvant giredestrant (GDC-9545) plus palbociclib (P) versus anastrozole (A) plus P in postmenopausal women with estrogen receptor–positive, HER2-negative, untreated early breast cancer (ER+/HER2– eBC): final analysis of the randomized, open-label, international phase 2 coopERA BC study. J. Clin. Oncol. 40:589
    [Google Scholar]
  17. Feng Y, Manka D, Wagner K-U, Khan SA. 2007. Estrogen receptor-α expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice. PNAS 104:14718–23
    [Google Scholar]
  18. Furman C, Puyang X, Zhang Z, Wu ZJ, Banka D et al. 2022. Covalent ERα antagonist H3B-6545 demonstrates encouraging preclinical activity in therapy-resistant breast cancer. Mol. Cancer Ther. 21:890–902
    [Google Scholar]
  19. Garner F, Shomali M, Paquin D, Lyttle CR, Hattersley G. 2015. RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs 26:948–56
    [Google Scholar]
  20. Gibson MK, Nemmers LA, Beckman WC Jr., Davis VL, Curtis SW, Korach KS. 1991. The mechanism of ICI 164,384 antiestrogenicity involves rapid loss of estrogen receptor in uterine tissue. Endocrinology 129:2000–10
    [Google Scholar]
  21. Goetz MP, Plourde P, Stover DG, Bagegni N, Vidal GA et al. 2022. LBA20 open-label, randomized study of lasofoxifene (LAS) versus fulvestrant (Fulv) for women with locally advanced/metastatic ER+/HER2− breast cancer (mBC), an estrogen receptor 1 (ESR1) mutation, and disease progression on aromatase (AI) and cyclin-dependent kinase 4/6 (CDK4/6i) inhibitors. Ann. Oncol. 33:S1387–88 (Abstr.)
    [Google Scholar]
  22. Gottardis MM, Wagner RJ, Borden EC, Jordan VC. 1989. Differential ability of antiestrogens to stimulate breast cancer cell (MCF-7) growth in vivo and in vitro. Cancer Res. 49:4765–69
    [Google Scholar]
  23. Guan J, Zhou W, Hafner M, Blake RA, Chalouni C et al. 2019. Therapeutic ligands antagonize estrogen receptor function by impairing its mobility. Cell 178:949–63.e18
    [Google Scholar]
  24. Guerrero-Zotano AL, Arteaga CL. 2017. Neoadjuvant trials in ER+ breast cancer: a tool for acceleration of drug development and discovery. Cancer Discov. 7:561–74
    [Google Scholar]
  25. Hodges-Gallagher L, Sun R, Myles D, Klein P, Zujewski JA et al. 2020. OP-1250: a potent orally available complete antagonist of estrogen receptor-mediated signaling that shrinks wild type and mutant breast tumors. Eur. J. Cancer 138:Suppl. 2S55 (Abstr.)
    [Google Scholar]
  26. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M et al. 2005. Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365:60–62
    [Google Scholar]
  27. Im S-A, Hamilton EP, Llombart Cussac A, Baird RD, Ettl J et al. 2021. SERENA-4: a phase 3 comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive, HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease. J. Clin. Oncol. 39:15 Suppl.TPS1101 Abstr. )
    [Google Scholar]
  28. Jeselsohn R, Bergholz JS, Pun M, Cornwell M, Liu W et al. 2018. Allele-specific chromatin recruitment and therapeutic vulnerabilities of ESR1 activating mutations. Cancer Cell 33:173–86.e5
    [Google Scholar]
  29. Jhaveri KL, Lim E, Hamilton EP, Saura C, Meniawy T et al. 2021. A first-in-human phase 1a/b trial of LY3484356, an oral selective estrogen receptor (ER) degrader (SERD) in ER+ advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): results from the EMBER study. J. Clin. Oncol. 39:15 Suppl.1050 Abstr. )
    [Google Scholar]
  30. Jordan VC. 2021. Turning scientific serendipity into discoveries in breast cancer research and treatment: a tale of PhD students and a 50-year roaming tamoxifen team. Breast Cancer Res. Treat. 190:19–38
    [Google Scholar]
  31. Joseph JD, Darimont B, Zhou W, Arrazate A, Young A et al. 2016. The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. eLife 5:e15828
    [Google Scholar]
  32. Kahraman M, Govek SP, Nagasawa JY, Lai A, Bonnefous C et al. 2019. Maximizing ER-α degradation maximizes activity in a tamoxifen-resistant breast cancer model: identification of GDC-0927. ACS Med. Chem. Lett. 10:50–55
    [Google Scholar]
  33. Katzenellenbogen JA, Mayne CG, Katzenellenbogen BS, Greene GL, Chandarlapaty S. 2018. Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance. Nat. Rev. Cancer 18:377–88
    [Google Scholar]
  34. Lai A, Kahraman M, Govek S, Nagasawa J, Bonnefous C et al. 2015. Identification of GDC-0810 (ARN-810), an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust activity in tamoxifen-resistant breast cancer xenografts. J. Med. Chem. 58:4888–904
    [Google Scholar]
  35. Lainé M, Fanning SW, Chang Y-F, Green B, Greene ME et al. 2021. Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer. Breast Cancer Res. 23:54
    [Google Scholar]
  36. Li S, Shen D, Shao J, Crowder R, Liu W et al. 2013. Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep. 4:1116–30
    [Google Scholar]
  37. Liang J, Zbieg JR, Blake RA, Chang JH, Daly S et al. 2021. GDC-9545 (giredestrant): a potent and orally bioavailable selective estrogen receptor antagonist and degrader with an exceptional preclinical profile for ER+ breast cancer. J. Med. Chem. 64:11841–56
    [Google Scholar]
