Review Article| Volume 37, ISSUE 1, P169-181, February 2023

The Clinical Utility of ESR1 Mutations in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer


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        • Fuentes N.
        • Silveyra P.
        Estrogen receptor signaling mechanisms.
        Adv Protein Chem Struct Biol. 2019; 116: 135-170
        • 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: 573-583
        • Jacobson A.
        Alpelisib plus fulvestrant or letrozole demonstrates sustained benefits across subgroups of patients with PIK3CA-mutated HR+/HER2- advanced breast cancer.
        Oncologist. 2022; 27: S13-S14
        • Hanker A.B.
        • Sudhan D.R.
        • Arteaga C.L.
        Overcoming endocrine resistance in breast cancer.
        Cancer Cell. 2020; 37: 496-513
        • Razavi P.
        • Chang M.T.
        • Xu G.
        • et al.
        The genomic landscape of endocrine-resistant advanced breast cancers.
        Cancer Cell. 2018; 34: 427-438 e6
        • Gutierrez M.C.
        • Detre S.
        • Johnston S.
        • et al.
        Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase.
        J Clin Oncol. 2005; 23: 2469-2476
        • Ades F.
        • Zardavas D.
        • Bozovic-Spasojevic I.
        • et al.
        Luminal B breast cancer: molecular characterization, clinical management, and future perspectives.
        J Clin Oncol. 2014; 32: 2794-2803
        • Pearson A.
        • Proszek P.
        • Pascual J.
        • et al.
        Inactivating NF1 mutations are enriched in advanced breast cancer and contribute to endocrine therapy resistance.
        Clin Cancer Res. 2020; 26: 608-622
        • Griffith O.L.
        • Spies N.C.
        • Anurag M.
        • et al.
        The prognostic effects of somatic mutations in ER-positive breast cancer.
        Nat Commun. 2018; 9: 3476
        • Anurag M.
        • Punturi N.
        • Hoog J.
        • et al.
        Comprehensive profiling of DNA repair defects in breast cancer identifies a novel class of endocrine therapy resistance drivers.
        Clin Cancer Res. 2018; 24: 4887-4899
        • Giltnane J.M.
        • Hutchinson K.E.
        • Stricker T.P.
        • et al.
        Genomic profiling of ER(+) breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance.
        Sci Transl Med. 2017; 9
        • Cancer Genome Atlas N.
        Comprehensive molecular portraits of human breast tumours.
        Nature. 2012; 490: 61-70
        • Zhang Q.X.
        • Borg A.
        • Wolf D.M.
        • et al.
        An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer.
        Cancer Res. 1997; 57: 1244-1249
        • Jeselsohn R.
        • Yelensky R.
        • Buchwalter G.
        • et al.
        Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer.
        Clin Cancer Res. 2014; 20: 1757-1767
        • Toy W.
        • Shen Y.
        • Won H.
        • et al.
        ESR1 ligand-binding domain mutations in hormone-resistant breast cancer.
        Nat Genet Dec. 2013; 45: 1439-1445
        • Ahn S.G.
        • Bae S.J.
        • Kim Y.
        • et al.
        Primary endocrine resistance of ER+ breast cancer with ESR1 mutations interrogated by droplet digital PCR.
        NPJ Breast Cancer. 2022; 8: 58
        • Leal M.F.
        • Haynes B.P.
        • Schuster E.
        • et al.
        Early enrichment of ESR1 mutations and the impact on gene expression in presurgical primary breast cancer treated with aromatase inhibitors.
        Clin Cancer Res. 2019; 25: 7485-7496
        • Allouchery V.
        • Beaussire L.
        • Perdrix A.
        • et al.
        Circulating ESR1 mutations at the end of aromatase inhibitor adjuvant treatment and after relapse in breast cancer patients.
        Breast Cancer Res. 2018; 20: 40
        • Hortobagyi G.N.
        • Stemmer S.M.
        • Burris H.A.
        • et al.
        Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.
        Ann Oncol. 2018; 29: 1541-1547
        • Pradines A.
        • Callens C.
        • Doussine A.
        • et al.
        Characterization of ESR1 mutations at metastatic relapse and outcome under first line aromatase inhibitor and palbociclib in the PADA-1 trial.
        Cancer Res. 2021; 81: CT189
        • 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
        • Reinert T.
        • Ramalho S.
        • de Vasconcelos V.C.A.
        • et al.
        ESR1 mutations are not a common mechanism of endocrine resistance in patients with estrogen receptor-positive breast cancer treated with neoadjuvant aromatase inhibitor therapy.
