{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:29:05Z","timestamp":1792690145823,"version":"4.5.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2017,4,3]],"date-time":"2017-04-03T00:00:00Z","timestamp":1491177600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2017,4,3]],"date-time":"2017-04-03T00:00:00Z","timestamp":1491177600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["K08 CA191058-02"],"award-info":[{"award-number":["K08 CA191058-02"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50CA058183"],"award-info":[{"award-number":["P50CA058183"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50CA186784"],"award-info":[{"award-number":["P50CA186784"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA125123"],"award-info":[{"award-number":["P30CA125123"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000869","name":"Susan G. Komen for the Cure","doi-asserted-by":"publisher","award":["PG12221410"],"award-info":[{"award-number":["PG12221410"]}],"id":[{"id":"10.13039\/100000869","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Curr Oncol Rep"],"published-print":{"date-parts":[[2017,5]]},"DOI":"10.1007\/s11912-017-0591-8","type":"journal-article","created":{"date-parts":[[2017,4,3]],"date-time":"2017-04-03T10:33:22Z","timestamp":1491215602000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":94,"title":["The Evolving Role of the Estrogen Receptor Mutations in Endocrine Therapy-Resistant Breast Cancer"],"prefix":"10.1007","volume":"19","author":[{"given":"Rinath","family":"Jeselsohn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"De Angelis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myles","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Schiff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,3]]},"reference":[{"key":"591_CR1","doi-asserted-by":"publisher","first-page":"10869","DOI":"10.1073\/pnas.191367098","volume":"98","author":"T Sorlie","year":"2001","unstructured":"Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869\u201374.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"591_CR2","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/ng1901","volume":"38","author":"JS Carroll","year":"2006","unstructured":"Carroll JS, Meyer CA, Song J, et al. Genome-wide analysis of estrogen receptor binding sites. Nat Genet. 2006;38:1289\u201397.","journal-title":"Nat Genet"},{"key":"591_CR3","doi-asserted-by":"publisher","first-page":"2219","DOI":"10.1101\/gad.1944810","volume":"24","author":"M Lupien","year":"2010","unstructured":"Lupien M, Meyer CA, Bailey ST, et al. Growth factor stimulation induces a distinct ER(alpha) cistrome underlying breast cancer endocrine resistance. Genes Dev. 2010;24:2219\u201327.","journal-title":"Genes Dev"},{"key":"591_CR4","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1097\/GCO.0000000000000039","volume":"26","author":"N Williams","year":"2014","unstructured":"Williams N, Harris LN. The renaissance of endocrine therapy in breast cancer. Curr Opin Obstet Gynecol. 2014;26:41\u20137.","journal-title":"Curr Opin Obstet Gynecol"},{"key":"591_CR5","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1038\/nrc2713","volume":"9","author":"EA Musgrove","year":"2009","unstructured":"Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009;9:631\u201343.","journal-title":"Nat Rev Cancer"},{"key":"591_CR6","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1146\/annurev-med-070909-182917","volume":"62","author":"CK Osborne","year":"2011","unstructured":"Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233\u201347.","journal-title":"Annu Rev Med"},{"key":"591_CR7","doi-asserted-by":"publisher","first-page":"4929","DOI":"10.1002\/cncr.27518","volume":"118","author":"LD Hoefnagel","year":"2012","unstructured":"Hoefnagel LD, Moelans CB, Meijer SL, et al. Prognostic value of estrogen receptor alpha and progesterone receptor conversion in distant breast cancer metastases. Cancer. 2012;118:4929\u201335.","journal-title":"Cancer"},{"key":"591_CR8","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.ccr.2004.06.027","volume":"6","author":"MI Torres-Arzayus","year":"2004","unstructured":"Torres-Arzayus MI, Font de Mora J, Yuan J, et al. High tumor incidence and activation of the PI3K\/AKT pathway in transgenic mice define AIB1 as an oncogene. Cancer Cell. 2004;6:263\u201374.","journal-title":"Cancer Cell"},{"key":"591_CR9","first-page":"447S","volume":"9","author":"R Schiff","year":"2003","unstructured":"Schiff R, Massarweh S, Shou J, Osborne CK. Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res. 2003;9:447S\u201354S.","journal-title":"Clin Cancer Res"},{"key":"591_CR10","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1016\/j.celrep.2013.08.022","volume":"4","author":"S Li","year":"2013","unstructured":"Li S, Shen D, Shao J, et al. Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep. 2013;4:1116\u201330.","journal-title":"Cell Rep"},{"key":"591_CR11","doi-asserted-by":"publisher","first-page":"4577","DOI":"10.1038\/ncomms5577","volume":"5","author":"J Veeraraghavan","year":"2014","unstructured":"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.","journal-title":"Nat Commun"},{"key":"591_CR12","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1038\/ng.2822","volume":"45","author":"W Toy","year":"2013","unstructured":"Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45:1439\u201345.","journal-title":"Nat Genet"},{"key":"591_CR13","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.1038\/ng.2823","volume":"45","author":"DR Robinson","year":"2013","unstructured":"Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45:1446\u201351.","journal-title":"Nat Genet"},{"key":"591_CR14","doi-asserted-by":"publisher","first-page":"6856","DOI":"10.1158\/0008-5472.CAN-13-1197","volume":"73","author":"K Merenbakh-Lamin","year":"2013","unstructured":"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\u201364.","journal-title":"Cancer Res"},{"key":"591_CR15","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1158\/1078-0432.CCR-13-2332","volume":"20","author":"R Jeselsohn","year":"2014","unstructured":"\u2022\u2022 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\u201367. ESR1 LBD mutations are detected in metastatic ER+ breast cancers only and the prevalnce is associated with number of treatment lines in the metastatic setting.","journal-title":"Clin Cancer Res"},{"key":"591_CR16","doi-asserted-by":"publisher","first-page":"1860","DOI":"10.1093\/annonc\/mdw286","volume":"27","author":"D Fumagalli","year":"2016","unstructured":"Fumagalli D, Wilson TR, Salgado R, et al. Somatic mutation, copy number and transcriptomic profiles of primary and matched metastatic estrogen receptor-positive breast cancers. Ann Oncol. 2016;27:1860\u20136.","journal-title":"Ann Oncol"},{"key":"591_CR17","first-page":"1244","volume":"57","author":"QX Zhang","year":"1997","unstructured":"Zhang QX, Borg A, Wolf DM, et al. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 1997;57:1244\u20139.","journal-title":"Cancer Res"},{"key":"591_CR18","first-page":"349","volume":"54","author":"PS Karnik","year":"1994","unstructured":"Karnik PS, Kulkarni S, Liu XP, et al. Estrogen receptor mutations in tamoxifen-resistant breast cancer. Cancer Res. 1994;54:349\u201353.","journal-title":"Cancer Res"},{"key":"591_CR19","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1093\/jnci\/87.6.446","volume":"87","author":"N Roodi","year":"1995","unstructured":"Roodi N, Bailey LR, Kao WY, et al. Estrogen receptor gene analysis in estrogen receptor-positive and receptor-negative primary breast cancer. J Natl Cancer Inst. 1995;87:446\u201351.","journal-title":"J Natl Cancer Inst"},{"key":"591_CR20","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","volume":"2","author":"E Cerami","year":"2012","unstructured":"Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401\u20134.","journal-title":"Cancer Discov"},{"key":"591_CR21","doi-asserted-by":"publisher","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","volume":"6","author":"J Gao","year":"2013","unstructured":"Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.","journal-title":"Sci Signal"},{"key":"591_CR22","doi-asserted-by":"publisher","first-page":"1130","DOI":"10.1158\/1078-0432.CCR-15-1534","volume":"22","author":"P Wang","year":"2016","unstructured":"Wang P, Bahreini A, Gyanchandani R, 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\u20137.","journal-title":"Clin Cancer Res"},{"key":"591_CR23","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1007\/s10549-016-3829-5","volume":"157","author":"L Gelsomino","year":"2016","unstructured":"Gelsomino L, Gu G, Rechoum Y, et al. ESR1 mutations affect anti-proliferative responses to tamoxifen through enhanced cross-talk with IGF signaling. Breast Cancer Res Treat. 2016;157:253\u201365.","journal-title":"Breast Cancer Res Treat"},{"key":"591_CR24","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1038\/nchembio.76","volume":"4","author":"KW Nettles","year":"2008","unstructured":"Nettles KW, Bruning JB, Gil G, et al. NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses. Nat Chem Biol. 2008;4:241\u20137.","journal-title":"Nat Chem Biol"},{"key":"591_CR25","unstructured":"\u2022\u2022 Fanning SW, Mayne CG, Dharmarajan 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. The ESR1 ligand-binding mutations Y537S and D538G have decreased affinity to estradiol and tamoxifen and ligand-independent binding to AIB1 which provides a mechanistic explanation to the phenotypes of these mutations."},{"key":"591_CR26","doi-asserted-by":"publisher","first-page":"11579","DOI":"10.1038\/ncomms11579","volume":"7","author":"JM Spoerke","year":"2016","unstructured":"Spoerke JM, 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.","journal-title":"Nat Commun"},{"key":"591_CR27","doi-asserted-by":"publisher","first-page":"224ra224","DOI":"10.1126\/scitranslmed.3007094","volume":"6","author":"C Bettegowda","year":"2014","unstructured":"Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra224.","journal-title":"Sci Transl Med"},{"key":"591_CR28","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1038\/nrclinonc.2013.110","volume":"10","author":"E Crowley","year":"2013","unstructured":"Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10:472\u201384.","journal-title":"Nat Rev Clin Oncol"},{"key":"591_CR29","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1056\/NEJMoa1213261","volume":"368","author":"SJ Dawson","year":"2013","unstructured":"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\u2013209.","journal-title":"N