  38. Lindeman GJ, Fernando TM, Bowen R, Jerzak KJ, Song X et al. 2022. VERONICA: randomized phase II study of fulvestrant and venetoclax in ER-positive metastatic breast cancer post-CDK4/6 inhibitors–efficacy, safety, and biomarker results. Clin. Cancer Res. 28:3256–67
    [Google Scholar]
  39. Liu H, Lee ES, De Los Reyes A, Zapf JW, Jordan VC. 2001. Silencing and reactivation of the selective estrogen receptor modulator-estrogen receptor α complex. Cancer Res. 61:3632–39
    [Google Scholar]
  40. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G et al. 1995. The nuclear receptor superfamily: the second decade. Cell 83:835–39
    [Google Scholar]
  41. Martin Jimenez M, Lim E, Chavez Mac Gregor M, Bardia A, Wu J et al. 2022. 211MO—giredestrant (GDC-9545) vs physician choice of endocrine monotherapy (PCET) in patients (pts) with ER+, HER2– locally advanced/metastatic breast cancer (LA/mBC): primary analysis of the phase II, randomised, open-label acelERA BC study. Ann. Oncol. 33:Suppl. 7S633–34 (Abstr.)
    [Google Scholar]
  42. McInerney EM, Katzenellenbogen BS. 1996. Different regions in activation function-1 of the human estrogen receptor required for antiestrogen- and estradiol-dependent transcription activation. J. Biol. Chem. 271:24172–78
    [Google Scholar]
  43. Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, Dvir A, Soussan-Gutman L et al. 2013. D538G mutation in estrogen receptor-α: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 73:6856–64
    [Google Scholar]
  44. Moore HM, Boni V, Bellet M, Bermejo De Las Heras B, Gión Cortés M et al. 2021. Evaluation of pharmacodynamic (PD) and biologic activity in a preoperative window-of-opportunity (WOO) study of giredestrant (GDC-9545) in postmenopausal patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2–) operable breast cancer (BC). J. Clin. Oncol. 39:15 Suppl.577 (Abstr.)
    [Google Scholar]
  45. Nicholson RI, Gee JM, Manning DL, Wakeling AE, Montano MM, Katzenellenbogen BS. 1995. Responses to pure antiestrogens (ICI 164384, ICI 182780) in estrogen-sensitive and -resistant experimental and clinical breast cancer. Ann. N.Y. Acad. Sci. 761:148–63
    [Google Scholar]
  46. O'Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X et al. 2018. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 8:1390–403
    [Google Scholar]
  47. Osborne CK, Coronado E, Allred DC, Wiebe V, DeGregorio M. 1991. Acquired tamoxifen resistance: correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen. J. Natl. Cancer Inst. 83:1477–82
    [Google Scholar]
  48. Preisler-Mashek MT, Solodin N, Stark BL, Tyriver MK, Alarid ET. 2002. Ligand-specific regulation of proteasome-mediated proteolysis of estrogen receptor-α. Am. J. Physiol. Endocrinol. Metab. 282:E891–98
    [Google Scholar]
  49. Quirke VM. 2017. Tamoxifen from failed contraceptive pill to best-selling breast cancer medicine: a case-study in pharmaceutical innovation. Front. Pharmacol. 8:620
    [Google Scholar]
  50. Robertson JFR, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L et al. 2016. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet 388:2997–3005
    [Google Scholar]
  51. Robertson JFR, Evans A, Henschen S, Kirwan CC, Jahan A et al. 2020. A randomized, open-label, presurgical, window-of-opportunity study comparing the pharmacodynamic effects of the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2 primary breast cancer. Clin. Cancer Res. 26:4242–49
    [Google Scholar]
  52. Robertson JFR, Lindemann J, Garnett S, Anderson E, Nicholson RI et al. 2014. A good drug made better: the fulvestrant dose-response story. Clin. Breast Cancer 14:381–89
    [Google Scholar]
  53. Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ et al. 2013. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat. Genet. 45:1446–51
    [Google Scholar]
  54. Santen RJ, Brodie H, Simpson ER, Siiteri PK, Brodie A. 2009. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr. Rev. 30:343–75
    [Google Scholar]
  55. Schiavon G, Hrebien S, Garcia-Murillas I, Cutts RJ, Pearson A et al. 2015. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci. Transl. Med. 7:313ra182
    [Google Scholar]
  56. Scott JS, Moss TA, Balazs A, Barlaam B, Breed J et al. 2020. Discovery of AZD9833, a potent and orally bioavailable selective estrogen receptor degrader and antagonist. J. Med. Chem. 63:14530–59
    [Google Scholar]
  57. Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ et al. 1998. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95:927–37
    [Google Scholar]
  58. Shomali M, Cheng J, Sun F, Koundinya M, Guo Z et al. 2021. SAR439859, a novel selective estrogen receptor degrader (SERD), demonstrates effective and broad antitumor activity in wild-type and mutant ER-positive breast cancer models. Mol. Cancer Ther. 20:250–62
    [Google Scholar]
  59. Smith I, Robertson J, Kilburn L, Wilcox M, Evans A et al. 2020. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 21:1443–54
    [Google Scholar]
  60. Snyder LB, Flanagan JJ, Qian Y, Gough SM, Andreoli M et al. 2021. Abstract 44: the discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer. Cancer Res. 81:13 Suppl.44 (Abstr.)