        Front Oncol. 2020; 10: 342
        • Zundelevich A.
        • Dadiani M.
        • Kahana-Edwin S.
        • et al.
        ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis.
        Breast Cancer Res. 2020; 22: 16
        • Spoerke J.M.
        • 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
        • Merenbakh-Lamin K.
        • Ben-Baruch N.
        • Yeheskel A.
        • et al.
        D538G mutation in estrogen receptor-alpha: a novel mechanism for acquired endocrine resistance in breast cancer.
        Cancer Res. 2013; 73: 6856-6864
        • Gerratana L.
        • Davis A.A.
        • Polano M.
        • et al.
        Understanding the organ tropism of metastatic breast cancer through the combination of liquid biopsy tools.
        Eur J Cancer. 2021; 143: 147-157
        • 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: 1310-1315
        • 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: 74448-74459
        • Robinson D.R.
        • Wu Y.M.
        • Vats P.
        • et al.
        Activating ESR1 mutations in hormone-resistant metastatic breast cancer.
        Nat Genet. 2013; 45: 1446-1451
        • Jeselsohn R.
        • Bergholz J.S.
        • Pun M.
        • et al.
        Allele-specific chromatin recruitment and therapeutic vulnerabilities of ESR1 activating mutations.
        Cancer Cell. 2018; 33: 173-186 e5
        • Arnesen S.
        • Blanchard Z.
        • Williams M.M.
        • et al.
        Estrogen receptor alpha mutations in breast cancer cells cause gene expression changes through constant activity and secondary effects.
        Cancer Res. 2021; 81: 539-551
        • Li Z.
        • McGinn O.
        • Wu Y.
        • et al.
        ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation.
        Nat Commun. 2022; 13: 2011
        • Bahreini A.
        • Li Z.
        • Wang P.
        • et al.
        Mutation site and context dependent effects of ESR1 mutation in genome-edited breast cancer cell models.
        Breast Cancer Res. 2017; 19: 60
        • O'Leary B.
        • Cutts R.J.
        • Liu Y.
        • et al.
        The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial.
        Cancer Discov. 2018; 8: 1390-1403
        • Kuang Y.
        • Siddiqui B.
        • Hu J.
        • et al.
        Unraveling the clinicopathological features driving the emergence of ESR1 mutations in metastatic breast cancer.
        NPJ Breast Cancer. 2018; 4: 22
        • Li X.
        • Lu J.
        • Zhang L.
        • et al.
        Clinical implications of monitoring ESR1 mutations by circulating tumor DNA in estrogen receptor positive metastatic breast cancer: a pilot study.
        Transl Oncol. 2020; 13: 321-328
        • Goetz M.P.
        • Hamilton E.P.
        • Campone M.
        • et al.
        Acquired genomic alterations in circulating tumor DNA from patients receiving abemaciclib alone or in combination with endocrine therapy.
        J Clin Oncol. 2020; 38: 3519
        • 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: 2961-2968
        • O'Leary B.
        • Hrebien S.
        • Morden J.P.
        • et al.
        Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer.
        Nat Commun. 2018; 9: 896
        • Tolaney S.M.
        • Toi M.
        • Neven P.
        • et al.
        Clinical significance of PIK3CA and ESR1 mutations in circulating tumor DNA: analysis from the MONARCH 2 study of abemaciclib plus fulvestrant.
        Clin Cancer Res. 2022; 28: 1500-1506
        • Bardia A.
        • Hurvitz S.A.
        • DeMichele A.
        • et al.
        Phase I/II trial of exemestane, ribociclib, and everolimus in women with HR(+)/HER2(-) advanced breast cancer after progression on CDK4/6 inhibitors (TRINITI-1).
        Clin Cancer Res. 2021; 27: 4177-4185
        • Turner N.C.
        • Hope S.R.
        • Ciruelos E.M.
        • et al.
        Impact of ESR1 mutations on endocrine therapy (ET) plus alpelisib benefit in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced breast cancer (ABC) who progressed on or after prior cyclin-dependent kinase inhibitor (CDK4/6i) therapy in the BYLieve trial.
        Cancer Res. 2022; 82: PD15-01
        • Bidard F.C.
        • Kaklamani V.G.
        • Neven P.
        • et al.
        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. 2022; : JCO2200338
        • Aftimos P.
        • Neven P.
        • Pegram M.
        • et al.
        Rintodestrant (G1T48), an oral selective estrogen receptor degrader, in ER+/HER2– locally advanced or metastatic breast cancer: updated phase 1 results and dose selection.
        Cancer Res. 2021; 81: PS12-04
        • Baird R.