Engl J Med"},{"key":"591_CR30","doi-asserted-by":"publisher","first-page":"313ra182","DOI":"10.1126\/scitranslmed.aac7551","volume":"7","author":"G Schiavon","year":"2015","unstructured":"\u2022\u2022 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. Detection of ESR1 mutations in ctDNA is highly sensitive and specific and associated with poor response to subsequent aromatase inhibitor treatment.","journal-title":"Sci Transl Med"},{"key":"591_CR31","doi-asserted-by":"publisher","first-page":"2961","DOI":"10.1200\/JCO.2016.67.3061","volume":"34","author":"C Fribbens","year":"2016","unstructured":"\u2022\u2022 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\u20138. Retrospective analysis of ESR1 mutations in ctDNA using archival blood samples from a randomized clinical trial.","journal-title":"J Clin Oncol"},{"key":"591_CR32","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1001\/jamaoncol.2016.1279","volume":"2","author":"S Chandarlapaty","year":"2016","unstructured":"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\u20135.","journal-title":"JAMA Oncol"},{"key":"591_CR33","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/nature10762","volume":"481","author":"M Greaves","year":"2012","unstructured":"Greaves M, Maley CC. Clonal evolution in cancer. Nature. 2012;481:306\u201313.","journal-title":"Nature"},{"key":"591_CR34","doi-asserted-by":"publisher","first-page":"e178","DOI":"10.1016\/S1470-2045(11)70335-7","volume":"13","author":"NC Turner","year":"2012","unstructured":"Turner NC, Reis-Filho JS. Genetic heterogeneity and cancer drug resistance. Lancet Oncol. 2012;13:e178\u201385.","journal-title":"Lancet Oncol"},{"key":"591_CR35","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1056\/NEJMoa1609709","volume":"375","author":"GN Hortobagyi","year":"2016","unstructured":"Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375:1738\u201348.","journal-title":"N Engl J Med"},{"key":"591_CR36","doi-asserted-by":"publisher","first-page":"2420","DOI":"10.1158\/1078-0432.CCR-12-3771","volume":"19","author":"SE Wardell","year":"2013","unstructured":"Wardell SE, Nelson ER, Chao CA, McDonnell DP. Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: implications for treatment of advanced disease. Clin Cancer Res. 2013;19:2420\u201331.","journal-title":"Clin Cancer Res"},{"key":"591_CR37","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1097\/CAD.0000000000000271","volume":"26","author":"F Garner","year":"2015","unstructured":"Garner F, Shomali M, Paquin D, et al. RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anti-Cancer Drugs. 2015;26:948\u201356.","journal-title":"Anti-Cancer Drugs"},{"key":"591_CR38","doi-asserted-by":"publisher","first-page":"4888","DOI":"10.1021\/acs.jmedchem.5b00054","volume":"58","author":"A Lai","year":"2015","unstructured":"Lai A, Kahraman M, Govek S, et al. 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. 2015;58:4888\u2013904.","journal-title":"J Med Chem"},{"key":"591_CR39","doi-asserted-by":"publisher","first-page":"5121","DOI":"10.1158\/1078-0432.CCR-15-0360","volume":"21","author":"SE Wardell","year":"2015","unstructured":"Wardell SE, Ellis MJ, Alley HM, et al. Efficacy of SERD\/SERM hybrid-CDK4\/6 inhibitor combinations in models of endocrine therapy-resistant breast cancer. Clin Cancer Res. 2015;21:5121\u201330.","journal-title":"Clin Cancer Res"},{"key":"591_CR40","unstructured":"Joseph JD, Darimont B, Zhou W et al. The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer. Elife 2016; 5."},{"key":"591_CR41","doi-asserted-by":"crossref","unstructured":"Lonard DM, O'Malley BW. Molecular pathways: targeting steroid receptor coactivators in cancer. Clin Cancer Res 2016.","DOI":"10.1158\/1078-0432.CCR-15-1958"}],"container-title":["Current Oncology Reports"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s11912-017-0591-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s11912-017-0591-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s11912-017-0591-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,5,17]],"date-time":"2020-05-17T17:56:48Z","timestamp":1589738208000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s11912-017-0591-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,3]]},"references-count":41,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2017,5]]}},"alternative-id":["591"],"URL":"https:\/\/doi.org\/10.1007\/s11912-017-0591-8","relation":{},"ISSN":["1523-3790","1534-6269"],"issn-type":[{"value":"1523-3790","type":"print"},{"value":"1534-6269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,3]]},"assertion":[{"value":"3 April 2017","order":1,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"Rinath Jeselsohn declares no conflict of interest.Carmine De Angelis declares that he has no conflict of interest.Myles Brown declares that he has no conflict of interest.Rachel Schiff has received research support through grants from Gilead and AstraZeneca.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}},{"value":"This article does not contain any studies with human or animal subjects performed by any of the authors.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights and Informed Consent"}}],"article-number":"35"}}