    [Google Scholar]
  61. Spoerke JM, Gendreau S, Walter K, Qiu J, Wilson TR et al. 2016. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat. Commun. 7:11579
    [Google Scholar]
  62. Stenoien DL, Patel K, Mancini MG, Dutertre M, Smith CL et al. 2000. FRAP reveals that mobility of oestrogen receptor-α is ligand- and proteasome-dependent. Nat. Cell Biol. 3:15–23
    [Google Scholar]
  63. Tolaney SM, Chan A, Petrakova K, Delaloge S, Campone M et al. 2022. 212MO AMEERA-3, a phase II study of amcenestrant (AMC) versus endocrine treatment of physician's choice (TPC) in patients (pts) with endocrine-resistant ER+/HER2− advanced breast cancer (aBC). Ann. Oncol. 33:S634–35 (Abstr.)
    [Google Scholar]
  64. Toy W, Shen Y, Won H, Green B, Sakr RA et al. 2013. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat. Genet. 45:1439–45
    [Google Scholar]
  65. Toy W, Weir H, Razavi P, Lawson M, Goeppert AU et al. 2017. Activating ESR1 mutations differentially affect the efficacy of ER antagonists. Cancer Discov. 7:277–87
    [Google Scholar]
  66. van Kruchten M, de Vries EG, Glaudemans AW, van Lanschot MC, van Faassen M et al. 2015. Measuring residual estrogen receptor availability during fulvestrant therapy in patients with metastatic breast cancer. Cancer Discov. 5:72–81
    [Google Scholar]
  67. Vidal M, Muñoz M, Margeli M, González X, Amillano K et al. 2022. Abstract OT2-11-07: Solti-1905. Elacestrant in preoperative setting, a window of opportunity study (ELIPSE trial). Cancer Res. 82:4 Suppl.OT2–11-07 (Abstr.)
    [Google Scholar]
  68. Wakeling AE. 1990. Therapeutic potential of pure antioestrogens in the treatment of breast cancer. J. Steroid Biochem. Mol. Biol. 37:771–75
    [Google Scholar]
  69. Wakeling AE, Bowler J. 1992. ICI 182,780, a new antioestrogen with clinical potential. J. Steroid Biochem. Mol. Biol. 43:173–77
    [Google Scholar]
  70. Walter P, Green S, Greene G, Krust A, Bornert JM et al. 1985. Cloning of the human estrogen receptor cDNA. PNAS 82:7889–93
    [Google Scholar]
  71. Wander SA, Han HS, Zangardi ML, Niemierko A, Mariotti V et al. 2021. Clinical outcomes with abemaciclib after prior CDK4/6 inhibitor progression in breast cancer: a multicenter experience. J. Natl. Compr. Canc. Netw. https://doi.org/10.6004/jnccn.2020.7662
    [Google Scholar]
  72. Wardell SE, Marks JR, McDonnell DP. 2011. The turnover of estrogen receptor α by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy. Biochem. Pharmacol. 82:122–30
    [Google Scholar]
  73. Wardell SE, Nelson ER, Chao CA, Alley HM, McDonnell DP. 2015. Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader. Endocr. Relat. Cancer 22:713–24
    [Google Scholar]
  74. Wardell SE, Nelson ER, Chao CA, McDonnell DP. 2013. Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease. Clin. Cancer Res. 19:2420–31
    [Google Scholar]
  75. Weir HM, Bradbury RH, Lawson M, Rabow AA, Buttar D et al. 2016. AZD9496: an oral estrogen receptor inhibitor that blocks the growth of ER-positive and ESR1-mutant breast tumors in preclinical models. Cancer Res. 76:3307–18
    [Google Scholar]
  76. Wolf DM, Jordan VC. 1994. Characterization of tamoxifen stimulated MCF-7 tumor variants grown in athymic mice. Breast Cancer Res. Treat. 31:117–27
    [Google Scholar]
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