        • Oliveira M.
        • Gil Circuelos E.M.
        • et al.
        Updated data from SERENA-1: a Phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer.
        Cancer Res. 2021; 81: PS11-05
        • Chandarlapaty S.
        • Linden H.M.
        • Neven P.
        • et al.
        AMEERA-1: Subgroup analyses of phase I/II study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC).
        Ann Oncol. 2021; 32: S457-S515
        • Jhaveri K.
        • Juric D.
        • Yap Y.S.
        • et al.
        A phase I study of LSZ102, an oral selective estrogen receptor degrader, with or without ribociclib or alpelisib, in patients with estrogen receptor-positive breast cancer.
        Clin Cancer Res. 2021; 27: 5760-5770
        • Jhaveri K.
        • Lim E.
        • Hamilton E.P.
        • et al.
        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. 2021; 39: 1050
        • Turner N.C.
        • Loi S.
        • Moore H.M.
        • et al.
        Activity and biomarker analyses from a phase Ia/b study of giredestrant (GDC-9545; G) with or without palbociclib (palbo) in patients with estrogen receptor-positive, HER2-negative locally advanced/metastatic breast cancer (ER+/HER2- LA/mBC).
        Cancer Res. 2022; 82 (Abstract nr PD13-07)
        • Qi S.M.
        • Dong J.
        • Xu Z.Y.
        • et al.
        PROTAC: an effective targeted protein degradation strategy for cancer therapy.
        Front Pharmacol. 2021; 12: 692574
        • Puyang X.
        • Furman C.
        • Zheng G.Z.
        • et al.
        Discovery of selective estrogen receptor covalent antagonists for the treatment of ERalpha(WT) and ERalpha(MUT) breast cancer.
        Cancer Discov. 2018; 8: 1176-1193
      1. Hodges-Gallagher L, Sun R, Myles DC, Harmon CL, Kushner PJ. OP-1250 is a Complete Estrogen Receptor Antagonist (CERAN) that Lacks Agonist Activity on Cell Signaling and Proliferation in Breast Cancer Cells. presented at EORTC-NCI-AACR 2020.

        • Hamilton E.P.
        • Wang J.S.
        • Pluard T.J.
        • et al.
        Phase I/II study of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.
        J Clin Oncol. 2021; 39: 1018
        • Patel M.
        • Alemany C.
        • Mitri Z.
        • et al.
        Preliminary Data From a Phase 1/2, Multicenter, Dose Escalation Study of OP-1250, an Oral CERAN/SERD, in Patients With Advanced and/or Metastatic Estrogen Receptor (ER)-Positive, HER2-Negative Breast Cancer.
        Cancer Res. 2022; 82: P1-17-12
        • Damodaran S.
        • Plourde P.V.
        • Moore H.C.F.
        • et al.
        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. 2022; 40 (abstr 1022))
        • Grinshpun A.
        • Tsuji J.
        • Li T.
        • et al.
        Longitudinal circulating tumor DNA (ctDNA) whole-exome sequencing (WES) in the phase Ib/II trial of palbociclib and bazedoxifene reveals genomic dynamics and clonal evolution with the acquisition of treatment resistance in hormone receptor-positive, HER2-negative (HR+ HER2-), advanced breast cancer (ABC).
        J Clin Oncol. 2022; 40: 1058
        • Bidard F.C.
        • Hardy-Bessard A.,C.
        • Bachelot T.
        • et al.
        Fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: Results of PADA-1, a UCBG-GINECO randomized phase 3 trial.
        Cancer Res. 2022; 82: GS3-05
        • Berger F.
        • Marce M.
        • Delaloge S.
        • et al.
        Randomised, open-label, multicentric phase III trial to evaluate the safety and efficacy of palbociclib in combination with endocrine therapy, guided by ESR1 mutation monitoring in oestrogen receptor-positive, HER2-negative metastatic breast cancer patients: study design of PADA-1.
        BMJ Open. 2022; 12: e055821
        • Bidard F.C.
        • Pistilli B.
        • Dalenc F.
        • et al.
        Circulating ESR1 mutation detection rate and early decrease under first line aromatase inhibitor and palbociclib in the PADA-1 trial (UCBG-GINECO).
        Cancer Res. 2019; 79: PD2-PD06
        • Williams M.M.
        • Spoelstra N.S.
        • Arnesen S.
        • et al.
        Steroid hormone receptor and infiltrating immune cell status reveals therapeutic vulnerabilities of ESR1-mutant breast cancer.
        Cancer Res. 2021; 81: 732-746